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23 Feb 2026	Monogenic hearing loss v5.55	ATOH1	Ida Ertmanska changed review comment from: PMID: 41592563 Bertola et al., 2026 Report of 5 unrelated families with heterozygous frameshift variants in ATOH1 associated with hearing loss, subtle motor impairments, and a pattern of brainstem malformations. Authors also report a homozygous early-truncating variant, causing a distinct neurodevelopmental syndrome with highly severe cerebellar and pontine hypoplasia. PMID: 35518571 Višnjar et al., 2022 A homozygous missense variant (NM_005172.1:c.481C>G) in the ATOH1 gene was identified in the proband and his affected sister, segregating with apparently recessive pontocerebellar hypoplasia (PCH), severe global developmental delay, intellectual disability, and hearing loss. Brain MRI findings were: posteriorly thin corpus callosum, small posterior fossa with the upward displacement of the tentorium, small cerebellum with more severely hypoplastic vermis than hemispheres, and small brainstem. PMID: 33111345 Brownstein et al., 2020 Family HL263: Mizrahi Jewish family, affected individuals heterozygous for ATOH1 c.1030delC, p.His344fs17Ter (affects C-terminus). Variant co-segregated over five generations with progressive non-syndromic hearing loss, with onset at birth or early childhood. Method: WES. Western analysis revealed a significantly slower rate of degradation for mutant ATOH1 protein compared to wild-type ATOH1. Increased protein stability = untimely expression leading to hearing loss. PMID: 27431290 Anazi et al., 2017 Cohort of ID patients. Patient 15DG1898 was homozygous for ATOH1: c.212del, p.(Gly71Alafs36); clinical presentation: generalised hypotonia, nystagmus, pontocerebellar hypoplasia, brain atrophy (frontal lobe). No mention of hearing loss (not assessed?). Functional evidence: Loss of Atoh1 in mice causes hearing impairment, cerebellar and cochlear malformations, and death (PMID: 9367153, Ben-Arie et al., 1997. ATOH1 previously known as MATH1). Conditional deletion of Atoh1 leads to lack of differentiated inner ear hair cells (PMID: 21146598 Pan et al., 2010). ATOH1 is putatively linked to ?Deafness, autosomal dominant 89, MIM:620284 in OMIM (accessed 23rd Feb 2026).; to: PMID: 41592563 Bertola et al., 2026 Report of 5 unrelated families with heterozygous frameshift variants in ATOH1 associated with hearing loss (7/7, mild to severe), cerebellar symptoms (4/6), and a pattern of brainstem malformations (7/7). Cerebellar symptoms are noted to be subtle: motor delay, balance issues, mild ataxia, tremor, and other cerebellar signs. Heterozygous variants detected: c.1030dup (p.His344ProfsTer6) - recurred de novo in 3 individuals; c.853-856dup (p.Ser286LeufsTer65); c.1053del (p.Asp351GlufsTer11). Authors also report a homozygous early-truncating variant c.102dup, (p.Pro35AlafsTer18), causing a distinct neurodevelopmental syndrome with severe pontocerebellar hypoplasia, severe ID, and profound hearing loss. Heterozygous parents were asymptomatic. PMID: 35518571 Višnjar et al., 2022 A homozygous missense variant NM_005172.1:c.481C>G, p.(Arg161Gly) in the ATOH1 gene was identified in the proband and his affected sister, segregating with apparently recessive pontocerebellar hypoplasia (PCH), severe global developmental delay, intellectual disability, and hearing loss. Brain MRI findings were: posteriorly thin corpus callosum, small posterior fossa with the upward displacement of the tentorium, small cerebellum with more severely hypoplastic vermis than hemispheres, and small brainstem. PMID: 33111345 Brownstein et al., 2020 Family HL263: Mizrahi Jewish family, affected individuals heterozygous for ATOH1 c.1030delC, p.His344fs17Ter (affects C-terminus). Variant co-segregated over five generations with progressive non-syndromic hearing loss, with onset at birth or early childhood. Method: WES. Western analysis revealed a significantly slower rate of degradation for mutant ATOH1 protein compared to wild-type ATOH1. Increased protein stability = untimely expression leading to hearing loss. PMID: 27431290 Anazi et al., 2017 Cohort of ID patients. Patient 15DG1898 was homozygous for ATOH1: c.212del, p.(Gly71Alafs36); clinical presentation: ID, generalised hypotonia, nystagmus, pontocerebellar hypoplasia, brain atrophy (frontal lobe). No mention of hearing loss (not assessed?). Functional evidence: Loss of Atoh1 in mice causes hearing impairment, cerebellar and cochlear malformations, and death (PMID: 9367153, Ben-Arie et al., 1997. ATOH1 previously known as MATH1). Conditional deletion of Atoh1 leads to lack of differentiated inner ear hair cells (PMID: 21146598 Pan et al., 2010). ATOH1 is putatively linked to ?Deafness, autosomal dominant 89, MIM:620284 in OMIM (accessed 23rd Feb 2026).
23 Feb 2026	Monogenic hearing loss v5.54	ATOH1	Ida Ertmanska changed review comment from: PMID: 41592563 Bertola et al., 2026 Report of 5 unrelated families with heterozygous frameshift variants in ATOH1 associated with hearing loss, subtle motor impairments, and a pattern of brainstem malformations. Authors also report a homozygous early-truncating variant, causing a distinct neurodevelopmental syndrome with highly severe cerebellar and pontine hypoplasia. PMID: 35518571 Višnjar et al., 2022 A homozygous missense variant (NM_005172.1:c.481C>G) in the ATOH1 gene was identified in the proband and his affected sister, segregating with apparently recessive pontocerebellar hypoplasia (PCH), severe global developmental delay, intellectual disability, and hearing loss. Brain MRI findings were: posteriorly thin corpus callosum, small posterior fossa with the upward displacement of the tentorium, small cerebellum with more severely hypoplastic vermis than hemispheres, and small brainstem. PMID: 33111345 Brownstein et al., 2020 Family HL263: Mizrahi Jewish family, affected individuals heterozygous for ATOH1 c.1030delC, p.His344fs17Ter (affects C-terminus). Variant co-segregated over five generations with progressive non-syndromic hearing loss, with onset at birth or early childhood. Method: WES. Western analysis revealed a significantly slower rate of degradation for mutant ATOH1 protein compared to wild-type ATOH1. Increased protein stability = untimely expression leading to hearing loss. Functional evidence: Loss of Atoh1 in mice causes hearing impairment, cerebellar and cochlear malformations, and death (PMID: 9367153, Ben-Arie et al., 1997. ATOH1 previously known as MATH1). Conditional deletion of Atoh1 leads to lack of differentiated inner ear hair cells (PMID: 21146598 Pan et al., 2010). ATOH1 is putatively linked to ?Deafness, autosomal dominant 89, MIM:620284 in OMIM (accessed 23rd Feb 2026).; to: PMID: 41592563 Bertola et al., 2026 Report of 5 unrelated families with heterozygous frameshift variants in ATOH1 associated with hearing loss, subtle motor impairments, and a pattern of brainstem malformations. Authors also report a homozygous early-truncating variant, causing a distinct neurodevelopmental syndrome with highly severe cerebellar and pontine hypoplasia. PMID: 35518571 Višnjar et al., 2022 A homozygous missense variant (NM_005172.1:c.481C>G) in the ATOH1 gene was identified in the proband and his affected sister, segregating with apparently recessive pontocerebellar hypoplasia (PCH), severe global developmental delay, intellectual disability, and hearing loss. Brain MRI findings were: posteriorly thin corpus callosum, small posterior fossa with the upward displacement of the tentorium, small cerebellum with more severely hypoplastic vermis than hemispheres, and small brainstem. PMID: 33111345 Brownstein et al., 2020 Family HL263: Mizrahi Jewish family, affected individuals heterozygous for ATOH1 c.1030delC, p.His344fs17Ter (affects C-terminus). Variant co-segregated over five generations with progressive non-syndromic hearing loss, with onset at birth or early childhood. Method: WES. Western analysis revealed a significantly slower rate of degradation for mutant ATOH1 protein compared to wild-type ATOH1. Increased protein stability = untimely expression leading to hearing loss. PMID: 27431290 Anazi et al., 2017 Cohort of ID patients. Patient 15DG1898 was homozygous for ATOH1: c.212del, p.(Gly71Alafs*36); clinical presentation: generalised hypotonia, nystagmus, pontocerebellar hypoplasia, brain atrophy (frontal lobe). No mention of hearing loss (not assessed?). Functional evidence: Loss of Atoh1 in mice causes hearing impairment, cerebellar and cochlear malformations, and death (PMID: 9367153, Ben-Arie et al., 1997. ATOH1 previously known as MATH1). Conditional deletion of Atoh1 leads to lack of differentiated inner ear hair cells (PMID: 21146598 Pan et al., 2010). ATOH1 is putatively linked to ?Deafness, autosomal dominant 89, MIM:620284 in OMIM (accessed 23rd Feb 2026).
23 Feb 2026	Monogenic hearing loss v5.51	ATOH1	Ida Ertmanska changed review comment from: PMID: 41592563 Bertola et al., 2026 Report of 5 unrelated families with heterozygous frameshift variants in ATOH1 associated with hearing loss, subtle motor impairments, and a pattern of brainstem malformations. Authors also report a homozygous early-truncating variant, causing a distinct neurodevelopmental syndrome with highly severe cerebellar and pontine hypoplasia. PMID: 35518571 Višnjar et al., 2022 A homozygous missense variant (NM_005172.1:c.481C>G) in the ATOH1 gene was identified in the proband and his affected sister, segregating with apparently recessive pontocerebellar hypoplasia (PCH), severe global developmental delay, intellectual disability, and hearing loss. Brain MRI findings were: posteriorly thin corpus callosum, small posterior fossa with the upward displacement of the tentorium, small cerebellum with more severely hypoplastic vermis than hemispheres, and small brainstem. PMID: 33111345 Brownstein et al., 2020 Family HL263: Mizrahi Jewish family, affected individuals heterozygous for ATOH1 c.1030delC, p.His344fs17Ter. Variant co-segregated over five generations with progressive non-syndromic hearing loss, with onset at birth or early childhood. Method: WES. Functional evidence: Loss of Atoh1 in mice causes hearing impairment, cerebellar and cochlear malformations, and death (PMID: 9367153, Ben-Arie et al., 1997. ATOH1 previously known as MATH1). Conditional deletion of Atoh1 leads to lack of differentiated inner ear hair cells (PMID: 21146598 Pan et al., 2010). ATOH1 is putatively linked to ?Deafness, autosomal dominant 89, MIM:620284 in OMIM (accessed 23rd Feb 2026).; to: PMID: 41592563 Bertola et al., 2026 Report of 5 unrelated families with heterozygous frameshift variants in ATOH1 associated with hearing loss, subtle motor impairments, and a pattern of brainstem malformations. Authors also report a homozygous early-truncating variant, causing a distinct neurodevelopmental syndrome with highly severe cerebellar and pontine hypoplasia. PMID: 35518571 Višnjar et al., 2022 A homozygous missense variant (NM_005172.1:c.481C>G) in the ATOH1 gene was identified in the proband and his affected sister, segregating with apparently recessive pontocerebellar hypoplasia (PCH), severe global developmental delay, intellectual disability, and hearing loss. Brain MRI findings were: posteriorly thin corpus callosum, small posterior fossa with the upward displacement of the tentorium, small cerebellum with more severely hypoplastic vermis than hemispheres, and small brainstem. PMID: 33111345 Brownstein et al., 2020 Family HL263: Mizrahi Jewish family, affected individuals heterozygous for ATOH1 c.1030delC, p.His344fs17Ter (affects C-terminus). Variant co-segregated over five generations with progressive non-syndromic hearing loss, with onset at birth or early childhood. Method: WES. Western analysis revealed a significantly slower rate of degradation for mutant ATOH1 protein compared to wild-type ATOH1. Increased protein stability = untimely expression leading to hearing loss. Functional evidence: Loss of Atoh1 in mice causes hearing impairment, cerebellar and cochlear malformations, and death (PMID: 9367153, Ben-Arie et al., 1997. ATOH1 previously known as MATH1). Conditional deletion of Atoh1 leads to lack of differentiated inner ear hair cells (PMID: 21146598 Pan et al., 2010). ATOH1 is putatively linked to ?Deafness, autosomal dominant 89, MIM:620284 in OMIM (accessed 23rd Feb 2026).
26 Nov 2025	Monogenic hearing loss v5.47	TBX2	Ida Ertmanska changed review comment from: There is some emerging evidence for the association of TBX2 and monogenic hearing loss. Several reported individuals with de novo microdeletions encompassing TBX2 had sensorineural hearing loss as one of the symptoms (PMID: 20206336 Ballif et al., 2010; PMID: 22052739 Schönewolf-Greulich et al., 2011; PMID: 21271665 Nimmakayalu et al., 2011). TBX2 and TBX4 are suggested as strong candidate genes. However, the effect of other genes being deleted is hard to decouple. A study by Hua et al. ( https://doi.org/10.1101/2024.07.18.24310488, pre-print, posted in July 2024) identified two Chinese families with late onset progressive sensorineural hearing loss. Affected members in each family were heterozygous for c.977delA p.(Asp326Alafs42) and c.987delC p.(Ala330Argfs38) respectively. Both variants are extremely rare and co-segregate with disease. Method: Linkage analysis + WGS. Family 1: five generations, 21/102 individuals had hearing loss (AD inheritance). Age of onset 4-40 years old. Monitoring at 10 year intervals showed slowly progressive auditory decline. 9 family member also exhibited spontaneous nystagmus (onset 0-5 years). Caveat: Six other shared variants were identified in RKD3, DYNC2LI1, FAHD2A, OR5K3, TBX2, ZNF135 - autosomal dominant pattern. Family 2: 4/14 members had hearing loss, proband had severe hearing loss with onset before 5yo; patient II.6 had late onset hearing loss (onset at 26-30yo) with nystagmus observed in childhood. Functional data: Tbx2 is essential for inner hair cell (IHC) differentiation in mice. Conditional Tbx2 knockout causes embryonic IHCs differentiate as outer hair cells (OHCs). Both inner and outer hair cells are required for hearing (PMID: 35508658 Garcia-Anoveros et al., 2022). Tbx2-/- knockout mouse embryos exhibit lethal cardiovascular defects (PMID: 15459098 Harrelson et a., 2004). In https://doi.org/10.1101/2024.07.18.24310488, Tbx2-/- mice were also embryonic lethal. Heterozygous Tbx2+/- mice had normal Auditory Brainstem Response thresholds at day 70. They started showing signs of hearing loss at day 100, and they exhibited severe hearing loss at day 150 – consistent with late-onset hearing loss reported in some patients. Interestingly, p.(Asp326Alafs42) knock-in mice did not show any signs of hearing loss. TBX2 is associated with Vertebral anomalies and variable endocrine and T-cell dysfunction (OMIM:618223, accessed 23 Sep 2025). Based on the available evidence, this gene should be rated amber for monogenic hearing loss. Sources: Literature; to: There is some emerging evidence for the association of TBX2 and monogenic hearing loss. Several reported individuals with de novo microdeletions encompassing TBX2 had sensorineural hearing loss as one of the symptoms (PMID: 20206336 Ballif et al., 2010; PMID: 22052739 Schönewolf-Greulich et al., 2011; PMID: 21271665 Nimmakayalu et al., 2011). TBX2 and TBX4 are suggested as strong candidate genes. However, the effect of other genes being deleted is hard to decouple. A study by Hua et al. ( https://doi.org/10.1101/2024.07.18.24310488, pre-print, posted in July 2024) identified two Chinese families with late onset progressive sensorineural hearing loss. Affected members in each family were heterozygous for c.977delA p.(Asp326Alafs42) and c.987delC p.(Ala330Argfs38) respectively. Both variants are extremely rare and co-segregate with disease. Method: Linkage analysis + WGS. Family 1: five generations, 21/102 individuals had hearing loss (AD inheritance). Age of onset 4-40 years old. Monitoring at 10 year intervals showed slowly progressive auditory decline. 9 family member also exhibited spontaneous nystagmus (onset 0-5 years). Caveat: Six other shared variants were identified in RKD3, DYNC2LI1, FAHD2A, OR5K3, TBX2, ZNF135 - autosomal dominant pattern. Family 2: 4/14 members had hearing loss, proband had severe hearing loss with onset before 5yo; patient II.6 had late onset hearing loss (onset at 26-30yo) with nystagmus observed in childhood. Functional data: Tbx2 is essential for inner hair cell (IHC) differentiation in mice. Conditional Tbx2 knockout causes embryonic IHCs differentiate as outer hair cells (OHCs). Both inner and outer hair cells are required for hearing (PMID: 35508658 Garcia-Anoveros et al., 2022). Tbx2-/- knockout mouse embryos exhibit lethal cardiovascular defects (PMID: 15459098 Harrelson et a., 2004). In https://doi.org/10.1101/2024.07.18.24310488, Tbx2-/- mice were also embryonic lethal. Heterozygous Tbx2+/- mice had normal Auditory Brainstem Response thresholds at day 70. They started showing signs of hearing loss at day 100, and they exhibited severe hearing loss at day 150 – consistent with late-onset hearing loss reported in some patients. Interestingly, p.(Asp326Alafs42) knock-in mice did not show any signs of hearing loss. TBX2 is associated with Vertebral anomalies and variable endocrine and T-cell dysfunction (OMIM:618223, accessed 23 Sep 2025). Based on the available evidence, this gene should be rated amber for monogenic hearing loss. Sources: Literature
27 Oct 2025	Monogenic hearing loss v5.46	ARSG	Ida Ertmanska changed review comment from: PMID: 29300381 Khateb et al, 2018 Reported 5 patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a founder missense variant, c.133G>T (p.D45Y) in ARSG. Vision and hearing loss appeared around the age of 40 years. PMID: 32455177 Abad-Morales et al., 2020 Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES. PMID: 33300174 Peter et al., 2021 3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age. Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12) Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp). PMID: 33629623 Fowler et al., 2021 Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys). PMID: 35226187 Velde et al., 2022 3 unrelated subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo): Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs41) and c.275T>C, p.(Leu92Pro). Subject F: compound het for c.1326del, p.(Ser443Ala fs12) and c.1024C>T, p.(Arg342Trp). Subject D: compound het for c.588C>A, p.(Tyr196) and c.705-3940_ 982+2952del, p.(Ser235Arg fs29).; to: PMID: 29300381 Khateb et al, 2018 Reported 5 patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a founder missense variant, c.133G>T (p.D45Y) in ARSG. Vision and hearing loss appeared around the age of 40 years. PMID: 32455177 Abad-Morales et al., 2020 Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES. PMID: 33300174 Peter et al., 2021 3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age. Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12) Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp). PMID: 33629623 Fowler et al., 2021 Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys). PMID: 35226187 Velde et al., 2022 3 unrelated subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo): Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs41) and c.275T>C, p.(Leu92Pro). Subject F: compound het for c.1326del, p.(Ser443Ala fs12) and c.1024C>T, p.(Arg342Trp). Subject D: compound het for c.588C>A, p.(Tyr196) and c.705-3940_ 982+2952del, p.(Ser235Arg fs29). ARSG is associated with AR Usher syndrome, type IV, 618144 in OMIM (accessed 27th Oct 2025).
27 Oct 2025	Monogenic hearing loss v5.46	ARSG	Ida Ertmanska changed review comment from: PMID: 29300381 Khateb et al, 2018 Reported 5 patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a founder missense variant, c.133G>T (p.D45Y) in ARSG. Vision and hearing loss appeared around the age of 40 years. PMID: 32455177 Abad-Morales et al., 2020 Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES. PMID: 33300174 Peter et al., 2021 3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age. Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12) Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp). PMID: 33629623 Fowler et al., 2021 Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys). PMID: 35226187 Velde et al., 2022 3 subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo): Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs41) and c.275T>C, p.(Leu92Pro). Subject F: compound het for c.1326del, p.(Ser443Ala fs12) and c.1024C>T, p.(Arg342Trp). Subject D: compound het for c.588C>A, p.(Tyr196) and c.705-3940_ 982+2952del, p.(Ser235Arg fs29).; to: PMID: 29300381 Khateb et al, 2018 Reported 5 patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a founder missense variant, c.133G>T (p.D45Y) in ARSG. Vision and hearing loss appeared around the age of 40 years. PMID: 32455177 Abad-Morales et al., 2020 Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES. PMID: 33300174 Peter et al., 2021 3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age. Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12) Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp). PMID: 33629623 Fowler et al., 2021 Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys). PMID: 35226187 Velde et al., 2022 3 unrelated subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo): Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs41) and c.275T>C, p.(Leu92Pro). Subject F: compound het for c.1326del, p.(Ser443Ala fs12) and c.1024C>T, p.(Arg342Trp). Subject D: compound het for c.588C>A, p.(Tyr196) and c.705-3940_ 982+2952del, p.(Ser235Arg fs29).
27 Oct 2025	Monogenic hearing loss v5.46	ARSG	Ida Ertmanska changed review comment from: PMID: 29300381 Khateb et al, 2018 five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a afounder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). Vision and hearing loss appeared around the age of 40 years. PMID: 32455177 Abad-Morales et al., 2020 Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES. PMID: 33300174 Peter et al., 2021 3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age. Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12) Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp). PMID: 33629623 Fowler et al., 2021 Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys). PMID: 35226187 Velde et al., 2022 3 subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo): Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs41) and c.275T>C, p.(Leu92Pro). Subject F: compound het for c.1326del, p.(Ser443Ala fs12) and c.1024C>T, p.(Arg342Trp). Subject D: compound het for c.588C>A, p.(Tyr196) and c.705-3940_ 982+2952del, p.(Ser235Arg fs29).; to: PMID: 29300381 Khateb et al, 2018 Reported 5 patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a founder missense variant, c.133G>T (p.D45Y) in ARSG. Vision and hearing loss appeared around the age of 40 years. PMID: 32455177 Abad-Morales et al., 2020 Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES. PMID: 33300174 Peter et al., 2021 3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age. Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12) Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp). PMID: 33629623 Fowler et al., 2021 Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys). PMID: 35226187 Velde et al., 2022 3 subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo): Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs41) and c.275T>C, p.(Leu92Pro). Subject F: compound het for c.1326del, p.(Ser443Ala fs12) and c.1024C>T, p.(Arg342Trp). Subject D: compound het for c.588C>A, p.(Tyr196) and c.705-3940_ 982+2952del, p.(Ser235Arg fs29).
27 Oct 2025	Monogenic hearing loss v5.46	ARSG	Ida Ertmanska changed review comment from: PMID: 29300381 Khateb et al, 2018 five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a afounder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). Vision and hearing loss appeared around the age of 40 years. PMID: 32455177 Abad-Morales et al., 2020 Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES. PMID: 33300174 Peter et al., 2021 3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age. Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12) Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp). PMID: 33629623 Fowler et al., 2021 Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys). Sources: Other; to: PMID: 29300381 Khateb et al, 2018 five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a afounder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). Vision and hearing loss appeared around the age of 40 years. PMID: 32455177 Abad-Morales et al., 2020 Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES. PMID: 33300174 Peter et al., 2021 3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age. Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12) Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp). PMID: 33629623 Fowler et al., 2021 Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys). PMID: 35226187 Velde et al., 2022 3 subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo): Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs41) and c.275T>C, p.(Leu92Pro). Subject F: compound het for c.1326del, p.(Ser443Ala fs12) and c.1024C>T, p.(Arg342Trp). Subject D: compound het for c.588C>A, p.(Tyr196) and c.705-3940_ 982+2952del, p.(Ser235Arg fs29).
27 Oct 2025	Monogenic hearing loss v5.40	ARSG	Ida Ertmanska gene: ARSG was added gene: ARSG was added to Monogenic hearing loss. Sources: Other Mode of inheritance for gene: ARSG was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ARSG were set to Usher syndrome, type IV, OMIM:618144; usher syndrome, type 4, MONDO:0029141 Review for gene: ARSG was set to GREEN Added comment: PMID: 29300381 Khateb et al, 2018 five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a afounder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). Vision and hearing loss appeared around the age of 40 years. PMID: 32455177 Abad-Morales et al., 2020 Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES. PMID: 33300174 Peter et al., 2021 3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age. Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12) Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp). PMID: 33629623 Fowler et al., 2021 Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys). Sources: Other
27 Oct 2025	Monogenic hearing loss v5.40	ARSG	Ida Ertmanska gene: ARSG was added gene: ARSG was added to Monogenic hearing loss. Sources: Other Mode of inheritance for gene: ARSG was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ARSG were set to Usher syndrome, type IV, OMIM:618144; usher syndrome, type 4, MONDO:0029141 Review for gene: ARSG was set to GREEN Added comment: PMID: 29300381 Khateb et al, 2018 five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a afounder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). Vision and hearing loss appeared around the age of 40 years. PMID: 32455177 Abad-Morales et al., 2020 Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES. PMID: 33300174 Peter et al., 2021 3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age. Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12) Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp). PMID: 33629623 Fowler et al., 2021 Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys). Sources: Other
17 Oct 2025	Monogenic hearing loss v5.31	AP1B1	Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019 Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings. Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome. PMID: 33452671 Vornweg et al., 2021 Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin. PMID: 33349978 Ito et al., 2021 Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618 and 2677C>T p.Gln893. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels. PMID: 32969855 Meriç et al., 2021 11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits. PMID: 35144013 Faghihi et al., 2022 Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions. AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025). This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024). Sources: ClinGen, Literature; to: PMID: 31630791 Alsaif et al., 2019 Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings. Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome. PMID: 33452671 Vornweg et al., 2021 Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin. PMID: 33349978 Ito et al., 2021 Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618 and 2677C>T p.Gln893. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels. PMID: 32969855 Meriç et al., 2021 11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits. PMID: 35144013 Faghihi et al., 2022 Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions. AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025). This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
17 Oct 2025	Monogenic hearing loss v5.31	AP1B1	Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019 Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings. Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome. PMID: 33452671 Vornweg et al., 2021 Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin. PMID: 33349978 Ito et al., 2021 Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618 and 2677C>T p.Gln893. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels. PMID: 32969855 Meriç et al., 2021 11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits. PMID: 35144013 Faghihi et al., 2022 Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions. AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025). Sources: ClinGen, Literature; to: PMID: 31630791 Alsaif et al., 2019 Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings. Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome. PMID: 33452671 Vornweg et al., 2021 Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin. PMID: 33349978 Ito et al., 2021 Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618 and 2677C>T p.Gln893. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels. PMID: 32969855 Meriç et al., 2021 11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits. PMID: 35144013 Faghihi et al., 2022 Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions. AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025). This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024). Sources: ClinGen, Literature
17 Oct 2025	Monogenic hearing loss v5.31	AP1B1	Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019 Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings. Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome. PMID: 33452671 Vornweg et al., 2021 Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia.. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin. PMID: 33349978 Ito et al., 2021 Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618 and 2677C>T p.Gln893. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels. PMID: 32969855 Meriç et al., 2021 11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits. PMID: 35144013 Faghihi et al., 2022 Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions. AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025). Sources: ClinGen, Literature; to: PMID: 31630791 Alsaif et al., 2019 Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings. Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome. PMID: 33452671 Vornweg et al., 2021 Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin. PMID: 33349978 Ito et al., 2021 Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618 and 2677C>T p.Gln893. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels. PMID: 32969855 Meriç et al., 2021 11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits. PMID: 35144013 Faghihi et al., 2022 Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions. AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025). Sources: ClinGen, Literature
17 Oct 2025	Monogenic hearing loss v5.31	AP1B1	Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019 Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings. Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome. PMID: 33452671 Vornweg et al., 2021 Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin. PMID: 33349978 Ito et al., 2021 Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618 and 2677C>T p.Gln893. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels. PMID: 32969855 Meriç et al., 2021 11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits. PMID: 35144013 Faghihi et al., 2022 Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions. AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025). Sources: ClinGen, Literature; to: PMID: 31630791 Alsaif et al., 2019 Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings. Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome. PMID: 33452671 Vornweg et al., 2021 Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia.. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin. PMID: 33349978 Ito et al., 2021 Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618 and 2677C>T p.Gln893. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels. PMID: 32969855 Meriç et al., 2021 11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits. PMID: 35144013 Faghihi et al., 2022 Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions. AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025). Sources: ClinGen, Literature
17 Oct 2025	Monogenic hearing loss v5.31	AP1B1	Ida Ertmanska gene: AP1B1 was added gene: AP1B1 was added to Monogenic hearing loss. Sources: ClinGen,Literature Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AP1B1 were set to 31630791; 33452671; 33349978; 32969855; 35144013 Phenotypes for gene: AP1B1 were set to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; ichthyosiform erythroderma, corneal involvement, and hearing loss, MONDO:0009440 Review for gene: AP1B1 was set to GREEN Added comment: PMID: 31630791 Alsaif et al., 2019 Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings. Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome. PMID: 33452671 Vornweg et al., 2021 Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin. PMID: 33349978 Ito et al., 2021 Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618 and 2677C>T p.Gln893. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels. PMID: 32969855 Meriç et al., 2021 11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits. PMID: 35144013 Faghihi et al., 2022 Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions. AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025). Sources: ClinGen, Literature
23 Sep 2025	Monogenic hearing loss v5.23	TBX2	Ida Ertmanska gene: TBX2 was added gene: TBX2 was added to Monogenic hearing loss. Sources: Literature Mode of inheritance for gene: TBX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TBX2 were set to 15459098; 20206336; 21271665; 22052739; 35508658 Phenotypes for gene: TBX2 were set to hearing loss disorder, MONDO:0005365 Review for gene: TBX2 was set to AMBER Added comment: There is some emerging evidence for the association of TBX2 and monogenic hearing loss. Several reported individuals with de novo microdeletions encompassing TBX2 had sensorineural hearing loss as one of the symptoms (PMID: 20206336 Ballif et al., 2010; PMID: 22052739 Schönewolf-Greulich et al., 2011; PMID: 21271665 Nimmakayalu et al., 2011). TBX2 and TBX4 are suggested as strong candidate genes. However, the effect of other genes being deleted is hard to decouple. A study by Hua et al. ( https://doi.org/10.1101/2024.07.18.24310488, pre-print, posted in July 2024) identified two Chinese families with late onset progressive sensorineural hearing loss. Affected members in each family were heterozygous for c.977delA p.(Asp326Alafs42) and c.987delC p.(Ala330Argfs38) respectively. Both variants are extremely rare and co-segregate with disease. Method: Linkage analysis + WGS. Family 1: five generations, 21/102 individuals had hearing loss (AD inheritance). Age of onset 4-40 years old. Monitoring at 10 year intervals showed slowly progressive auditory decline. 9 family member also exhibited spontaneous nystagmus (onset 0-5 years). Caveat: Six other shared variants were identified in RKD3, DYNC2LI1, FAHD2A, OR5K3, TBX2, ZNF135 - autosomal dominant pattern. Family 2: 4/14 members had hearing loss, proband had severe hearing loss with onset before 5yo; patient II.6 had late onset hearing loss (onset at 26-30yo) with nystagmus observed in childhood. Functional data: Tbx2 is essential for inner hair cell (IHC) differentiation in mice. Conditional Tbx2 knockout causes embryonic IHCs differentiate as outer hair cells (OHCs). Both inner and outer hair cells are required for hearing (PMID: 35508658 Garcia-Anoveros et al., 2022). Tbx2-/- knockout mouse embryos exhibit lethal cardiovascular defects (PMID: 15459098 Harrelson et a., 2004). In https://doi.org/10.1101/2024.07.18.24310488, Tbx2-/- mice were also embryonic lethal. Heterozygous Tbx2+/- mice had normal Auditory Brainstem Response thresholds at day 70. They started showing signs of hearing loss at day 100, and they exhibited severe hearing loss at day 150 – consistent with late-onset hearing loss reported in some patients. Interestingly, p.(Asp326Alafs*42) knock-in mice did not show any signs of hearing loss. TBX2 is associated with Vertebral anomalies and variable endocrine and T-cell dysfunction (OMIM:618223, accessed 23 Sep 2025). Based on the available evidence, this gene should be rated amber for monogenic hearing loss. Sources: Literature
22 Mar 2025	Monogenic hearing loss v4.82	DAP3	Achchuthan Shanmugasundram changed review comment from: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available. This gene has been associated with relevant phenotypes in OMIM (MIM #621101). Sources: Literature; to: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available. This gene has been associated with relevant phenotypes in OMIM (MIM #621101), but not yet in Gene2Phenotype. Sources: Literature
22 Mar 2025	Monogenic hearing loss v4.80	DAP3	Achchuthan Shanmugasundram changed review comment from: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available for this gene. This gene has been associated with relevant phenotypes in OMIM (MIM #621101). Sources: Literature; to: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available. This gene has been associated with relevant phenotypes in OMIM (MIM #621101). Sources: Literature
22 Mar 2025	Monogenic hearing loss v4.80	DAP3	Achchuthan Shanmugasundram gene: DAP3 was added gene: DAP3 was added to Monogenic hearing loss. Sources: Literature Mode of inheritance for gene: DAP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DAP3 were set to 39701103 Phenotypes for gene: DAP3 were set to Perrault syndrome 7, OMIM:621101 Review for gene: DAP3 was set to GREEN Added comment: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available for this gene. This gene has been associated with relevant phenotypes in OMIM (MIM #621101). Sources: Literature
21 Aug 2023	Monogenic hearing loss v4.14	GOSR2	Achchuthan Shanmugasundram gene: GOSR2 was added gene: GOSR2 was added to Monogenic hearing loss. Sources: Literature Mode of inheritance for gene: GOSR2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GOSR2 were set to 37074134 Phenotypes for gene: GOSR2 were set to hearing loss, autosomal recessive, MONDO:0019588 Review for gene: GOSR2 was set to RED Added comment: Four children from two sibships from an extended consanguineous Palestinian family were reported with congenital profound hearing loss, whereas the parents of both sibships are first cousins with normal hearing. The families reported occasional febrile seizures in infancy for each of the deaf children, but these did not persist into adolescence. These affected children were identified with autosomal recessive GOSR2 variant, c.1A > C, p.Met1Leu. This variant appeared once in the gnomAD database, as a heterozygote, and not in any of ~2000 in-house controls of Palestinian ancestry. All previously reported cases with biallelic GOSR2 variants had normal hearing and hence the differences in translation efficiency due to the effect of this variant may be responsible for this hearing loss phenotype (PMID:37074134). Sources: Literature
28 Jul 2023	Monogenic hearing loss v4.11	DNAJC3	Achchuthan Shanmugasundram changed review comment from: PMID:25466870 - Five individuals from two different families were identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)), of which all three individuals from family 1 and one of two individuals from family 2 were reported with sensorineural hearing loss among several clinical manifestations. PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with sensorineural hearing loss. PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorineural hearing loss. PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, and both had sensorineural hearing loss. PMID:34654017 - Ttwo siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with sensorineural hearing loss. Sources: Literature; to: PMID:25466870 - Five individuals from two different families were identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)), of which all three individuals from family 1 and one of two individuals from family 2 were reported with sensorineural hearing loss among several clinical manifestations. PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with sensorineural hearing loss. PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorineural hearing loss. PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, and both had sensorineural hearing loss. PMID:34654017 - Two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with sensorineural hearing loss. Sources: Literature
28 Jul 2023	Monogenic hearing loss v4.11	DNAJC3	Achchuthan Shanmugasundram gene: DNAJC3 was added gene: DNAJC3 was added to Monogenic hearing loss. Sources: Literature Mode of inheritance for gene: DNAJC3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNAJC3 were set to 25466870; 28940199; 32738013; 33486469; 34654017 Phenotypes for gene: DNAJC3 were set to Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus, OMIM:616192 Review for gene: DNAJC3 was set to GREEN Added comment: PMID:25466870 - Five individuals from two different families were identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)), of which all three individuals from family 1 and one of two individuals from family 2 were reported with sensorineural hearing loss among several clinical manifestations. PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with sensorineural hearing loss. PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorineural hearing loss. PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, and both had sensorineural hearing loss. PMID:34654017 - Ttwo siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with sensorineural hearing loss. Sources: Literature
25 May 2022	Monogenic hearing loss v2.246	KCNJ16	Eleanor Williams changed review comment from: Associated with Hypokalemic tubulopathy and deafness OMIM#619406 (AR) PMID:33811157 - Schlingmann et al 2021 - unable to access publication. Abstract does not give numbers of cases but OMIM states that "In 8 patients, including 1 sib pair, with hypokalemic tubulopathy and deafness, Schlingmann et al. (2021) identified homozygous or compound heterozygous mutations in the KCNJ16 gene". Details of the hearing loss could not be acertained. PMID:33840812 - Webb et al 2021 - report a homozygous loss-of-function variant identified by WES in KCNJ16 in a 2-year-old female with a hypokalemic metabolic acidosis phenotype. Hearing loss is NOT mentioned. Sources: Literature; to: Associated with Hypokalemic tubulopathy and deafness OMIM#619406 (AR) PMID:33811157 - Schlingmann et al 2021 - report 8 patients from 7 families with hypokalemic tubulopathy and deafness. All patients had acidosis and sensorineural deafness. Hearing loss was diagnosed in childhood or adolescence. All were found to have homozygous or compound heterozygous variants in the KCNJ16 gene. 6 different variants were identified, either missense or nonsesnse. Functional studies showed that variants affect the function of heteromeric potassium channels. PMID:33840812 - Webb et al 2021 - report a homozygous loss-of-function variant identified by WES in KCNJ16 in a 2-year-old female with a hypokalemic metabolic acidosis phenotype. Hearing loss is NOT mentioned. Sources: Literature
21 May 2022	Monogenic hearing loss v2.245	KCNJ16	Eleanor Williams gene: KCNJ16 was added gene: KCNJ16 was added to Hearing loss. Sources: Literature watchlist tags were added to gene: KCNJ16. Mode of inheritance for gene: KCNJ16 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KCNJ16 were set to 33811157; 33840812 Phenotypes for gene: KCNJ16 were set to Hypokalemic tubulopathy and deafness, OMIM:619406 Review for gene: KCNJ16 was set to AMBER Added comment: Associated with Hypokalemic tubulopathy and deafness OMIM#619406 (AR) PMID:33811157 - Schlingmann et al 2021 - unable to access publication. Abstract does not give numbers of cases but OMIM states that "In 8 patients, including 1 sib pair, with hypokalemic tubulopathy and deafness, Schlingmann et al. (2021) identified homozygous or compound heterozygous mutations in the KCNJ16 gene". Details of the hearing loss could not be acertained. PMID:33840812 - Webb et al 2021 - report a homozygous loss-of-function variant identified by WES in KCNJ16 in a 2-year-old female with a hypokalemic metabolic acidosis phenotype. Hearing loss is NOT mentioned. Sources: Literature
31 Aug 2021	Monogenic hearing loss v2.181	GJA1	Arina Puzriakova Phenotypes for gene: GJA1 were changed from to Craniometaphyseal dysplasia, autosomal recessive, OMIM:218400
20 Aug 2021	Monogenic hearing loss v2.180	SERAC1	Arina Puzriakova Phenotypes for gene: SERAC1 were changed from 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 614739; MEGDEL syndrome; 3-MEthylGlutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome; MEGDHEL syndrome to 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, OMIM:614739
09 Jun 2021	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
01 Dec 2020	Monogenic hearing loss v2.131	MET	Eleanor Williams Classified gene: MET as Amber List (moderate evidence)
01 Dec 2020	Monogenic hearing loss v2.131	MET	Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber as two cases reported, with segregation data.
01 Dec 2020	Monogenic hearing loss v2.131	MET	Eleanor Williams Gene: met has been classified as Amber List (Moderate Evidence).
01 Dec 2020	Monogenic hearing loss v2.130	MET	Eleanor Williams gene: MET was added gene: MET was added to Hearing loss. Sources: Expert list Mode of inheritance for gene: MET was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MET were set to 25941349; 27717089 Phenotypes for gene: MET were set to Deafness, autosomal recessive 97 OMIM:616705; autosomal recessive nonsyndromic deafness 97 MONDO:0014739 Review for gene: MET was set to AMBER Added comment: Gene suggested by Professor Sadaf Naz, PhD, School of Biological Sciences, University of the Punjab, Pakistan Provisionally associated with ?Deafness, autosomal recessive 97 MIM#616705 in OMIM. 2 cases reported: PMID: 25941349 - Mujtaba et al 2015 - report a large consanguineous Pakistani family with some members affected by hearing loss. They identified, through genome-wide homozygosity mapping and then whole exome sequencing, a homozygous missense variant located in MET (NM_000245.2), c.2521T>G (p.F841V) that segregates with hearing loss in 9 affected individuals. PMID: 27717089 - Alabdullatif et al 2017 - from a review of clinical and molecular data for 227 individuals from a highly consanguineous population who underwent a combined (CGH+SNP) CMA test, they report 2 brothers with hearing loss and arthrogryposis in which a homozygous variant c.3557T>G (p.F1186C) in MET was identified through WES after a region of homozygosity was identified. The first cousin parents were both heterozygous for this variant. They suggest that the arthrogryposis could be a variable feature of the disease or be caused by a second recessive disease not detected in this study. Sources: Expert list
08 Sep 2020	Monogenic hearing loss v2.57	TMTC2	Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM. PMID: 29671961- Guillen‐Ahlers et al 2018 - report a mother and son with of Northern European descent (mother and son) with Sensorineural hearing loss were found by exome sequencing to share a variant (rs35725509, missense variant) in the TMTC2 gene. This variant showed a minor allele frequency below 1% in 2,203 individuals of European American (EA) ancestry (NHLBI GO Exome Sequencing Project. PMID: 27311106 - Runge et al 2016 - report a large multigenerational Northern European family in which 9 family members had bilateral, symmetric, progressive Sensorineural hearing loss that reached severe to profound loss in childhood. Using exome sequencing and linkage and association analyses they identified a fully penetrant sequence variant (rs35725509) in the TMTC2 gene region. The variant segregates with SNHL in the family. However, the mutation is found in a relatively high percentage of individuals of Northern European descent in the 1000 Genomes and Exome Sequencing (http://evs.gs.washington.edu/EVS/) European call sets (1% and 0.8%, respectively).; to: Not associated with a phenotype in OMIM. PMID: 29671961- Guillen‐Ahlers et al 2018 - report a mother and son with of Northern European descent (mother and son) with Sensorineural hearing loss were found by exome sequencing to share a variant (rs35725509, missense variant) in the TMTC2 gene. This variant showed a minor allele frequency below 1% in 2,203 individuals of European American (EA) ancestry (NHLBI GO Exome Sequencing Project. In two generations, the trait has been passed through the maternal side PMID: 27311106 - Runge et al 2016 - report a large multigenerational Northern European family in which 9 family members had bilateral, symmetric, progressive Sensorineural hearing loss that reached severe to profound loss in childhood. Using exome sequencing and linkage and association analyses they identified a fully penetrant sequence variant (rs35725509) in the TMTC2 gene region. The variant segregates with SNHL in the family. However, the mutation is found in a relatively high percentage of individuals of Northern European descent in the 1000 Genomes and Exome Sequencing (http://evs.gs.washington.edu/EVS/) European call sets (1% and 0.8%, respectively).
07 Aug 2019	Monogenic hearing loss v1.122	GJB2	Eleanor Williams edited their review of gene: GJB2: Added comment: Adding publication PMID: 31160754 Shen et al 2019 Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel as additional information.; Changed rating: AMBER; Changed publications: 31160754
17 Feb 2019	Monogenic hearing loss v1.76	KITLG	Eleanor Williams Phenotypes for gene: KITLG were changed from to Deafness, autosomal dominant 69, unilateral or asymmetric 616697
12 Feb 2019	Monogenic hearing loss v1.56	HTRA2	Anna de Burca reviewed gene: HTRA2: Rating: RED; Mode of pathogenicity: None; Publications: 27208207, 27696117; Phenotypes: Infantile neurodegeneration and 3-methylglutaconic aciduria; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal