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Monogenic hearing loss v6.32 COL4A6 Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu).

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15.
Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss.

Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP).; to: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). Parents unaffected, not genotyped.

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15.
Both variants were inherited from heterozygous affected mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss.

Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP).
Monogenic hearing loss v6.30 COL4A6 Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu).

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15.
Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss.

Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026).; to: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu).

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15.
Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss.

Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP).
Monogenic hearing loss v6.30 COL4A6 Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu).

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951 + 1 G > T leads to skipping of exon 15.
Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 varinats in the two kindreds, which are also likely to contribute to hearing loss.

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026).; to: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu).

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15.
Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss.

Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026).
Monogenic hearing loss v6.26 ZBTB20 Ida Ertmanska changed review comment from: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).
Sources: Literature; to: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).

https://www.ncbi.nlm.nih.gov/books/NBK570205/ - Primrose syndrome GeneReviews entry mentions 52 reported individuals. Skeletal abnormalities are not noted to be the main characteristic features. Some patients present with scoliosis and skull specific abormalities e.g., wormian bones, without wider skeletal involvement. The primary features consistent in most cases are: intellectual disability (100%), hearing loss (83%), dysmorphic facial features (>70%), hypotonia (76%), and autism (70%), with many other less specific features.

ZBTB20 is associated with AD Primrose syndrome, OMIM:259050 (OMIM accessed 7th July 2026).
Sources: Literature
Monogenic hearing loss v6.26 ZBTB20 Ida Ertmanska gene: ZBTB20 was added
gene: ZBTB20 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: ZBTB20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB20 were set to 32473227
Phenotypes for gene: ZBTB20 were set to Primrose syndrome, OMIM:259050; Primrose syndrome, MONDO:0009798; intellectual disability-cataracts-calcified pinnae-myopathy syndrome
Review for gene: ZBTB20 was set to AMBER
Added comment: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).
Sources: Literature
Monogenic hearing loss v6.22 CLRN2 Ida Ertmanska changed review comment from: PMID: 39446282 Ahmad et al., 2025
Consanguineous family, 2 sibs with non-syndromic profound hearing loss, homozygous for CLRN2: c.414C>A, p.Cys138*. Seq method: WES + Sanger. Variant has 1 allele reported in gnomAD (no homozygotes). Parents both heterozygous for the variant and unaffected.

PMID: 33496845 (Vona et al 2021): Clrn2 mouse mutant, in which exon 2 has been deleted (Clrn2del629). Clrn2del629/del629 mice exhibit a severe-to-profound hearing loss affecting all frequencies tested.

The association between CLRN2 and AR nonsyndromic genetic hearing loss was classified as Moderate in ClinGen (Hearing Loss GCEP, Sept 2025).; to: PMID: 39446282 Ahmad et al., 2025
Consanguineous family, 2 sibs with non-syndromic profound hearing loss, homozygous for CLRN2: c.414C>A, p.Cys138*. Seq method: WES + Sanger. Variant has 1 allele reported in gnomAD (no homozygotes). Parents both heterozygous for the variant and unaffected.

PMID: 33496845 Vona et al 2021
Iranian family, where homozygous CLRN2: c.494C > A, p.Thr165Lys variant (expected to result in p.(Gly146Lysfs*26)) change) segregated with non-syndromic hearing loss.
Clrn2 mouse mutant, in which exon 2 has been deleted (Clrn2del629). Clrn2del629/del629 mice exhibit a severe-to-profound hearing loss affecting all frequencies tested.

The association between CLRN2 and AR nonsyndromic genetic hearing loss was classified as Moderate in ClinGen (Hearing Loss GCEP, Sept 2025).
Monogenic hearing loss v6.21 CLRN2 Ida Ertmanska changed review comment from: PMID: 39446282 Ahmad et al., 2025
Consanguineous family, 2 sibs with non-syndromic profound hearing loss, homozygous for CLRN2: c.414C>A, p.Cys138*. Seq method: WES + Sanger. Variant has 1 allele reported in gnomAD (no homozygotes). Parents both heterozygous for the variant and unaffected.

The association between CLRN2 and AR nonsyndromic genetic hearing loss was classified as Moderate in ClinGen (Hearing Loss GCEP, Sept 2025).; to: PMID: 39446282 Ahmad et al., 2025
Consanguineous family, 2 sibs with non-syndromic profound hearing loss, homozygous for CLRN2: c.414C>A, p.Cys138*. Seq method: WES + Sanger. Variant has 1 allele reported in gnomAD (no homozygotes). Parents both heterozygous for the variant and unaffected.

PMID: 33496845 (Vona et al 2021): Clrn2 mouse mutant, in which exon 2 has been deleted (Clrn2del629). Clrn2del629/del629 mice exhibit a severe-to-profound hearing loss affecting all frequencies tested.

The association between CLRN2 and AR nonsyndromic genetic hearing loss was classified as Moderate in ClinGen (Hearing Loss GCEP, Sept 2025).
Monogenic hearing loss v6.16 CD164 Ida Ertmanska changed review comment from: PMID: 35254497 Oziębło et al., 2022
Family 1 - large Polish pedigree with AD progressive hearing loss; CD164: c.574C>T, p.Arg192Ter segregated in affected individuals
Family 2 - Korean family, 25 yo proband with bilateral progressive hearing loss onset around 22 years old; also het for CD164 p.Arg192Ter
Same variant as reported in PMID 26197441 Nyegaard et al (2015) in a Danish family with hearing loss - recurrent hot spot mutation?
CD164: c.574C>T, p.Arg192Ter - only 2 hets reported in gnomAD v4.1.1, MAF = 0.000001696
Age of onset of hearing loss for all 3 families ranged from newborn stage to adulthood.

PMID: 36454368 Moresco et al., 2023
Family 7 - AD nonsyndromic hearing loss, affected individuals harboured het CD164: c.574C>T, p.Arg192Ter variant - segregated with disease. Seq method: Trio WES.; to: PMID: 35254497 Oziębło et al., 2022
Family 1 - large Polish pedigree with AD progressive hearing loss; CD164: c.574C>T, p.Arg192Ter segregated in affected individuals
Family 2 - Korean family, 25 yo proband with bilateral progressive hearing loss onset around 22 years old; also het for CD164 p.Arg192Ter
Same variant as reported in PMID 26197441 Nyegaard et al (2015) in a Danish family with hearing loss - recurrent hot spot mutation?
CD164: c.574C>T, p.Arg192Ter - only 2 hets reported in gnomAD v4.1.1, MAF = 0.000001696
Age of onset of hearing loss for all 3 families ranged from newborn stage to adulthood.

PMID: 36454368 Moresco et al., 2023
Family 7 - AD nonsyndromic hearing loss, affected individuals harboured het CD164: c.574C>T, p.Arg192Ter variant - segregated with disease. Seq method: Trio WES.

The assocation between CD164 and autosomal dominant nonsyndromic hearing loss has been classified as Moderate by ClinGen Hearing Loss GCEP in 2024.
Monogenic hearing loss v6.16 COL11A1 Ida Ertmanska changed review comment from: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C which affects splicing of exon 9 (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."
"While exon 9 is expressed in both vitreous and immature chondrocytes, it is not expressed in mature chondrocytes" - so any variants affecting exon 9 do not cause fibrochondrogenesis, but a Stickler syndrome phenotype with severe hearing loss.

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous exon 9 c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband of European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss. ; to: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C which affects splicing of exon 9 (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."
"While exon 9 is expressed in both vitreous and immature chondrocytes, it is not expressed in mature chondrocytes" - apart from inner ear cartilage - so any variants affecting exon 9 do not cause fibrochondrogenesis, but a Stickler syndrome phenotype with severe hearing loss.

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous exon 9 c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband of European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss.
Monogenic hearing loss v6.15 COL11A1 Ida Ertmanska changed review comment from: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband, European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss. ; to: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C which affects splicing of exon 9 (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."
"While exon 9 is expressed in both vitreous and immature chondrocytes, it is not expressed in mature chondrocytes" - so any variants affecting exon 9 do not cause fibrochondrogenesis, but a Stickler syndrome phenotype with severe hearing loss.

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous exon 9 c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband of European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss.
Monogenic hearing loss v6.15 COL11A1 Ida Ertmanska changed review comment from: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband, European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss. ; to: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband, European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss.
Monogenic hearing loss v6.15 COL11A1 Ida Ertmanska changed review comment from: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C.
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively.
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.; to: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband, European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss.
Monogenic hearing loss v6.13 DSPP Ida Ertmanska changed review comment from: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI), both het for DSPP variant c.49C>A (p.Pro17Thr). Method: linkage analysis, followed by DSPP sequencing.

PMID: 17686168
Chinese family with DI and the same DSPP residue mutated as in PMID: 11175790 (c.49C>T, p.Pro17Ser), and no hearing loss.

PMID: 29741433 Li ey al., 2018
Proband with Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II, harboured DSPP c.3085A>G, p.Asn1029Asp and c.3087C>T, p.Asn1029= variants in cis. Method: WGS of proband and 7 family members. 3 affected individuals: father and his two male sons (twins), all with the same DSPP allele.
Both DSPP variants have high gnomAD frequencies in East Asian population (0.01039 and 0.009011), with homozygous individuals also reported; p.Asn1029Asp is Likely Benign in ClinVar - unlikely to be causal.

PMID: 33229591 Boucher et al., 2020
Age-related hearing loss cohort. Patient 6708 - harboured a c.776C > T; p.(Ser259Phe) variant in DSPP.

Hearing loss has not been mentioned as a feature in numerous other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025).; to: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI), both het for DSPP variant c.49C>A (p.Pro17Thr). Method: linkage analysis, followed by DSPP sequencing.

PMID: 17686168
Chinese family with DI and the same DSPP residue mutated as in PMID: 11175790 (c.49C>T, p.Pro17Ser), and no hearing loss.

PMID: 29741433 Li et al., 2018
Chinese proband with Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II, harboured DSPP c.3085A>G, p.Asn1029Asp and c.3087C>T, p.Asn1029= variants in cis. Method: WGS of proband and 7 family members. 3 affected individuals: father and his two male sons (twins), all with the same DSPP allele.
Both DSPP variants have high gnomAD frequencies in East Asian population (0.01039 and 0.009011), with homozygous individuals also reported; p.Asn1029Asp is Likely Benign in ClinVar - unlikely to be causal.

PMID: 33229591 Boucher et al., 2020
Age-related hearing loss cohort. Patient 6708 - harboured a c.776C > T; p.(Ser259Phe) variant in DSPP.

Hearing loss has not been mentioned as a feature in numerous other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025).
Monogenic hearing loss v6.13 DSPP Ida Ertmanska changed review comment from: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI).

Hearing loss has not been reported in any other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025); to: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI), both het for DSPP variant c.49C>A (p.Pro17Thr). Method: linkage analysis, followed by DSPP sequencing.

PMID: 17686168
Chinese family with DI and the same DSPP residue mutated as in PMID: 11175790 (c.49C>T, p.Pro17Ser), and no hearing loss.

PMID: 29741433 Li ey al., 2018
Proband with Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II, harboured DSPP c.3085A>G, p.Asn1029Asp and c.3087C>T, p.Asn1029= variants in cis. Method: WGS of proband and 7 family members. 3 affected individuals: father and his two male sons (twins), all with the same DSPP allele.
Both DSPP variants have high gnomAD frequencies in East Asian population (0.01039 and 0.009011), with homozygous individuals also reported; p.Asn1029Asp is Likely Benign in ClinVar - unlikely to be causal.

PMID: 33229591 Boucher et al., 2020
Age-related hearing loss cohort. Patient 6708 - harboured a c.776C > T; p.(Ser259Phe) variant in DSPP.

Hearing loss has not been mentioned as a feature in numerous other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025).
Monogenic hearing loss v6.6 LOXL3 Ida Ertmanska changed review comment from: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature; to: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence:
PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
PMID: 34150778 Liu et al., 2021 - targeted deletion of Loxl3 in the inner ear caused progressive hearing loss, degeneration of hair cells and secondary degeneration of spiral ganglion neurons in mouse.
Sources: Literature
Monogenic hearing loss v6.5 LOXL3 Ida Ertmanska gene: LOXL3 was added
gene: LOXL3 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOXL3 were set to 25663169; 30362103; 36610533; 36917121; 38957076; 41052910
Phenotypes for gene: LOXL3 were set to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354
Review for gene: LOXL3 was set to GREEN
Added comment: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature
Monogenic hearing loss v6.4 CLIC5 Ida Ertmanska changed review comment from: ADDITIONAL CASES SINCE 2019:

PMID: 40957967 Pshennikova et al., 2026
Founder variant in Eastern Siberia: CLIC5 c.644 G>A p.(Trp215*) causes progressive AR deafness. Found in homozygous state in 22 patients from 16 unrelated families in Siberia (Russia). Hearing loss was sensorineural, symmetrical and variable by severity (from moderate to profound). Founder calculated to have arisen 78 generations ago.

PMID: 40928595 Jagannath et al., 2025
Cohort of 105 Indian individuals with hearing loss. Family 19 - proband with congenital bilateral severe-to-profound sensorineural hearing loss, homozygous for variant (CLIC5):c.401A > G, (p.Asn134Ser) - only 1 het individual in gnomAD v4.1.1. Heterozygous family members unaffected. Method: Exome seq + Sanger. *Assessed to be VUS by ACMG criteria in the article.

PMID: 33114113 Wonkam-Tingang et al., 2020
Report of a Cameroonian family with non-syndromic hearing impairment and biallelic CLIC5 variants NM_016929.5:c.224T>C; p.(L75P) and NM_016929.5: c.63+1G>A. The variants segregated with disease, with 3 affected family members carrying both variants, and other individuals being unaffected if WT or carrying one of the mutations. The 3 affected sibs were 25-36 years old, no age of onset given.; to: ADDITIONAL CASES SINCE 2019:

PMID: 40957967 Pshennikova et al., 2026
Founder variant in Eastern Siberia: CLIC5 c.644 G>A p.(Trp215*) causes progressive AR deafness. Found in homozygous state in 22 patients from 16 unrelated families in Siberia (Russia). Hearing loss was sensorineural, symmetrical and variable by severity (from moderate to profound). Founder calculated to have arisen 78 generations ago. Method: WES + Sanger.

PMID: 40928595 Jagannath et al., 2025
Cohort of 105 Indian individuals with hearing loss. Family 19 - proband with congenital bilateral severe-to-profound sensorineural hearing loss, homozygous for variant (CLIC5):c.401A > G, (p.Asn134Ser) - only 1 het individual in gnomAD v4.1.1. Heterozygous family members unaffected. Method: Exome seq + Sanger. *Assessed to be VUS by ACMG criteria in the article.

PMID: 33114113 Wonkam-Tingang et al., 2020
Report of a Cameroonian family with non-syndromic hearing impairment and biallelic CLIC5 variants NM_016929.5:c.224T>C; p.(L75P) and NM_016929.5: c.63+1G>A. The variants segregated with disease, with 3 affected family members carrying both variants, and other individuals being unaffected if WT or carrying one of the mutations. The 3 affected sibs were 25-36 years old, no age of onset given.
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.(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).; 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.(Gly71Alafs*36); 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).
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).
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).
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.(Asp326Alafs*42) and c.987delC p.(Ala330Argfs*38) 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; 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.(Asp326Alafs*42) and c.987delC p.(Ala330Argfs*38) 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
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.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).; 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.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).

ARSG is associated with AR Usher syndrome, type IV, 618144 in OMIM (accessed 27th 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.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).; 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.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).
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.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).; 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.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).
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.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).
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
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
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.Leu752Serfs*26). 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.Leu752Serfs*26). 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).
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.Leu752Serfs*26). 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.Leu752Serfs*26). 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
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.Leu752Serfs*26). 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.Leu752Serfs*26). 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
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.Leu752Serfs*26). 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.Leu752Serfs*26). 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
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.Leu752Serfs*26). 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
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.(Asp326Alafs*42) and c.987delC p.(Ala330Argfs*38) 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
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
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
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
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
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
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
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
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
Monogenic hearing loss v2.181 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from to Craniometaphyseal dysplasia, autosomal recessive, OMIM:218400
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
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
Monogenic hearing loss v2.131 MET Eleanor Williams Classified gene: MET as Amber List (moderate evidence)
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.
Monogenic hearing loss v2.131 MET Eleanor Williams Gene: met has been classified as Amber List (Moderate Evidence).
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
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).
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
Monogenic hearing loss v1.76 KITLG Eleanor Williams Phenotypes for gene: KITLG were changed from to Deafness, autosomal dominant 69, unilateral or asymmetric 616697
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