- Browse by Author
Browsing by Author "Hirsch, Yoel"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Biallelic Loss-of-Function Variants in BICD1 Are Associated with Peripheral Neuropathy and Hearing Loss(MDPI, 2023-05-17) Hirsch, Yoel; Chung, Wendy K.; Novoselov, Sergey; Weimer, Louis H.; Rossor, Alexander; LeDuc, Charles A.; McPartland, Amanda J.; Cabrera, Ernesto; Ekstein, Josef; Scher, Sholem; Nelson, Rick F.; Schiavo, Giampietro; Henderson, Lindsay B.; Booth, Kevin T. A.; Otolaryngology -- Head and Neck Surgery, School of MedicineHearing loss and peripheral neuropathy are two clinical entities that are genetically and phenotypically heterogeneous and sometimes co-occurring. Using exome sequencing and targeted segregation analysis, we investigated the genetic etiology of peripheral neuropathy and hearing loss in a large Ashkenazi Jewish family. Moreover, we assessed the production of the candidate protein via western blotting of lysates from fibroblasts from an affected individual and an unaffected control. Pathogenic variants in known disease genes associated with hearing loss and peripheral neuropathy were excluded. A homozygous frameshift variant in the BICD1 gene, c.1683dup (p.(Arg562Thrfs*18)), was identified in the proband and segregated with hearing loss and peripheral neuropathy in the family. The BIDC1 RNA analysis from patient fibroblasts showed a modest reduction in gene transcripts compared to the controls. In contrast, protein could not be detected in fibroblasts from a homozygous c.1683dup individual, whereas BICD1 was detected in an unaffected individual. Our findings indicate that bi-allelic loss-of-function variants in BICD1 are associated with hearing loss and peripheral neuropathy. Definitive evidence that bi-allelic loss-of-function variants in BICD1 cause peripheral neuropathy and hearing loss will require the identification of other families and individuals with similar variants with the same phenotype.Item Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel(Springer Nature, 2019-11) Shen, Jun; Oza, Andrea M.; Del Castillo, Ignacio; Duzkale, Hatice; Matsunaga, Tatsuo; Pandya, Arti; Kang, Hyunseok P.; Mar-Heyming, Rebecca; Guha, Saurav; Moyer, Krista; Lo, Christine; Kenna, Margaret; Alexander, John J.; Zhang, Yan; Hirsch, Yoel; Luo, Minjie; Cao, Ye; Choy, Kwong Wai; Cheng, Yen-Fu; Avraham, Karen B.; Hu, Xinhua; Garrido, Gema; Moreno-Pelayo, Miguel A.; Greinwald, John; Zhang, Kejian; Zeng, Yukun; Brownstein, Zippora; Basel-Salmon, Lina; Davidov, Bella; Frydman, Moshe; Weiden, Tzvi; Nagan, Narasimhan; Willis, Alecia; Hemphill, Sarah E.; Grant, Andrew R.; Siegert, Rebecca K.; DiStefano, Marina T.; Amr, Sami S.; Rehm, Heidi L.; Abou Tayoun, Ahmad N.; Clin Gen Hearing Loss Working Group; Biostatistics, School of Public HealthPurpose: 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.