PURPOSE-Pathogenic 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. METHODS-The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Shen et al.

BACKGROUND By identifying pathogenic variants across hundreds of genes, expanded carrier screening (ECS) enables prospective parents to assess the risk of transmitting an autosomal recessive or X-linked condition. Detection of at-risk couples depends on the number of conditions tested, the prevalence of the respective diseases, and the screen's analytical sensitivity for identifying disease-causing variants. Disease-level analytical sensitivity is often <100% in ECS tests because copy number variants (CNVs) are typically not interrogated because of their technical complexity. METHODS We present an analytical validation and preliminary clinical characterization of a 235-gene sequencing-based ECS with full coverage across coding regions, targeted assessment of pathogenic noncoding variants, panel-wide CNV calling, and specialized assays for technically challenging genes. Next-generation sequencing, customized bioinformatics, 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 precluded novel variant identification or interpretation. RESULTS Screening of 36859 patients' blood or saliva samples revealed the substantial impact on fetal disease-risk detection attributable to novel CNVs (9.19% of risk) and technically challenging conditions (20.2% of risk), such as congenital adrenal hyperplasia. Of the 7498 couples screened, 335 were identified as at risk for an affected pregnancy, underscoring the clinical importance of the test. Validation of our ECS demonstrated >99% analytical sensitivity and >99% analytical specificity. CONCLUSIONS Validated high-fidelity identification of different variant types—especially for diseases with complicated molecular genetics—maximizes at-risk couple detection.

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.Methods: 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.Results: 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 screen's sensitivity is greatly impacted by two factors: (i) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping) and (ii) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome). Conclusion:The described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.

ClinVar provides open access to variant classifications shared from many clinical laboratories. While most classifications are consistent across laboratories, classification differences exist. To facilitate resolution of classification differences on a large scale, clinical laboratories were encouraged to reassess outlier classifications of variants with medically significant differences. Outliers were identified by first comparing ClinVar submissions from 41 clinical laboratories to detect variants with medically significant differences between the laboratories (650 variants). Next, medically significant differences were filtered for variants with ≥3 classifications (244 variants), of which 87.6% (213 variants) had a majority consensus in ClinVar, thus allowing for identification of outlier classifications in need of reassessment. Laboratories with outlier classifications were sent a custom report and encouraged to reassess variants. Results were returned for 204 (96%) variants, of which 62.3% (127) were resolved. Of those 127, 64.6% (82) were resolved due to reassessment prompted by this study and 35.4% (45) resolved by a previously completed reassessment. This study demonstrates a scalable approach to classification resolution and capitalizes on the value of data sharing within ClinVar. These activities will help the community move toward more consistent variant classifications which will improve the care of patients with, or at risk for, genetic disorders.

Objective-Stearoyl-CoA desaturase 1 (SCD1) is the rate-limiting enzyme involved in the synthesis of monounsaturated fatty acids, and in mice SCD1 activity is associated with plasma triglyceride levels. We used the fatty acid desaturation index (the plasma ratio of 18:1/18:0) as a marker of SCD1 activity to investigate the relationship of SCD1 to familial combined hyperlipidemia (FCHL). Methods and Results-The fatty acid desaturation index was measured in 400 individuals from 18 extended FCHL pedigrees. FCHL-affected individuals exhibited increased SCD1 activity when compared to unrelated controls (PϽ0.0001). The fatty acid desaturation index was found to be highly heritable (h 2 ϭ0.48, Pϭ2.2ϫ10 Ϫ11 ) in this study sample. QTL analysis in 346 sibling pairs from 18 FCHL families revealed suggestive linkage of the desaturation index to chromosomes 3p26.1 to 3p13 (zϭ2.7, Pϭ0.003), containing the peroxisome proliferator-activated receptor gamma (PPAR␥) gene, and 20p11.21 to 20q13.32 (zϭ1.7, Pϭ0.04), containing the hepatocyte nuclear factor 4, alpha (HNF4␣) gene. A specific haplotype of HNF4␣ was found to be associated with the desaturation index in these FCHL families (Pϭ0.002). Conclusion-Our results demonstrate that the fatty acid desaturation index is a highly heritable trait that is associated with the dyslipidemia observed in FCHL. (Arterioscler Thromb Vasc Biol 2008;28:1193-1199)Key Words: familial combined hyperlipidemia Ⅲ genetics Ⅲ Stearoyl-CoA desaturase 1 Ⅲ peroxisome proliferator-activated receptor gamma Ⅲ hepatocyte nuclear factor 4 alpha S tearoyl-coenzyme A (CoA) desaturase (SCD) is the major enzyme which catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids. The primary products of SCD-1, palmitate and oleate, are the most abundant monounsaturated fatty acids of phospholipids, triglycerides, wax esters, and cholesterol esters. 1 Mice homozygous for either a naturally occurring mutation or a targeted disruption of the SCD1 gene exhibit a marked reduction in VLDL triglycerides. 2 SCD1 Ϫ/Ϫ mice on a leptin-deficient ob/ob background exhibit reduced adiposity and increased fatty acid oxidation when compared to control animals, demonstrating a key role for SCD1 in the regulation of lipid homeostasis. 2 Familial combined hyperlipidemia (FCHL) is characterized by elevated plasma triglyceride or cholesterol levels. 3 FCHL often occurs in combination with insulin resistance, central adiposity, altered fatty acid metabolism, and other dyslipidemic phenotypes that predispose to early coronary artery disease (CAD). 4,5 The observed role of SCD1 in the regulation of VLDL metabolism and its involvement in many of the lipid parameters that are perturbed in FCHL suggest that the activity of this enzyme may be altered in FCHL subjects. In fact, the desaturation index was strongly correlated with both triglyceride and HDL levels in a human cohort of which approximately 60% of the subjects had FCHL. 6 In mice, studies of SCD activity in the HYPLIP mouse model of hyperlipidemia showed that hepa...