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

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 Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed. Results: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants. Conclusion: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance

Upstream transcription factor 1 influences plasma lipid and metabolic traits in mice

Upstream transcription factor 1 (USF1) has been associated with familial combined hyperlipidemia, the metabolic syndrome, and related conditions, but the mechanisms involved are unknown. In this study, we report validation of Usf1 as a causal gene of cholesterol homeostasis, insulin sensitivity and body composition in mouse models using several complementary approaches and identify associated pathways and gene expression network modules. Over-expression of human USF1 in both transgenic mice and mice with transient liver-specific over-expression influenced metabolic trait phenotypes, including obesity, total cholesterol level, LDL/VLDL cholesterol and glucose/insulin ratio. Additional analyses of trait and hepatic gene expression data from an F2 population derived from C57BL/6J and C3H/HeJ strains in which there is a naturally occurring variation in Usf1 expression supported a causal role for Usf1 for relevant metabolic traits. Gene network and pathway analyses of the liver gene expression signatures in the F2 population and the hepatic over-expression model suggested the involvement of Usf1 in immune responses and metabolism, including an Igfbp2-centered module. In all three mouse model settings, notable sex specificity was observed, consistent with human studies showing differences in association with USF1 gene polymorphisms between sexes