Category Archives: Molecular Genetics

Medical Laboratory Technologist (bioanalyytikko) position is immediately available at the Biomedicum Functional Genomics Unit (FuGU) at the HiLIFE Genome Analysis Infrastructure (HGI).

The position includes implementation of next-generation sequencing (NGS) and targeted genomics services together with the FuGU team. FuGU provides a wide variety of nucleic acid QC analyses and genomics technology services including NGS technologies, NanoString and Olink systems as well as bioinformatics services. In the position, you will have the responsibility of day-to-day genome profiling analyses as well as implementation of novel services related to these technologies.

The position requires hands-on experience and basic knowledge on genome profiling technologies. Excellent communication and team working skills in interaction with the FuGU core facility personnel as well as with domestic and international customers is required.

Ideal candidate has BSc degree from University of Applied Sciences, MSc in genetics, molecular biology or cell biology or equivalent degree. Excellent team working and communication skills are required. Successful implementation of your tasks will require ability to work independently and in a team of core facility and research personnel. An ideal candidate is also competent of having presentations in laboratory courses and/or other educational events within HiLIFE network. Strong candidate will have existing experience from next-generation sequencing.

The salary is based on the job requirement scheme for specialist and support staff according to the salary system of the Finnish universities. In addition, the appointee will be paid a salary component based on personal work performance. In total, the gross salary is about 2500-2800 EUR per month depending on the qualifications and merits of the applicant.

The appointment is fixed term until the end of August 2023, starting as soon as possible. Extension beyond this is possible depending on the availability of funding. The position will be filled with 6 months probationary period.

Please submit your application, together with the required attachments as a single pdf file, through the University of Helsinki Recruitment System via the button Apply for the position. To apply, please submit motivation letter, CV and names of two referees. You may fill in only the mandatory fields (*) in the Recruitment System. The above-mentioned documents must be written in Finnish or in English. The Applicants who are employees of the University of Helsinki should submit their application via SAP Fiori (https://msap.helsinki.fi).

The closing date of the application is April 30, 2022 (23:59 EET), but the position is filled as soon as a suitable candidate is found.

Further information: Dr. Outi Monni: outi.monni@helsinki.fi (tel. +358 040 7639302).

For more information on Biomedicum Functional Genomics Unit, please visit https://www2.helsinki.fi/en/infrastructures/genome-analysis/infrastructu... and https://www2.helsinki.fi/en/researchgroups/oncogenomics.

Due date

30.04.2022 23:59 EEST

See more here:
Medical Laboratory Technologist job with UNIVERSITY OF HELSINKI | 289858 - Times Higher Education

Introduction

Inherited retinal diseases (IRDs) are a group of heterogeneous degenerative retinal conditions estimated to occur in up to 1 in 1000 individuals.1,2 IRDs are now the most common cause of legal blindness in adults of working age in Australia3 and the United Kingdom (UK).4 Previous experimental treatments for IRD have included Vitamin A supplementation, valproate,5 ciliary neurotrophic factor supplementation6 and electrical stimulation through the skin7 or cornea,8 but their efficacies are unclear, and none have reached regulatory approval.

Recently, gene augmentation therapy for RPE65-associated IRD (Leber Congenital Amaurosis) has been approved by the United States (US) Food and Drug Administration (FDA, 2017), European Medicines Agency (2018), and the Therapeutic Goods Administration in Australia (2020). This has accelerated the development of further gene therapies for other forms of IRD, including gene augmentation, gene editing (CRISPR/Cas9) and RNA-based therapies.9 Currently, there are over 30 active clinical trials for gene therapy for patients with IRD.10

Assessment of eligibility for ocular gene therapies requires identification of patients pathogenic genetic variant. Therefore, genetic testing is recommended as standard of care in Australia11 and internationally.12 In addition to exploring potential gene therapy opportunities, genetic testing is recommended to confirm the clinical diagnosis and inheritance of the condition, which may inform prognosis for patients and their family members, including family planning considerations.1315

Genetic testing has evolved over the years, allowing case-by-case selection of appropriate molecular testing strategies.16 While Sanger sequencing is typically chosen for suspected monogenic disorders, more advanced methods such as next-generation sequencing (NGS) and whole-exome sequencing (WES) are available for patients with uncertain clinical diagnoses and/or inheritance patterns.16 These novel methods have increased the success rate of IRD genetic testing (defined as identification of at least one pathogenic variation) to between 56% and 76% in most developed countries.14,1719 The success of genetic testing in identifying the disease-causing variant varies depending on patients specific diagnosis,17 age,20 and whether the responsible gene and/or pathogenic variant has been previously identified in IRD patients and/or family members.21 New developments in testing methodology and gene therapy have further highlighted the important role of genetic testing for IRDs.

A recent study by Strait et al (2020) explored self-reported genetic testing practices of optometrists and ophthalmologists managing patients with IRDs in the US.15 Respondents indicated that while there are discussions surrounding genetics (64.7% and 70.6% of the clinicians reported taking family history of IRD and explaining inheritance patterns to their IRD patients, respectively), 78.4% of the clinicians have not ordered genetic testing for their patients with IRD.15 Reported reasons for not completing genetic testing included the opinion that genetic test results do not alter IRD patients clinical management, lack of clinicians confidence in their ability to order the appropriate test, preference to refer to experienced clinicians, and/or patient refusal.15

To our knowledge, there are no studies exploring the rate and outcomes of IRD genetic testing ordered by Australian ophthalmologists in a clinical private tertiary care setting. This study sought to evaluate the current prevalence of genetic testing, distribution of IRDs and genetic diagnoses in a private tertiary retinal practice in Victoria, Australia. This should be taken as an indication of historical referral processes, when genetic testing was not key in the management of IRD. We aim to reassess in several years to observe the changes following the recent Royal Australian and New Zealand College of Ophthalmologists (RANZCO) IRD management guidelines,11 which have highlighted the need for more widespread genetic testing with the availability of gene-based therapies for these patients.

This retrospective analysis involved evaluation of electronic medical records of pre-existing patients of Eye Surgery Associates, a large private ophthalmic practice in Victoria, Australia, with 18 sub-specialty ophthalmologists. Patients are referred to this clinic for tertiary level medical retina care and/or diagnostic retinal electrophysiology services.

The senior author and ophthalmologist HM completed a search of the practices electronic database (VIP.net Version Ruby, Best Practice Software, Bundaberg, QLD) to identify all confirmed or suspected IRD patients seen between 1995 and 2021 using the following search terms: retinitis pigmentosa (or abbreviation, RP), retinal dystrophy, cone dystrophy, cone-rod dystrophy, macular dystrophy, Best, Stargardt, congenital stationary night blindness, monochromat, achromatopsia, Bietti, choroideremia, familial exudative vitreoretinopathy, Usher, Wagner, gyrate and Sorsby.

After removing duplicate records, clinical records were reviewed by HM for accuracy of diagnosis, and those with incorrect or uncertain diagnoses as documented by clinicians were excluded, including 20 cases of possible adult vitelliform macular dystrophy, which were not possible to distinguish from age-related macular degeneration from clinical records.

A two-stage clinical record review was undertaken by the senior author (HM), followed by two co-first authors experienced in IRD (YJ, SG). The analysis was completed between June and August 2021. The senior author (HM) is an experienced ophthalmologist in the management of medical retina disorders, particularly IRDs. Both co-first authors are optometry trained with further training in research (MPhil, SG) and medicine (MD, YJ). Data were captured as documented in the clinical records by the treating clinician. Unclear records (n=10) were discussed by the broader research team (YJ, SG, HM, LA, ACBJ) to obtain consensus.

The following de-identified information was collected, based only upon information available in the patient record: patient age, gender (female, male, non-binary), duration of care at the practice (months), clinical diagnosis of IRD, suspected mode of inheritance, history of consanguinity, and genetic testing results for the patient and/or family members. Suspected mode of inheritance was determined through family history (Supplementary Figure 1), and when present, genetic test results of the patient and their family members.

If a genetic test report was available, the following data were collected: testing methodology (NGS, WES, Sanger sequencing, microarray, unknown), clinical grade or research grade testing, and whether the pathogenic or likely pathogenic variant was identified.

If no genetic test results were available, the status of planned testing was captured (awaiting geneticist, awaiting test results, patient refused, or not further specified). Clinical records that did not capture whether genetic testing was ordered or the patients response to genetic testing, were considered not further specified.

De-identified data were collected using REDCap, a secure web application for building and managing online surveys and databases. REDCap includes a full analysis trail and specified user-based privileges. Access to study data in REDCap was restricted to the members of the study team. Only de-identified data was exported for the purposes of analysis and reporting.

De-identified data were imported into R (R Core Team, Vienna, Austria) for descriptive statistical analyses. IRD clinical diagnosis was grouped into panretinal pigmentary retinopathies, macular dystrophies, stationary diseases, and hereditary vitreoretinopathies according to Coco-Martin et al.22

Age subgroups are presented as young patients (less than 45 years of age) versus older patients (45 years and older) as an appropriate cut-off age for family planning23 and childbearing.24 The distribution of the data was explored and comparison between subgroups was performed using Wilcoxon rank sum test for non-parametric continuous variables and Fisher exact test for categorical variables. An alpha value of 0.05 was used to define statistical significance. Binary logistic regression was performed using IBM SPSS Statistics for Windows, version 27 (IBM Corp., Armonk, NY, USA), to calculate the odds of patients having had genetic testing based on patients gender, age, and duration of care.

All patients had provided written consent for their health information to be used for research, and audit purposes at the time of their initial visit at Eye Surgery Associates, therefore, were not re-contacted for consent specifically for this study. Ophthalmologists of all reviewed patients gave permission for record access. This study was approved by the Human Research Ethics committee of the RANZCO (#124.21) and abided by the Declaration of Helsinki.

An initial search of the database containing 194,716 unique patient records at Eye Surgery Associates revealed 541 patients with an IRD. Exclusion of incomplete patient records and/or incorrect or uncertain clinical diagnoses resulted in 464 patient records in this retrospective study.

Demographic variables are presented in Table 1. Approximately half of the patients were male (239, 51.5%). Included patients had a median age of 46 years (interquartile range [IQR]: 2860) and a median duration of care of 5 months (IQR: 063 months). Based on clinical diagnosis, patients were grouped as having panretinal pigmentary retinopathies (284, 61.2%), macular dystrophies (137, 29.5%), stationary diseases (23, 5%), hereditary vitreoretinopathies (14, 3%), and other IRDs (6, 1.3%). The suspected pattern of inheritance of patients IRD was predominantly autosomal recessive (205, 44.2%), followed by autosomal dominant (60, 12.9%), X-linked (22, 4.7%), and mitochondrial (6, 1.3%). There were patients with unknown (85, 18.3%) or multiple (86, 18.5%) possible modes of inheritance based on clinical records (Figure 1). Consanguinity was noted in a small percentage of patients (17, 3.6%).

Table 1 Demographics of All Patients and as Categorised by Age (Less Than 45 Years of Age, 45 Years or Older)

Figure 1 Suspected mode of inheritance of inherited retinal disease, based upon genetic test results, family history of inherited retinal disease, or clinicians suspected mode of inheritance (as documented). Data presented as n, (%).

In the study cohort, there was a predominance of younger males (less than 45 years of age) and older females (45 years or older). Age-stratified analysis showed that the younger patients were less likely to have attended the practice for more than a year (younger vs older: 61.1% vs 48.1%, p<0.01) but more likely to have genetic testing performed (13.1% vs 6.2%, p=0.01) than older patients. Younger patients were also more likely to have received care for stationary disease (8.6% vs 1.6%, p<0.01). More patients in the older age group had macular dystrophies (34.6% vs 24%, p<0.01); however, the number of patients with panretinal pigmentary retinopathies (60.5% vs 62%, p=0.78) was similar in both groups.

Genetic testing results were available in patients clinical records for 44 patients (9.5%). Genetic testing was performed mostly for patients less than 45 years of age (13.1% for <45 years vs 6.2% 45 years of age, p=0.01) and those with duration of care of 12 months or longer (16% for 12 months of care vs 4% for <12 months of care, p<0.01). For three patients, immediate family members had genetic testing results available. While clinical information from a family member or research grade testing is useful in a clinical setting, only patients who have undergone clinical testing themselves were included in this analysis.

Reasons for not having genetic testing results available were documented as: awaiting an appointment with a geneticist (75, 17.9%), awaiting test results following sample collection (19, 4.5%), and patient refusal of genetic testing (35, 8.4%). However, in most cases, the reason was not further specified (290, 69.2%) (Figure 2).

Figure 2 Documented reasons for absence of genetic test results, n (%). Awaiting geneticist and test results indicate patient has been referred for genetic testing, however, has not been seen or has not received results yet. Not further specified indicates that counselling regarding genetic testing was not documented on patients clinical records. Results presented as n, (%).

Multivariate logistic regression revealed that younger patients (OR: 2.95, p<0.01) and those with duration of care of 12 months or longer (OR: 5.48, p<0.01) are more likely to have had genetic testing performed (Table 2). There was no association between gender and the likelihood of patients having genetic testing results available (univariate OR: 0.79, p=0.46).

Table 2 Univariate and Multivariate Logistic Regression Assessing Predictors of Having Genetic Testing Results Among Patients

Of the genetic testing results obtained, 43.2% were clinical grade and 6.8% were research grade; however, for 50% of the genetic tests, this information was not documented in the patients clinical record or genetic report. In this cohort, the diagnostic yield of genetic testing was 65.9%. Among the genes identified, the most common was ABCA4 (13.6%), followed by BEST1 and USH2A (6.8% each), MFRP, RHO, CRB1 (4.5% each) and BBS1, BBS9, CHM, CNGA3, CRX, CSPP1, EYS, HFE, IFT2, INPP5E, FSCN2, MT-ND5, MT-TL1, NMNAT1, PEX7, PRPF8, PRPS1, RGR, RP1, RP1L1, RPGR, SPATA7 (2.3% each). In all cases, the ABCA4 gene variant was determined to be pathogenic from laboratory reports, and there were two to three pathogenic variants identified per patient. No further familial testing data was reported within the clinical records for any of the patients with an ABCA4 gene mutation. Two patients had only one ABCA4 mutation identified; therefore, these patients were not included in the diagnostic yield of genetic testing reported. In 31.8% of the genetic reports, the disease-causing variant was not documented or undetected. The most common genes and their frequency in our cohort are summarised in Table 3.

Table 3 Frequency of Genes Identified During Genetic Testing

This retrospective, single centre study presents data of the frequencies of IRD at a private subspecialty tertiary referral retinal practice, servicing predominantly Victoria, Australia. To our knowledge, this is the first Australian study reporting genetic test ordering in a large tertiary practice with a large database of patients with IRD. This information is valuable for ophthalmologists and other healthcare professionals to reflect on their current genetic test ordering and the benefits of identifying patient-specific variants. The rate of genetic testing results was 9.5%, which lags behind similar cohorts in developed countries such as the US (55%)25 and Spain (26.85%).26 This is likely due to several factors: the very recent approval of gene-based therapies that require this information (voretigene neparvovec-rzyl approved in Australia in 2020), improvements in genetic testing technologies, and slower introduction of genetic testing programs in Australia. Sponsored IRD genetic testing programs were introduced in Australia in 2021 but have been available overseas for several years. Access to free testing for patients undoubtedly has the potential to increase genetic testing uptake. In addition, the RANZCO guidelines for IRD management,11 which emphasise the importance of genetic testing for a broader group of patients than previously thought beneficial, will change future practice. Finally, this practice is a specialist tertiary care provider, where patients are often referred for specialised testing (such as electrophysiology or confirmation of diagnosis, etc). Hence, there is a high percentage of single-visit patients in this cohort, which means it is less likely that genetic testing would have been discussed. The results of this study are intended as a benchmark of historical practice (19952021), and we will reassess in the future to determine the changes due to the above factors.

The predominant phenotypic diagnosis in this patient cohort was retinitis pigmentosa/rod-cone dystrophy. Macular dystrophy with flecks was the second most common IRD category, suggesting ABCA4 retinopathy as the most common macular IRD diagnosis. The distribution of IRD phenotypes in our cohort is similar to those reported in Spain,26,27 the US,14,28 the UK,29 Iran,30 and Norway.31 The Australian Inherited Retinal Disease Registry and DNA Bank also reported that retinitis pigmentosa and Stargardt disease are the most common two diagnoses among over 9000 Australian patients.32

Among those who had genetic testing performed, the most common molecular diagnoses were ABCA4, followed by BEST1, USH2A, RHO, RP1, CRB1. This compares well to other study cohorts in Brazil,31 New Zealand33 and UK.29 Similarly, a study by Mansfield et al (2020) reported that ABCA4, USH2A, RHO, BEST1 and CRB1 are among the top 10 genes identified in the My Retina Tracker Registry containing approximately 27,000 registered individuals with IRD.28

Obtaining a history of consanguinity in patients with an IRD may assist in selecting appropriate genes for screening and interpreting whole-genome sequencing results.29 In the current cohort, 3.5% of the patients reported consanguinity, which is mid-range between reported Chinese (<1%)34 and Norwegian (6%)31 IRD patient cohorts. However, our results are less than those reported in Brazil (>10%),35 Spain (11%),22 and Iran (76%).30 A study by Khan et al (2017) found that diagnostic yield increased from 45% to 60% when consanguinity was considered to select the most appropriate test.36 This result supports the importance of capturing patients ethnic background and pedigree structure to increase detection rates of the disease-causing variant.36

In the current study cohort, the predominant inheritance pattern was autosomal recessive (44.2%) followed by autosomal dominant (12.9%) and X-linked inheritance (4.7%). A study by Liu et al (2021) similarly reported that in a registry containing 800 Chinese families, the inheritance pattern was also predominantly autosomal recessive (43.88%), followed by X-linked (9.25%) and autosomal dominant (7%).34 Studies in the UK20,29,36 and the US14 also report similar frequencies of inheritance patterns. However, a study by Coco-Martin et al (2021) reported that the most common inheritance pattern based on family history in their cohort of IRD patients was autosomal dominant (52%) followed by autosomal recessive (23%) and X-linked (10%) inheritance.22 This may be attributed to a greater proportion of macular dystrophies in their study (n=161), mainly following an autosomal dominant inheritance, compared to panretinal pigmentary retinopathies (n=39) following an autosomal recessive inheritance pattern.22 This variation in IRD phenotype may further be explained by the extensive macular dystrophies reported in the Spanish cohort,22 potentially as a result of geographic disparities and greater frequencies of certain mutations in common racial classifications (Africa, Europe, Asia, Oceania, Americas).37

A proportion of our cohort had inconclusive results, which included both negative (31.8%) results from genetic test reports and unavailable or pending (22.4%) results from tests ordered. Our solve rate was 65.9% for those patients who had genetic testing, which is comparable to diagnostic yield reported by studies in the US (76%),14 China (60%),34 and New Zealand (83.6%).33 Motta et al (2017) reported results similar to the current study, with 71.6% of their cohort receiving a conclusive molecular diagnosis compared to 28% individuals receiving negative or inconclusive results.35 Our results were significantly greater than the solution rate reported in Norway (32%).31 Gene-panel testing for IRD was not available at the time of that publication (prior to 2016) in Norway; therefore, arrayed primer extension was the test of choice which involves testing each patient for a panel of known disease-causing genes.31 NGS testing increases diagnostic yield; however, it may also increase detection of variant of unknown significance (VUS). Therefore, further investigation is required in this area.11,38

The diagnostic yield for genetic testing also varies depending on the provisional IRD diagnosis, testing methodology and whether the IRD is genetically simple or exhibits complex disease phenotypes.38,39 Jiman et al (2020) reported a significant improvement in genetic diagnosis for people with a provisional clinical diagnosis compared to individuals without a clinical diagnosis at the time of genetic testing (71% compared to 25%).39 Furthermore, Li et al (2019) suggested that tailoring the panel of genes to the clinical presentation increases the diagnostic yield of genetic testing and reduces the false-positive rate of VUS.40 Incorporation of clinical diagnoses into genetic testing must be considered along with genetic testing methods and gene panel selection.

Among the patients who did not have genetic testing results available, 8.4% of clinical records documented patient refusal; however, this figure may be higher since approximately 70% of clinical records did not have documented counselling regarding genetic testing. It is important to consider the clinical context of genetic testing. At the time of care, genetic testing was often clinically unjustified in many of our patients with an established IRD diagnosis, stable clinical phenotype, or beyond reproductive age. Patient visits with the sole intention of providing legal blindness certification to established IRD patients or performing single procedure services such as electroretinography were considered exempt from genetic testing counselling and ordering.

Patient-related barriers to uptake of genetic testing have been explored in several studies. Li et al (2019) found that patients were reluctant to agree to genetic testing due to cost involved, advanced age, mobility challenges due to poor vision and difficulty arranging transportation among the visually impaired.40 However, 73% of the eligible patients consent to genetic testing when at no cost to them.40 Recently announced industry sponsored testing programs (including Invitae and the Blueprint/Novartis collaboration, both commencing in 2021) offer IRD patients free access to panel testing in Australia, which may overcome this barrier. However, whether clinicians are aware of such programs remains unknown. Previous studies also recognise patients education, family status and age affect acceptance of genetic testing.23,41,42 The main reasons for negative attitudes were due to the assumption that abortion rates will increase, exposure to social discrimination, misuse of results by ordering clinician, and anxieties surrounding their own health and that of their childs.23,42 Therefore, there is a role for clinicians to earn their patients trust and provide informative advice regarding the advantages of genetic testing.

In addition, Neiweem et al (2021) recognised that many clinicians in medicine and ophthalmology are unfamiliar with genetic testing due to the several complexities involved.43 Clinicians may be unaware which patients are suitable candidates, the appropriate test to order, how to interpret results, or the associated cost of genetic testing.21,43 Further education may be required to educate clinicians and patients regarding the benefits of genetic testing using informative resources such as the Retina International Campaign, Know Your Code (www.kyc.retinaint.org).44 Confoundingly, there is also variation in testing guidelines between international and Australian guidelines, with international patient advocacy groups such as Retina International detailing a need for global consensus in published guidelines.44 The RANZCO have recently published comprehensive IRD management guidelines, which emphasise the importance of genetic testing in accordance with clinical benefits.11 With emerging gene-dependent treatment options such as gene therapy, it is important to screen IRD patients to facilitate appropriate referral for clinical trials efficiently when it becomes available. Of note, in unsolved cases, the current literature recommends a retest interval of at least 18 months.45

Previously reported resource-related barriers to genetic testing include long turnaround times of genetic testing (up to 6 months in some cases),46 limitations of genetic testing methods,39 and limited integration of different medical specialities such as ophthalmology and genetic counsellors.21 The latter challenge is being addressed in Australia, and other countries, through multi-disciplinary clinics such as the Ocular Genetics Clinic at the Royal Victorian Eye and Ear Hospital. Another Australian-based resource for genetic data on IRD is the Australian Inherited Retinal Disease Register and DNA Biobank (https://www.scgh.health.wa.gov.au/Research/DNA-Bank), which holds the largest collection of DNA samples in Australia.

A key strength of our study is the relatively large patient cohort, consisting of 464 patients from a single large tertiary ophthalmic practice. Furthermore, the study constituted a rigorous process of selecting appropriate patients using a two-stage clinical record review by the senior author (HM), followed by an ophthalmology registrar (YJ) and an optometrist experienced in IRD (SG) to assess clinical diagnoses and genetic testing results.

Study limitations include the large heterogeneity in patient follow-up duration, ranging from single visits to regular patients attending for up to 27 years. The relatively high number of single visits at this clinic is due to high numbers of referrals solely for electrophysiological testing, diagnosing patients and/or certifying legal blindness. Once patients receive their clinical diagnosis, they return to their primary eyecare provider for ongoing management, who may have ordered genetic testing however forwarded these results with patient referrals. Furthermore, the relatively high not further specified reason for lack of genetic testing may be indicative of the variation of clinicians clinical record documentation patterns that did not capture discussions, referrals, and/or patient opinions. For pathogenicity determination, we relied on information provided by the laboratory and/or geneticist or genetic counsellor available in patients clinical records. In some cases, the letter provided to the ophthalmologist contained only information on the name of the affected gene and number of variants identified but no information on the specific variants.

In the future, we expect these figures to improve with availability of higher precision genetic testing methods, free sponsored programs, FDA-approved gene therapy, and potentially greater awareness of genetic testing benefits. We aim to repeat this study in 2 years, to assess the impact these policy and practice changes have on genetic test ordering for people with IRD. Future research should evaluate genetic testing in the public system, as well as additional barriers, policies, and patient perceptions of the genetic testing process in Australia.

Our study cohort shows low uptake of genetic testing of patients with IRD in a large private tertiary retinal practice in Australia, compared to international studies. Currently, our cohort demonstrates that younger patients with longer duration of care are more likely to have received genetic test results. This study provides a snapshot of ophthalmic practices in genetic test ordering for definitive clinical diagnoses, establishing inheritance patterns, family planning, and assessing patients suitability for gene-targeted therapies, which will be of interest to many general and specialised retinal ophthalmologists. We expect that the availability of sponsored testing programs and increased awareness relating to the importance of genetic testing will increase uptake of genetic testing in the future. To achieve this, we advocate further clinician and patient education based upon the established IRD guidelines (such as RANZCO11), streamlined access to public genetic clinics, detailed and standardised reporting of genetic test results, continued support of large IRD databases, and funding for reduced-cost testing to improve ongoing management and clinical outcomes for IRD patients.

DNA, deoxyribonucleic acid; FDA, Food and Drug Administration; IRD, inherited retinal disease; NGS, next-generation sequencing; QLD, Queensland; RANZCO, Royal Australian and New Zealand College of Ophthalmologists; RNA, ribonucleic acid; RP, RETINITIS PIGmentosa; UK, United Kingdom; US, United States; VUS, variant of unknown significance; WES, whole-exome sequencing.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

The authorship team would like to thank the many IRD patients who have been seen at Eye Surgery Associates and the ophthalmologists caring for them who agreed to patient file review: Jacqueline Beltz, Ben Connell, Anthony JH Hall, Andrew Symons, Wilson Heriot and Grant Snibson. LA is supported by a National Health and Medical Research Council (NHMRC) MRFF Fellowship (MRF# 1151055) and EL2 Investigator Grant (GNT#1195713). CERA receives Operational Infrastructure Support from the Victorian Government. Sena A. Gocuk and Yuanzhang Jiao are co-first authors, and Lauren N. Ayton and Heather G. Mack are co-senior authors, on this paper.

Dr Lyndell Lim reports grants, personal fees from Bayer, personal fees from Novartis, personal fees from Allergan, outside the submitted work. The authors report no other conflicts of interest in this work.

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26. Coco-Martin RM, Diego-Alonso M, Orduz-Montaa WA, Sanabria MR, Sanchez-Tocino H. Descriptive Study of a Cohort of 488 Patients with Inherited Retinal Dystrophies. Clin Ophthalmol. 2021;15:10751084.

27. Holtan JP, Selmer KK, Heimdal KR, Bragadttir R. Inherited retinal disease in Norway - a characterization of current clinical and genetic knowledge. Acta Ophthalmol. 2020;98(3):286295.

28. Mansfield BC, Yerxa BR, Branham KH. Implementation of a registry and open access genetic testing program for inherited retinal diseases within a non-profit foundation. Am J Med Genet C Semin Med Genet. 2020;184(3):838845.

29. Pontikos N, Arno G, Jurkute N, et al. Genetic basis of inherited retinal disease in a molecularly characterized cohort of more than 3000 families from the United Kingdom. Ophthalmology. 2020;127(10):13841394.

30. Sabbaghi H, Daftarian N, Suri F, et al. The first inherited retinal disease registry in Iran: research protocol and results of a pilot study. Arch Iran Med. 2020;23(7):445454.

31. Holtan JP, Selmer KK, Heimdal KR, Bragadttir R. Inherited retinal disease in Norwaya characterization of current clinical and genetic knowledge. Acta Ophthalmol. 2020;98(3):286295.

32. De Roach JN, McLaren TL, Thompson JA, et al. The Australian Inherited Retinal Disease Registry and DNA Bank. Tasman Med J. 2020;2(3):6067.

33. Hull S, Kiray G, Chiang JP, Vincent AL. Molecular and phenotypic investigation of a New Zealand cohort of childhood-onset retinal dystrophy. Am J Med Genet C Semin Med Genet. 2020;184(3):708717.

34. Liu X, Tao T, Zhao L, Li G, Yang L. Molecular diagnosis based on comprehensive genetic testing in 800 Chinese families with non-syndromic inherited retinal dystrophies. Clin Exp Ophthalmol. 2021;49(1):4659.

35. Motta FL, Martin RP, Filippelli-Silva R, Salles MV, Sallum JMF. Relative frequency of inherited retinal dystrophies in Brazil. Sci Rep. 2018;8(1):15939.

36. Khan K, Chana R, Ali N, et al. Advanced diagnostic genetic testing in inherited retinal disease: experience from a single tertiary referral centre in the UK National Health Service. Clin Genet. 2017;91(1):3845.

37. Tishkoff SA, Kidd KK. Implications of biogeography of human populations forraceand medicine. Nat Genet. 2004;36(11):S21S7.

38. Kohl S, Biskup S. [Genetic diagnostic testing in inherited retinal dystrophies]. Klin Monbl Augenheilkd. 2013;230(3):243246.

39. Jiman OA, Taylor RL, Lenassi E, et al. Diagnostic yield of panel-based genetic testing in syndromic inherited retinal disease. Eur J Hum Genet. 2020;28(5):576586.

40. Li AS, MacKay D, Chen H, Rajagopal R, Apte RS. Challenges to routine genetic testing for inherited retinal dystrophies. Ophthalmology. 2019;126(10):14661468.

41. Suther S, Goodson P. Barriers to the provision of genetic services by primary care physicians: a systematic review of the literature. Genet Med. 2003;5(2):7076.

42. Suther S, Kiros G-E. Barriers to the use of genetic testing: a study of racial and ethnic disparities. Genet Med. 2009;11(9):655662.

43. Neiweem AE, Hariprasad SM, Ciulla TA. Genetic testing prevalence, guidelines, and pitfalls in large, university-based medical systems. Ophthalmic Surg Lasers Imaging Retina. 2021;52(1):610.

44. Retinal International Campaign - Know Your Code. 2021. Available from: https://kyc.retinaint.org/. Accessed April 1, 2022

45. Tan NB, Stapleton R, Stark Z, et al. Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review. Mol Genet Genomic Med. 2020;8(11):e1508.

46. Stone EM, Aldave AJ, Drack AV, et al. Recommendations for genetic testing of inherited eye diseases: report of the American Academy of Ophthalmology task force on genetic testing. Ophthalmology. 2012;119(11):24082410.

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Genetic testing of IRD in Australia | OPTH - Dove Medical Press

Margaret McGovern, MD, PhD, has been appointed deputy dean for clinical affairs at Yale School of Medicine and chief executive officer of Yale Medicine, effective July 1, 2022.

McGovern is currently Knapp Professor of Pediatrics and dean for clinical affairs at Renaissance School of Medicine at Stony Brook University and vice president of Stony Brook Medicine (SBM) Health System clinical programs and strategy. Prior to assuming these roles in 2018, she was chair of Pediatrics and physician-in-chief at Stony Brook Childrens Hospital. She led the development and planning of Stony Brook Childrens Hospital and markedly expanded its pediatric clinical research and education programs. McGovern also led the Stony Brook faculty practice plan for six years during her tenure as chair of Pediatrics. In 2019, she led the formation of the SBM Clinically Integrated Network, which is engaged in delivering high-quality, high value care by building a population health platform. She serves as the physician executive leader for the initiative.

She received her PhD in genetics from the Mount Sinai Graduate School of Biomedical Sciences and her MD from Mount Sinai School of Medicine (now called Icahn School of Medicine at Mount Sinai). She completed her residency training in pediatrics and fellowships in clinical and molecular genetics at Mount Sinai Hospital before joining the faculty. At Icahn, she was vice chair of the Department of Genetics and Molecular Medicine and professor of human genetics, and of oncological sciences and obstetrics and gynecology. She was the program director for the NIH-funded General Clinical Research Center (GCRC) and carried out CDC- and NIH-funded research focused primarily on the integration of molecular genetic diagnostic testing into clinical practice and inborn errors of metabolism. She is considered a world authority on sphingolipidoses.

At Yale, McGovern will play an essential role in the development of clinical strategy for the School of Medicine at an important juncture in the relationship between YSM and Yale New Haven Health System. She will provide strategic counsel and otherwise work to realize YSMs vision for its clinical enterprise. As CEO of YM, she will participate actively in the senior leadership group of the medical schools academic health system and play a key role in setting and realizing strategic goals. As deputy dean for clinical affairs, she will serve as the physician leader who represents the clinical mission of the School of Medicine in all venues. In this role, she will work closely with the clinical chairs in the recruitment of clinical faculty, mentor the next generation of clinical leaders, and collaborate with the deputy deans of research and education to balance the needs for enhancing the academic and educational missions of YSM with clinical ambulatory operational efficiencies, quality improvement, and sound clinical finances.

Submitted by Robert Forman on April 05, 2022

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Margaret McGovern, MD, PhD, Appointed YSM Deputy Dean and CEO of Yale Medicine - Yale School of Medicine

image:The HUSH and NEXT complexes function to control expression of TE transcripts at either the transcriptional or post-transcriptional level, respectively. HUSH is recruited to TE loci decorated with H3K9me3 histone marks and is required for transcriptional (txn) suppression. NEXT is recruited to HUSH-bound loci through a physical connection that requires ZCCHC8 and MPP8 and functions to decay pA- RNAs produced at TE loci view more

Credit: William Garland, Aarhus University

Mammalian genomes have been colonised by transposable elements (TEs), so called genetic parasites, which occupy ~ 50% of genomic DNA and harbour the potential to propagate, resulting in genetic instability. These elements are therefore subjected to tight cellular control. Whilst our understanding of TE regulation has been dominated by transcriptional and epigenetic models, the role of post-transcriptional RNA decay regulation has until now been unexplored.

A Danish team has identified a connection between the mouse orthologous nuclear exosome targeting (NEXT) and the human silencing hub (HUSH) complexes, involved in nuclear RNA decay and epigenetic silencing of TEs respectively. The researchers show that NEXT globally supresses TE RNA levels in mouse embryonic stem (ES) cells, and that this is aided by a recruitment to TE loci via the HUSH complex. This reveals an unprecedented collaborative mechanism of transcriptional and post-transcriptional control to limit the genotoxic activity of TE RNAs.

Previously, the Torben Heick Jensen laboratory identified and characterised the NEXT complex that target non-adenylated (pA-) RNAs to the nuclear exosome complex for decay. Upon depletion of NEXT, cells stabilise and accumulate such RNAs, but a putative role of NEXT in the regulation of TE RNAs had remained unexplored.

To investigate this, the NEXT component ZCCHC8 was knocked out (KO) in ES cells using CRISPR/Cas9 followed by high-throughput RNA sequencing and a focussed analysis of TE RNAs. Interestingly, this showed that TE RNAs were stabilised in NEXT KO conditions.

Upon further examination, it was shown that NEXT physically interact with HUSH via ZCCHC8 and that this connection provides a method of recruitment to target NEXT to DNA to degrade pA- TE RNAs whilst HUSH functions to regulate pA+ TE RNAs. This combinatorial mechanism ensures that TEs remain restricted by the collaborative functions of NEXT and HUSH.

These findings are a result of a collaborative project between the laboratories of Torben Heick Jensen at the Department of Molecular Biology and Genetics, Aarhus University, Kristian Helin at the Center for Epigenetics, Memorial Sloan Kettering Cancer Center and Albin Sandelin at the Biotech Relearch and Innovation Centre (BRIC), Copenhagen University. The studies were spearheaded by postdoc Will Garland from Aarhus University.

This study was published in the internationally recognised journalMolecular Cell.

Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression.William Garland, Iris Mller, Mengjun Wu, Manfred Schmid, Katsutoshi Imamura, Leonor Rib, Albin Sandelin, Kristian Helin and Torben Heick Jensen.Molecular Cell(2022) doi:10.1016/j.molcel.2022.03.004.

Assistant ProfessorWill Garland-garland@mbg.au.dkProfessorTorben Heick Jensen-thj@mbg.au.dkDepartment of Molecular Biology and Genetics, Aarhus University, Denmark

Experimental study

Cells

Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression

28-Mar-2022

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Summary: Mutations in the IL18RAP gene reduce inflammation and appear to protect the brain against ALS.

Source: Weizmann Institute of Science

Genetic mutations linked to a disease often spell bad news. Mutations in over 25 genes, for example, are associated with amyotrophic lateral sclerosis, or ALS, and they all increase the risk of developing this incurable disorder.

Now, a research team headed by Prof. Eran Hornstein of the Weizmann Institute of Science has linked a new gene to ALS, but this one contains mutations of a different sort: They seem to play a defensive rather than an offensive role in the disease.

The gene newly linked to ALS is located in the part of our genome once called junk DNA. This DNA makes up over 97 percent of the genome, but because it does not encode proteins, it used to be considered junk.

Today, though this noncoding DNA is still regarded as biological dark matter, its already known to serve as a crucial instruction manual. Among other things, it determines whengeneswithin the coding DNAthe ones that do encode proteinsare turned on and off.

Hornsteins lab in Weizmanns Molecular Neuroscience and Molecular Genetics Departments studies neurodegenerative diseasesthat is, diseases in which neurons degenerate and die. The team is focusing on our noncoding DNA.

This massive, noncoding part of the genome has been overlooked in the search for the genetic origins of neurodegenerative diseases like ALS, Hornstein explains.

This is despite the fact that for most ALS cases, proteins cannot explain the emergence of the disease.

Many people know about ALS thanks to the Ice Bucket Challenge that went viral a few years ago. This rare neurological disease attacks motor neurons, the nerve cells responsible for controlling voluntary muscle movement involved in everything from walking to talking and breathing.

The neurons gradually die off, ultimately causing respiratory failure and death. One of the symptoms of ALS is inflammation in the brain regions connected to the dying neurons, caused by immune mechanisms in the brain.

Our brain has an immune system, explains Dr. Chen Eitan, who led the study in Hornsteins lab together with Aviad Siany. If you have a degenerative disease, your brains immune cells, calledmicroglia, will try to protect you, attacking the cause of the neurodegeneration.

The problem is that in ALS, the neurodegeneration becomes so severe that the chronic microglial activation in the brain rises to extremely high levels, turning toxic. The immune system thus ends up causing damage to thebrainit set out to protect, leading to the death of more motor neurons.

Thats where the new findings, published today inNature Neuroscience, come in. The Weizmann scientists focused on a gene called IL18RAP, long known to affect microglia, and found that it can contain mutations that mitigate the microglias toxic effects. We have identified mutations in this gene that reduce inflammation, Eitan says.

After analyzing the genomes of more than 6,000 ALS patients and of more than 70,000 people who do not have ALS, the researchers concluded that the newly identified mutations reduce the risk of developing ALS nearly fivefold.

It is therefore extremely rare for ALS patients to have these protective mutations, and those rare patients who do harbor them tend to develop the disease roughly six years later, on average, than those without the mutations. In other words, the mutations seem to be linked to a core ALS process, slowing the disease down.

To confirm the findings, the researchers used gene-editing technology to introduce the protective mutations into stem cells from patients with ALS, causing these cells to mature into microglia in a laboratory dish.

They then cultured microglia, with or without the protective mutations, in the same dishes with motor neurons. Microglia harboring the protective mutations were found to be less aggressive towardmotor neuronsthan microglia that did not have themutations.

Motor neurons survived significantly longer when cultured with protective microglia, rather than with regular ones, Siany says.

Eitan notes that the findings have potential implications for ALS research and beyond. Weve found a new neuroprotective pathway, she says.

Future studies can check whether modulating this pathway may have a positive effect on patients. On a more general level, our findings indicate that scientists should not ignore noncoding regions of DNAnot just in ALS research, but in studying other diseases with a genetic component as well.

Author: Press OfficeSource: Weizmann Institute of ScienceContact: Press Office Weizmann Institute of ScienceImage: The image is in the public domain

Original Research: Closed access.Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3UTR protect against ALS by Chen Eitan et al. Nature Neuroscience

Abstract

Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3UTR protect against ALS

The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies.

Here, we performed region-based rare variant association analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls.

We identified interleukin-18 receptor accessory protein (IL18RAP) 3 untranslated region (3UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in theIL18RAP3UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins.

Finally, the variants of theIL18RAP3UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion inC9orf72, and this depends on NF-B signaling.

This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.

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Mutations in Noncoding DNA Are Found to Protect the Brain From ALS - Neuroscience News

Summary: Researchers have identified 75 regions of the genome associated with Alzheimers disease, including 42 novel regions. The findings shed new light on the biological mechanisms of Alzheimers and provide a new avenue for the treatment of this neurodegenerative disorder.

Source: INSERM

Identifying genetic risk factors for Alzheimers disease is essential if we are to improve our understanding and treatment of it. Progress in human genome analysis along with genome-wide association studies [1]are now leading to major advances in the field.

Researchers in Europe, the US and Australia have identified 75regions of the genome that are associated with Alzheimers disease. Forty-two of these regions are novel, meaning that they have never before been implicated in the disease.

The findings, published inNature Genetics, bring new knowledge of the biological mechanisms at play and open up new avenues for treatment and diagnosis.

Alzheimers disease is the most common form of dementia, affecting around 1,200,000 people in France. This complex, multifactorial disease, which usually develops after the age of 65, has a strong genetic component. The majority of cases are thought to be caused by the interaction of different genetic predisposition factors with environmental factors.

Although our understanding of the disease continues to improve, there is no cure at this time. The medications available are mainly aimed at slowing cognitive decline and reducing certain behavioral disorders.

In order to better understand the origins of the disease, one of the major challenges of research is to better characterize its genetic risk factors by identifying the pathophysiological processes at play [2], and thereby propose novel therapeutic targets.

As part of an international collaboration, researchers from Inserm, Institut Pasteur de Lille, Lille University Hospital and Universit de Lille conducted a genome-wide association study (GWAS) on the largest Alzheimers patient group set up until now [3], under the coordination of Inserm Research Director Jean-Charles Lambert.

Encouraged by advances in genome analysis, these studies consist of analyzing the entire genome of tens of thousands or hundreds of thousands of individuals, whether healthy or sick, with the aim of identifying genetic risk factors associated with specific aspects of the disease.

Using this method, the scientists were able to identify 75regions (loci) of the genome associated with Alzheimers, 42of which had never previously been implicated in the disease.

Following this major discovery, we characterized these regions in order to give them meaning in relation to our clinical and biological knowledge, and thereby gain a better understanding of the cellular mechanisms and pathological processes at play, explains Lambert.

Highlighting pathological phenomena

In Alzheimers disease, two pathological brain phenomena are already well documented: namely, the accumulation of amyloid-beta peptides and the modification of the protein Tau, aggregates of which are found in the neurons.

Here, the scientists confirmed the importance of these pathological processes. Their analyses of the various genome regions confirm that some are implicated in amyloid peptide production and Tau protein function.

Furthermore, these analyses also reveal that a dysfunction of innate immunity and of the action of the microglia (immune cells present in the central nervous system that play a trash collector role by eliminating toxic substances) is at play in Alzheimers disease.

Finally, this study shows for the first time that the tumor necrosis factor alpha (TNF-alpha)-dependent signaling pathway is involved in disease [4].

These findings confirm and add to our knowledge of the pathological processes involved in the disease and open up new avenues for therapeutic research. For example, they confirm the utility of the following: the conduct of clinical trials of therapies targeting the amyloid precursor protein, the continuation of microglial cell research that was initiated a few years ago, and the targeting of the TNF-alpha signaling pathway.

Risk score

Based on their findings, the researchers also devised a genetic risk score in order to better evaluate which patients with cognitive impairment will, within three years of its clinical manifestation, go on to develop Alzheimers disease.

While this tool is not at all intended for use in clinical practice at present, it could be very useful when setting up therapeutic trials in order to categorize participants according to their risk and improve the evaluation of the medications being tested,explains Lambert.

In order to validate and expand their findings, the team would now like to continue its research in an even broader group. Beyond this exhaustive characterization of the genetic factors of Alzheimers disease, the team is also developing numerous cellular and molecular biology approaches to determine their roles in its development.

Furthermore, with the genetic research having been conducted primarily on Caucasian populations, one of the considerations for the future will be to carry out the same type of studies in other groups in order to determine whether the risk factors are the same from one population to the next, which would reinforce their importance in the pathophysiological process.

Notes

[1]These studies consist of analyzing the entire genome of thousands or tens of thousands of people, whether healthy or sick, to identify genetic risk factors associated with specific aspects of the disease.

[2]All functional problems caused by a particular disease or condition.

[3]Here, the researchers were interested in the genetic data of 111,326 people who were diagnosed with Alzheimers disease or had close relatives with the condition, and 677,663 healthy controls. These data are derived from several large European cohorts grouped within the EuropeanAlzheimer & DementiaBioBank(EADB) consortium.

[4] Tumor necrosis factor alpha is a cytokine: an immune system protein implicated in the inflammation cascade, particularly in tissue lesion mechanisms.

Author: Priscille RiviereSource: INSERMContact: Priscille Riviere INSERMImage: The image is in the public domain

Original Research: Open access.New insights into the genetic etiology of Alzheimers disease and related Dementias by Jean-Charles Lambert et al. Nature Genetics

Abstract

New insights into the genetic etiology of Alzheimers disease and related Dementias

Characterization of the genetic landscape of Alzheimers disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes.

We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/proxy AD cases and 677,663 controls.

We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication.

Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex.

We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia.

The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and theAPOE4 allele.

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Alzheimers Disease: The Identification of 75 Genetic Risk Factors Brings New Insights - Neuroscience News

ROCKVILLE, Md. Apr. 5, 2022 The Association for Molecular Pathology (AMP), the premier global, molecular diagnostic professional society, called on Congress to allow for a thorough evaluation of the Verifying Accurate Leading-edge IVCT Development (VALID) Act of 2021, or any other legislation to change regulations for laboratory developed testing procedures (LDPs). Representatives from AMP, the American Association for Clinical Chemistry (AACC), the American College of Medical Genetics and Genomics (ACMG), and the Association of Pathology Chairs (APC) hosted a congressional briefing yesterday to educate lawmakers about how diagnostic tests are currently regulated and the substantial impact the VALID Act would have on clinical testing laboratories, healthcare providers, and patients throughout the U.S.

The VALID Act is a complex bill proposing dramatic modifications to current oversight mechanisms and a wide range of stakeholders have expressed significant concerns with the current draft. In February, AMP joined a number of other organizations asking that Congress consider the VALID Act separately from the must-pass Medical Device User Fee Agreement (MDUFA V) legislative process. To allow for thorough discussions and appropriate stakeholder engagement, it is important that this legislation goes through regular order with its own independent hearing, mark-up, and scheduled votes. More time and diverse stakeholder agreement are needed to ensure the policy is sound and in the best interest of patients and public health.

Congress needs to consider the lessons learned during the COVID-19 pandemic about how over burdensome and unnecessary regulation of laboratory testing affects testing capacity within the U.S. In February 2020, the U.S. declared a public health emergency and in turn, the U.S. Food and Drug Administration (FDA) began requiring emergency use authorization of all countermeasures used for clinical care. Subsequently, the FDA asserted authority to require regulatory review of COVID-19 tests before they could be offered to patients, halting the development and deployment of these tests, and leaving laboratory professionals paralyzed and unable to provide the care they are trained to do. As a result, this country went weeks without access to these critical public health tools while COVID-19 spread undetected throughout our communities.

AMP remains committed to working with and educating members of Congress and other key stakeholders to create an appropriate LDP oversight framework that modernizes the current regulatory system, demonstrates quality, enhances transparency, and fosters the rapid innovation and promise of new diagnostic technologies and tests, said Mary Steele Williams, AMP Executive Director. The current COVID-19 public health emergency highlights the critical need for laboratories to be allowed to respond quickly, and to continue advancing and offering the tens of thousands of high-quality, validated LDPs that benefit patients each and every day.

ABOUT AMP

The Association for Molecular Pathology (AMP) was founded in 1995 to provide structure and leadership to the emerging field of molecular diagnostics. AMP's 2,500+ members practice various disciplines of molecular diagnostics, including bioinformatics, infectious diseases, inherited conditions, and oncology. Our members are pathologists, clinical laboratory directors, basic and translational scientists, technologists, and trainees that practice in a variety of settings, including academic and community medical centers, government, and industry. Through the efforts of its Board of Directors, Committees, Working Groups, and Members, AMP is the primary resource for expertise, education, and collaboration in one of the fastest growing fields in healthcare. AMP members influence policy and regulation on the national and international levels, ultimately serving to advance innovation in the field and protect patient access to high-quality, appropriate testing. For more information, visit http://www.amp.org and follow AMP on Twitter: @AMPath.

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Association for Molecular Pathology Hosted a Congressional Briefing to Urge Lawmakers to Consider the VALID Act of 2021 Separately from the Medical...

Multi-Center Study on Track to Commence in Late 2022Initiated Reimbursement Process with The Centers for Medicare and Medicaid Services

BERKELEY, Calif. and MAINZ, Germany, March 31, 2022 (GLOBE NEWSWIRE) -- Mainz Biomed N.V. (NASDAQ:MYNZ) (Mainz Biomed or the Company), a molecular genetics diagnostic company specializing in the early detection of cancer, announced today that it has received supportive feedback from the U.S. Food & Drug Administration (FDA) on the Companys pre-submission package profiling the potential pivotal clinical trial design for ColoAlert, its highly efficacious, and easy-to-use detection test for colorectal cancer (CRC). As Mainz prepares to launch ColoAlerts pivotal clinical trial, the Company is also pleased to announce the formal commencement of its reimbursement process for ColoAlert by scheduling an initial meeting with The Centers for Medicare and Medicaid Services (CMS) in April 2022. The CMS is a federal agency in the U.S. Department of Health and Human Services (HHS) that administers the Medicare program and works in partnership with state governments to administer Medicaid, the Children's Health Insurance Program (CHIP), and health insurance portability standards.

We are encouraged by the FDAs supportive commentary on our proposed pivotal clinical trial design for ColoAlert and will now work with our clinical team to finalize the studys protocols and make the necessary preparations to ensure premier trial execution, commented Guido Baechler, Chief Executive Officer of Mainz Biomed. In concert with final pivotal clinical trial preparations, we are excited to pursue reimbursement for ColoAlert and are looking forward to commencing formal discussions with the CMS.

An integral part of Mainzs clinical execution and medical reimbursement strategies is its partnership with Precision for Medicine, a leading global Clinical Research Organization. Precision for Medicine will continue to work with Mainzs management team to implement the U.S. focused regulatory and market access strategy for ColoAlert by finalizing ColoAlerts clinical development plan to ensure the trial design is cost-effective, robust, and efficient. The Company is planning to integrate CMS guidelines into ColoAlerts pivotal trial design, utilizing currently marketed CRC screening tests as benchmarks to provide the test with an optimal product profile for regulatory approval and success in the marketplace.

Mainz is marketing ColoAlert across Europe through its unique business model of partnering with third-party laboratories for test kit processing versus the traditional methodology of operating a single facility. The Company is also running ColoFuture, an international clinical study evaluating the potential to integrate a portfolio of in-licensed novel mRNA biomarkers into the product which have previously demonstrated the unique ability to identify curable precancerous colonic polyps, as well as treatable early-stage CRC (Herring et al 2021). ColoFuture is evaluating the effectiveness of these biomarkers to enhance ColoAlerts technical profile to extend its capability to include the identification of advanced adenomas (AA), a type of pre-cancerous polyp often attributed to CRC, while increasing ColoAlerts rates of diagnostic sensitivity and specificity. The results of the study will ultimately impact the configuration of ColoAlert prior to commencing the U.S. pivotal study which is on track to begin in late 2022.

About ColoAlert ColoAlert detects colorectal cancer (CRC) via a simple-to-administer test with a sensitivity and specificity nearly as high as the invasive colonoscopy*. The test utilizes proprietary methods to analyze cell DNA for specific tumor markers combined with the fecal immunochemical test (FIT) and is designed to detect tumor DNA and CRC cases in their earliest stages. The product is CE-IVD marked (complying with EU safety, health and environmental requirements) and is transitioning to compliance with IVDR. The product is commercially available in a selection of countries in the European Union. Mainz Biomed currently distributes ColoAlert through a number of clinical affiliates. Once approved in the U.S., the Companys commercial strategy is to establish scalable distribution through a collaborative partner program with regional and national laboratory service providers across the country. * Dollinger MM et al. (2018)

About the ColoFuture Study The ColoFuture study is an international clinical trial evaluating over 600 patients (women or men) in the age range of 40-85 at two participating centers in Norway and two in Germany. Subjects are invited to potentially participate in the trial when referred for a colonoscopy (pre-inclusion) to screen for CRC or an overall diagnostic analysis. Those who agree to provide a stool sample in advance of the procedure will be eligible for participation. Inclusion criteria are based on one of the following diagnostic outcomes: CRC, advanced precancerous lesions in colon, or normal colon. Then, each patient outcome will compare the observations recorded from the colonoscopy to the results from the ColoAlert test that incorporates the novel biomarkers. The primary endpoints of the study are to determine sensitivity and specificity rates for CRC with ColoAlert plus the new mRNA biomarkers. There are multiple secondary endpoints for evaluating the modified ColoAlert test, including, determining sensitivity for AA lesions in colon, specificity for advanced precancerous lesions in colon and, specificity for no colorectal finding (normal colon). The Company is expecting to complete enrollment during the second half of 2022 and is targeting reporting study results in early 2023.

About Colorectal Cancer Colorectal cancer (CRC) is the second most lethal cancer in the U.S. and Europe, but also the most preventable with early detection providing survival rates above 90%. Annual testing costs per patient are minimal, especially when compared to late-stage treatments of CRC which cost patients an average of $38,469 per year. The American Cancer Society estimates that in 2021 there will be approximately 149,500 new cases of colon and rectal cancer in the U.S. with 52,980 resulting in death. Recent FDA decisions suggest that screening with stool DNA tests such as ColoAlert in the US should be conducted once every three years starting at age 45. Currently there are 112 million Americans aged 50+, a total that is expected to increase to 157 million within 10 years. Appropriately testing these US-based 50+ populations every three years as prescribed equates to a US market opportunity of approximately $3.7 Billion per year.

About Mainz Biomed N.V. Mainz Biomed develops market-ready molecular genetic diagnostic solutions for life-threatening conditions. The Companys flagship product is ColoAlert, an accurate, non-invasive, and easy-to-use early detection diagnostic test for colorectal cancer. ColoAlert is currently marketed across Europe with FDA clinical study and submission process intended to be launched in the first half of 2022 for U.S. regulatory approval. Mainz Biomeds product candidate portfolio includes PancAlert, an early-stage pancreatic cancer screening test based on Real-Time Polymerase Chain Reaction-based (PCR) multiplex detection of molecular-genetic biomarkers in stool samples, and the GenoStick technology, a platform being developed to detect pathogens on a molecular genetic basis.

For more information, please visit http://www.mainzbiomed.com

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Forward-Looking Statements Certain statements made in this press release are forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by the use of words such as anticipate, believe, expect, estimate, plan, outlook, and project and other similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These forward-looking statements reflect the current analysis of existing information and are subject to various risks and uncertainties. As a result, caution must be exercised in relying on forward-looking statements. Due to known and unknown risks, actual results may differ materially from the Companys expectations or projections. The following factors, among others, could cause actual results to differ materially from those described in these forward-looking statements: (i) the failure to meet projected development and related targets; (ii) changes in applicable laws or regulations; (iii) the effect of the COVID-19 pandemic on the Company and its current or intended markets; and (iv) other risks and uncertainties described herein, as well as those risks and uncertainties discussed from time to time in other reports and other public filings with the Securities and Exchange Commission (the SEC) by the Company. Additional information concerning these and other factors that may impact the Companys expectations and projections can be found in its initial filings with the SEC, including its registration statement on Form F-1 filed on January 21, 2022. The Companys SEC filings are available publicly on the SECs website at http://www.sec.gov. Any forward-looking statement made by us in this press release is based only on information currently available to Mainz Biomed and speaks only as of the date on which it is made. Mainz Biomed undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise, except as required by law.

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Mainz Biomed Completes Successful Pre-Submission Process with the U.S FDA for ColoAlert's ... - KULR-TV

The American Association for Cancer Research (AACR) has presented two awards to further diversity, equity, and inclusion in cancer research to the Escobar-Hoyos Lab, under the direction of Luisa Escobar-Hoyos, MSc, PhD.

Dr. Escobar-Hoyos is the 2022 recipient of an AACR Career Development Award. The AACR Career Development Award is intended to further diversity, equity, and inclusion in Cancer Research and has been established to support the development of highly talented cancer researchers from under-represented groups. The Escobar-Hoyos laboratory recently discovered that pancreatic cancers are exquisitely susceptible to a range of therapies directed at RNA splicing. Dr. Escobar-Hoyos will use the AACR award to continue her research and specifically to characterize the role of RNA splicing factor mutations in pancreatic cancer pathogenesis and treatment response. These results will uncover a fundamental, yet novel non-mutational mechanism required for pancreatic cancer pathogenesis and tumor maintenance:altered RNA splicing.

A postdoctoral associate in the Escobar-Hoyos laboratory, Natasha Pinto Medici, PhD, is the recipient of a 2022 AACR Career Development Award to further diversity, equity, and inclusion in cancer research. Originally from Brazil, Dr. Pinto Medici obtained her undergraduate and masters degrees in immunology from Universidad Federal do Rio de Janeiro. After being awarded with a competitive Brazilian fellowship for studies abroad, she came to the USA and obtained her PhD in molecular genetics and microbiology from Stony Brook University. Currently she researches the molecular regulation of immunity in pancreatic cancer in the Escobar-Hoyos laboratory.

Submitted by Renee Gaudette on March 24, 2022

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AACR Presents Awards to Further Diversity, Equity, and Inclusion in Cancer Research to Escobar-Hoyos Lab - Yale School of Medicine

image:Testis tissue section from a wild-type mouse stained for meiotic markers (in pink and green) and DNA (in blue). view more

Credit: Courtesy of Devanshi Jain

Researchers at Rutgers University, Memorial Sloan Kettering Cancer Center, Rockefeller University, and Cornell University are teaming up to examine how the processes that regulate gene expression and chromosome behaviors can lead to health issues, including cancer, birth defects, miscarriage, and infertility.

Cells undergo a remarkable transformation process to form eggs and sperm, which upon fertilization can form an entire organism. A key step of this transformation involves meiosis, a cell division that halves the genome content of cells. During early stages of egg and sperm development, cells divide by mitosis, the process used by most cells in our body. They then undergo a complete remodeling of the gene expression landscape, and switch to meiosis. Mis-regulation of the mitosis-to-meiosis switch can lead to tumor-like growth, depletion of the reproductive cell pool or failure to complete meiosis.

In the new Rutgers-led study in the journal Genes & Development, the researchers applied powerful methods for mapping genome-wide protein-RNA interactions and innovative genetic mouse mutants to define how the RNA helicase, YTHDC2, binds RNA and controls gene expression to regulate meiosis. YTHDC2 and its interacting protein partners form an essential pathway that controls the mitosis-to-meiosis switch. Prior to this study, little was known about the mechanisms regulating this switch in mammals.

Our work sheds light on the genetic and molecular mechanisms that are required for normal meiosis, which is an essential step towards understanding how and why these processes go wrong and lead to reproductive disorders, said Devanshi Jain, a principal investigator of the study and an Assistant Professor of Genetics at the School of Arts and Sciences (SAS) at Rutgers University-New Brunswick. Additionally, as YTHDC2 has been implicated in multiple diseases, especially cancers, our work will have broad implications on those fields as well.

Jain said this new study, along with ongoing research at the Rutgers-housed Jain Lab, explores the genetic and molecular mechanisms of meiosis, and the processes that regulate gene expression and chromosome behaviors. Researchers at the Jain Lab use the mouse model system to explore these fundamental aspects of cell biology.

Understanding meiosis is of paramount importance to reproductive health as errors in meiosis can lead to reproductive cell death and infertility, said Jain. Going forward, we plan to delve deeper into the molecular mechanisms of the YTHDC2 pathway and its control of gene expression. We also continue to study other fundamental aspects of how meiosis is regulated.

Genes & Development

YTHDC2 control of gametogenesis requires helicase activity but not m6A binding

20-Jan-2022

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New research sheds light on causes of reproductive disorders, infertility, miscarriage, birth defects - EurekAlert