Due to the high genetic heterogeneity of hearing loss, current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants. Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of hearing loss. As one of its major tasks, our Expert Panel has adapted the ACMG/AMP guidelines for the interpretation of sequence variants in hearing loss genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP hearing loss rules. Three rules remained unchanged, four rules were removed, and the remaining twenty-one rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and expert opinion. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. These hearing loss-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with hearing loss.
Thymopoietins (Tmpos) are a group of ubiquitously expressed nuclear proteins, with sequence homology to lamina-associated polypeptide 2 (LAP2). Here we report the isolation and characterization of seven mouse Tmpo mRNA transcripts named Tmpo alpha, beta, beta', gamma, epsilon, delta, and zeta. The alpha, beta, and gamma Tmpo cDNA clones are the mouse homologs of the previously characterized human alpha, beta, and gamma TMPOs, respectively, whereas Tmpo epsilon, delta, and zeta are novel cDNAs. Additionally, the mouse Tmpo gene was cloned and characterized. It is a single-copy gene organized in 10 exons spanning approximately 22 kb, which encodes all of the described Tmpo cDNA sequences, located in the central region of mouse chromosome 10. The almost identical genomic organization between the human and mouse genes, and the novel alternatively spliced mouse transcripts, led us to reanalyze the human TMPO gene. The human beta-specific domain was found to be encoded by 3 exons designated 6a, 6b, and 6c and not by a single exon as described previously. These findings suggest that there may be more human transcripts than currently recognized. The possible involvement of the new growing family of Tmpo proteins in nuclear architecture and cell cycle control is discussed.
Mutations in the connexin 31 (GJB3) gene have been found in subjects with dominant and recessive deafness and in patients with erythrokeratodermia variabilis. We report here a dominant mutation in the GJB3 gene (D66del) in a family affected with peripheral neuropathy and sensorineural hearing impairment. A wide range of disease severity for peripheral neuropathy, from asymptomatic cases to subjects with chronic skin ulcers in their feet and osteomyelitis leading to amputations, was detected in D66del patients. Mild, often asymmetrical, hearing impairment was found in all but one patient with mutation D66del of this family and the same mutation was present in an independent family ascertained because of hearing impairment. We have found mouse connexin 31 (Gjb3) gene expression in the cochlea and in the auditory and sciatic nerves, showing a pattern similar to that of Gjb1 (connexin 32), of which the human ortholog (GJB1) is involved in X-linked peripheral neuropathy. This expression pattern, together with auditory-evoked brainstem anomalous response in D66del patients, indicates that hearing impairment due to GJB3 mutations involves alterations in both the cochlea and the auditory nerve. Peripheral neuropathy is the third phenotypic alteration linked to GJB3 mutations, which enlarges the list of genes that cause this group of heterogeneous disorders.
Erythrokeratodermia variabilis (EKV) is a skin disorder characterized by variable (transient) erythemas and fixed keratosis. The disorder maps to chromosome 1p34-35, a location that contains the GJB3 gene encoding the gap junction protein connexin 31. Until now, only heterozygote mutations in the form of dominant inheritance have been described in this gene associated with EKV. We report here a homozygote mutation in the connexin 31 gene, found in a family that shows recessive inheritance of the disorder, thus providing the first molecular support for a recessive variant of EKV. The entire GJB3 coding sequence was scanned for mutations by sequencing. We detected a T-->C transition at position 101 of the coding sequence, which replaces a leucine with a proline at residue 34 of the protein (L34P). Evolutionary analysis shows that this mutation is located at a highly conserved region of connexin in the first putative transmembrane helix (TMH). In transfected keratinocytes, L34P connexin 31 had a cytoplasmic distribution, suggesting that the mutant form of this protein will not form normal gap junctions between adjacent cells. The change of leucine to proline is likely to alter the structure of the first TMH of connexin by inducing a kink, thus influencing connexon structure and function.
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.
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