Biology subjects

Mar-Heyming, R.

Publications and source records attributed to Mar-Heyming, R..

3 recordsLinked to original sources

bioRxiv2018

Consensus interpretation of the Met34Thr and Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel

PURPOSEPathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants.\n\nMETHODSThe ClinGen Hearing Loss Expert Panel (HL-EP) collected published data and shared unpublished information from participating laboratories regarding the two variants. Functional, computational, allelic, and segregation data were also obtained.\n\nRESULTSThe panel reviewed the synthesized information, and classified the Met34Thr and Val37Ile variants according to professional variant interpretation guidelines. We found that Met34Thr and Val37Ile are significantly overrepresented in hearing loss patients, compared to the general population. Met34Thr or Val37Ile homozygotes or compound heterozygotes typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for those two variants.\n\nCONCLUSIONResolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification rules, review evidence, and reach a consensus. The ClinGen HL-EP concluded that Met34Thr and Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and age-dependent penetrance.

genetics↗

bioRxiv2017

Development and validation of an expanded carrier screen that optimizes sensitivity via full-exon sequencing and panel-wide copy-number-variant identification

PurposeBy identifying pathogenic variants across hundreds of genes, expanded carrier screening (ECS) enables prospective parents to assess risk of transmitting an autosomal recessive or X-linked condition. Detection of at-risk couples depends on the number of conditions tested, the diseases respective prevalences, and the screens sensitivity for identifying disease-causing variants. Here we present an analytical validation of a 235-gene sequencing-based ECS with full coverage across coding regions, targeted assessment of pathogenic noncoding variants, panel-wide copy-number-variant (CNV) calling, and customized assays for technically challenging genes.\n\nMethodsNext-generation sequencing, a customized bioinformatics pipeline, and expert manual call review were used to identify single-nucleotide variants, short insertions and deletions, and CNVs for all genes except FMR1 and those whose low disease incidence or high technical complexity precludes novel variant identification or interpretation. Variant calls were compared to reference and orthogonal data.\n\nResultsValidation of our ECS data demonstrated >99% analytical sensitivity and >99% specificity. A preliminary assessment of 15,177 patient samples reveals the substantial impact on fetal disease-risk detection attributable to novel CNV calling (13.9% of risk) and technically challenging conditions (15.5% of risk), such as congenital adrenal hyperplasia.\n\nConclusionValidated, high-fidelity identification of different variant types--especially in diseases with complicated molecular genetics--maximizes at-risk couple detection.

genetics↗

bioRxiv2016

Systematic Design and Comparison of Expanded Carrier Screening Panels

Purpose: The recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.\n\nMethods: Guided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.\n\nResults: Based on modeled fetal risks for \"severe\" and \"profound\" diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screens sensitivity is greatly impacted by two factors: (1) the methodology used (e.g., full-exon sequencing finds up to 46 more affected fetuses per 100,000 than targeted genotyping with an optimal 50 variant panel), and (2) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome, spinal muscular atrophy, 21-hydroxylase deficiency, and alpha-thalassemia account for 54 affected fetuses per 100,000).\n\nConclusion: The described approaches allow principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.

genetics↗