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| Monogenic hearing loss v2.186 | RNF220 |
Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies. There is enough evidence to support a gene-disease association; however, the ID severity in these patients do not meet the criteria (moderate to severe) for this panel (patients show mild (mostly) to moderate severity). Therefore, this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies. There is enough evidence to support a gene-disease association. Therefore, this gene should be Green at the next review. |
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| Monogenic hearing loss v2.168 | CRYM |
Eleanor Williams edited their review of gene: CRYM: Added comment: Associated with Deafness, autosomal dominant 40 #616357 (AD) in OMIM. PMID: 32742378 - Wang et al 2020 - report a 4 generation Chinese family with 31 members, of which 7 have hearing loss. WES identified a heterozygous missense mutation in CRYM (c.152C>T; Pro51Leu) which segregated with the phenotype in the family. As Zornitza Stark reports gnomad (3.1.1) has 2 hets reported (allele freq of 1.32e-5). PMID: 12471561 - Abe et al 2003 - used genome-wide cDNA microarray analysis to investigate gene-expression profiles in human cochlea and vestibule and identified CRYM as a candidate gene. They then screened CRYM, among 192 patients with nonsyndromic deafness. Two unrelated Japanese patients were identified with variants in CRYM; one with a de novo change (c.945A→T, p.X315Y) which results in an extended protein in a patient with unaffected parents, and the other was a missense mutation (c.941A→C;p.K314T) that segregated dominantly in the proband’s family. PMID: 16740909 - Oshima et al 2006 - looked at the effect of the two variants found by Abe et al, X315Y and K314T by looking at T3 binding activity of the mutant μ‐crystallin (product of CRYM) proteins. They found the K314T mutation impaired the NADPH dependent T3 binding (but did not find this for the X315Y variant). They also showed that μ‐crystallin protein localisation in mouse cochlea using immunocytochemical methods. PMID: 18448257 - Usami et al 2009 - showed that Crym protein localizes in type II fibrocytes of the spiral ligament in the cochlea in mice and rats PMID: 24676347 - Yoshimura et al 2014 - show a gradient of gene expression of CRYM in mouse cochlea PMID: 26915689 - Hosoya et al 2016 - immunohistochemical analysis of expression of CRYM in cochlea of a non-human primate, the common marmoset and found a different expression pattern compared to mouse, with expression not only in the lateral wall spiral ligament and the spiral limbus, but also in both inner and outer hair cells, supporting cells.; Changed publications to: 32742378, 12471561, 16740909, 18448257, 24676347, 26915689; Changed phenotypes to: Deafness, autosomal dominant 40, OMIM:616357, autosomal dominant nonsyndromic deafness 40, MONDO:0014603; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown |
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| Monogenic hearing loss v2.144 | GJB3 |
Eleanor Williams changed review comment from: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen. A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell Monoallelic cases: PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER). PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss. PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects. PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene. PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed. PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed. PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant. PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31. PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed. PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype. PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr. Biallelic cases: PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del. Functional studies: PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31.; to: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen. A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in to the cell surface in a similar way to wild type protein. Monoallelic cases: PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER). PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss. PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects. PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene. PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed. PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed. PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant. PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31. PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed. PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype. PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr. Biallelic cases: PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del. Functional studies: PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WT Cx31. |
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| Monogenic hearing loss v2.144 | GJB3 |
Eleanor Williams changed review comment from: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen. A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in many cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535) . 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell Monoallelic cases: PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER). PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss. PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects. PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene. PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed. PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed. PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant. PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31. PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed. PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype. PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr. Biallelic cases: PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del. Functional studies: PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31.; to: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen. A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell Monoallelic cases: PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER). PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss. PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects. PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene. PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed. PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed. PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant. PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31. PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed. PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype. PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr. Biallelic cases: PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del. Functional studies: PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31. |
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| Monogenic hearing loss v2.94 | COL2A1 |
Eleanor Williams changed review comment from: Associated with Stickler syndrome, type I #108300 (AD) in OMIM. PMID: 23110709 - Acke et al 2012 - review the literature to give an overview of hearing loss in Stickler syndrome, correlated with the genotype. 313 patients from 102 families were reviewed. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%). PMID: 27408751 - Kondo et al 2016 - report 21 cases (some familial, most sporadic) with COL2A1 variants. 4/21 showed hearing loss. PMID: 20179744 - Hoornaert et al 2010 - identified 77 different heterozygous COL2A1 mutations in 100 affected individuals out of a group of 188 individuals referred with a potential diagnosis of Stickler syndrome. 30% of COL2A1-variant positive patients had sensorineural hearing loss. However, over a higher percentage (50%) of patients without a COL2A1 mutation have sensorineural hearing loss.; to: Associated with Stickler syndrome, type I #108300 (AD) in OMIM. PMID: 23110709 - Acke et al 2012 - review the literature to give an overview of hearing loss in Stickler syndrome, correlated with the genotype. 313 patients from 102 families were reviewed. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%). PMID: 27408751 - Kondo et al 2016 - report 21 cases (some familial, most sporadic) with COL2A1 variants. 4/21 (20%) showed hearing loss. PMID: 20179744 - Hoornaert et al 2010 - identified 77 different heterozygous COL2A1 mutations in 100 affected individuals out of a group of 188 individuals referred with a potential diagnosis of Stickler syndrome. 30% of COL2A1-variant positive patients had sensorineural hearing loss. However, over a higher percentage (50%) of patients without a COL2A1 mutation have sensorineural hearing loss. |
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| Monogenic hearing loss v2.93 | FOXI1 | Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber. There are 2 homozygous and several heterozygous cases reported and it could be promoted to green after GMS review. Although most cases are syndromic hearing loss is a major feature. There is some debate about the whether it is homozygous only or also heterozygously inherited, however the homozygous cases are more convincing. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v2.41 | MN1 |
Arina Puzriakova gene: MN1 was added gene: MN1 was added to Hearing loss. Sources: Literature for-review tags were added to gene: MN1. Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MN1 were set to 31834374; 31839203 Phenotypes for gene: MN1 were set to CEBALID syndrome, 618774 Review for gene: MN1 was set to GREEN Added comment: Associated with phenotype in OMIM, and a probable gene for MN1 C-terminal truncation syndrome in G2P. Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum). 20/25 individuals had conductive and/or sensorineural hearing loss (no report on hearing status in a further 6 individuals across the two studies). Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Sources: Literature |
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| Monogenic hearing loss v2.10 | SLC52A3 |
Eleanor Williams commented on gene: SLC52A3: Associated with Brown-Vialetto-Van Laere syndrome 1 #211530 (AR) in OMIM, a form of progressive bulbar palsy with sensorineural deafness. Multiple cases of variants in this gene have been found in patients with Brown-Vialetto-Van Laere syndrome 1: PMID: 20206331 Green et al 2010 - identified homozygous or compound heterozygous variants in C20orf54 (SLC52A3) in individuals with Brown-Vialetto-Van Laere syndrome from 7 families of European, Pakistani and Arabic ancestry. Nonsense and missense variants were found. Used homozgyosity mapping in the first family and then candidate gene analysis. They also report that 58 cases have been documented in the literature, with the age at onset ranged from infancy to early in the third decade, with the majority presenting in the second decade. Hearing loss preceded the onset of neurological signs in most cases. C20ORF54 is thought to play a role in riboflavin transport. PMID: 20920669 Johnson et al 2010 - performed exome sequencing in patients with Brown-Vialetto-van Laere syndrome. In one patient in common with Green et al 2010 they found compound heterozygous variants in C20orf54 (patient 2008-410) rather than the homozygous variant Green et al reported (case 4). The results were confirmed by Sanger sequence and the parents were found to each have 1 heterozygous variant. They also report an additional family (DZ) from Eastern Turkey with a homozygous variant in affected individuals. |
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| Monogenic hearing loss v1.117 | ATP2B2 |
Eleanor Williams edited their review of gene: ATP2B2: Added comment: PMID: 30535804 - Smits et al 2019 - report 5 independant cases. Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2. Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo. Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment. In most cases HI was early onset, but in one individual hearing loss was reported around 55 years. Whole exome sequence (WES) data were analyzed for variants in a panel of 142 genes known to be associated with nonsyndromic hearing impairment (HI) and relatively common syndromic forms of HI. All variants affect exons, or their splice sites, that encode the ortholog of the rat PMCA2 w/a isoform. This isoform is highly abundant in stereocilia of outer hair cells (OHC) and to a lesser extent at the apical surface of inner hair cells of rats. Although rare CDH23 variants cooccurred with ATP2B2 variants in all five index cases, they state their findings indicate that mono-allelic loss-of-function variants of ATP2B2 are the underlying cause of HI. However, variants in deep intronic regions or promoter regions were not addressed and can, therefore, not be excluded. CNVs of CDH23 can be excluded for the index cases only. They state they cannot exclude a modifying effect of the CDH23 variants on HI in the affected subjects in their study.; Changed publications: 30535804 |
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