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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 v5.38 PTRH2 Achchuthan Shanmugasundram changed review comment from: PMID:25574476 (2014) reported a consanguineous family of Yazidian-Turkish descent infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). The two affected children presented with intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. They were identified with a homozygous frameshift variant in PTRH2 gene.

PMID:25558065 (2015) reported a patient with global developmental delay, hearing loss, and ataxia and was identified with a homozygous missense variant PTRH2 gene.

PMID:27129381 (2016) reported the identification of a different homozygous missense variant in five further IMNEPD patients from two different families of Tunisian and Saudi Arabian descent. Sensorineural hearing impairment was present in all five reported patients.

PMID:31057140 (2019) reported three brothers of Syrian descent with a novel homozygous stop-gain variant in PTRH2 gene presenting with IMNEPD. All three had hearing loss.

This gene has been associated with IMNEPD in OMIM (MIM #616263, OMIM accessed on 24 October 2025), which includes sensorineural deafness as one of the clinical manifestations.
Sources: Literature; to: PMID:25574476 (2014) reported a consanguineous family of Yazidian-Turkish descent infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). The two affected children presented with intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. They were identified with a homozygous frameshift variant in PTRH2 gene.

PMID:25558065 (2015) reported a patient with global developmental delay, hearing loss, and ataxia and was identified with a homozygous missense variant PTRH2 gene.

PMID:27129381 (2016) reported the identification of a different homozygous missense variant in five further IMNEPD patients from two different families of Tunisian and Saudi Arabian descent. Sensorineural hearing impairment was present in all five reported patients.

PMID:31057140 (2019) reported three brothers of Syrian descent with a novel homozygous stop-gain variant in PTRH2 gene presenting with IMNEPD. All three had hearing loss.

This gene has been associated with IMNEPD in OMIM (MIM #616263, OMIM accessed on 24 October 2025), which includes sensorineural deafness as one of the clinical manifestations. This gene is also associated with relevant phenotypes on the DD panel of Gene2Phenotype with 'definitive' rating.
Sources: Literature
Monogenic hearing loss v5.38 PTRH2 Achchuthan Shanmugasundram gene: PTRH2 was added
gene: PTRH2 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: PTRH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTRH2 were set to 25574476; 25558065; 27129381; 31057140
Phenotypes for gene: PTRH2 were set to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
Review for gene: PTRH2 was set to GREEN
Added comment: PMID:25574476 (2014) reported a consanguineous family of Yazidian-Turkish descent infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). The two affected children presented with intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. They were identified with a homozygous frameshift variant in PTRH2 gene.

PMID:25558065 (2015) reported a patient with global developmental delay, hearing loss, and ataxia and was identified with a homozygous missense variant PTRH2 gene.

PMID:27129381 (2016) reported the identification of a different homozygous missense variant in five further IMNEPD patients from two different families of Tunisian and Saudi Arabian descent. Sensorineural hearing impairment was present in all five reported patients.

PMID:31057140 (2019) reported three brothers of Syrian descent with a novel homozygous stop-gain variant in PTRH2 gene presenting with IMNEPD. All three had hearing loss.

This gene has been associated with IMNEPD in OMIM (MIM #616263, OMIM accessed on 24 October 2025), which includes sensorineural deafness as one of the clinical manifestations.
Sources: Literature
Monogenic hearing loss v5.37 SIX5 Arina Puzriakova Phenotypes for gene: SIX5 were changed from Branchiootorenal syndrome 2, 610896 to Branchiootorenal syndrome 2, OMIM:610896
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 v4.56 RFC4 Achchuthan Shanmugasundram gene: RFC4 was added
gene: RFC4 was added to Monogenic hearing loss. Sources: Literature
Q3_24_promote_green tags were added to gene: RFC4.
Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFC4 were set to 39106866
Phenotypes for gene: RFC4 were set to sensorineural hearing loss disorder, MONDO:0020678
Review for gene: RFC4 was set to GREEN
Added comment: PMID:39106866 reported nine individuals (aged birth to 47 years) from eight unrelated families with a multisystem disorder.

They presented with muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9).

They were identified with biallelic loss-of-function variants in RFC4 gene (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions and 2 missense)

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Monogenic hearing loss v4.23 PSMC3 Achchuthan Shanmugasundram gene: PSMC3 was added
gene: PSMC3 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC3 were set to 32500975; 37256937
Phenotypes for gene: PSMC3 were set to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092; autosomal dominant nonsyndromic hearing loss, MONDO:0019587
Review for gene: PSMC3 was set to GREEN
Added comment: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. They were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.

PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). 9/19 patients had hearing loss, of which two were labelled as sensorineural and one was labelled as conductive. In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.

The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.
Sources: Literature
Monogenic hearing loss v2.125 PMP22 Eleanor Williams changed review comment from: Associated with Charcot-Marie-Tooth disease, type 1E #118300 (AD) in which hearing loss is listed as a clinical feature

PMID: 12578939 - Sambuughin et al 2003 - report deafness associated with a demyelinating neuropathy in three individuals of a family in whom a novel 12bp deletion resulting in the deletion of four-amino acid deletion (115-118) in the PMP22 gene was identified (targeted sequencing of PMP22). No asymptomatic family members had the deletion nor was it detected in 55 healthy controls.

PMID: 11835375 - Boerkoel et al 2002 - screened PMP22, GJB1, and MPZ contained 159 unrelated patients with primary peripheral demyelinating neuropathy or a primary peripheral axonal neuropathy and report 5 which have heterozygous variants in PMP22, 1 of which had a clinical diagnosis of CMT1 + deafness (variant 82T>C W28R). An affected sibling had the same variant.

PMID: 10330345 - Kovach et al 1999 - analysis of a 7 generation family from central Illinois with autosomal dominant CMT and deafness. In the 31 affected family members, hearing loss ranged from borderline normal to profound hearing loss, with all having at least mild bilateral hearing loss by adulthood. Following haplotype analysis they sequenced PMP22 and a point mutation was found in affected individuals G->C at position 248 in exon 4 in the heterozygous state (p.Ala67Pro).

PMID: 8355122 - Hamiel et al 1993 - Abstract only accessed. Describe a family with hereditary motor-sensory neuropathy with sensorineural deafness is described; the neurologic features and deafness were apparent in early childhood and infancy.

Summary: 3 cases in which hearing loss is reported in CMT patients with PMP22 variants. In all cases a limited number of genes were sequenced.; to: Associated with Charcot-Marie-Tooth disease, type 1E #118300 (AD) in which hearing loss is listed as a clinical feature

PMID: 12578939 - Sambuughin et al 2003 - report deafness associated with a demyelinating neuropathy in three individuals of a family in whom a novel 12bp deletion resulting in the deletion of four-amino acid deletion (115-118) in the PMP22 gene was identified (targeted sequencing of PMP22). No asymptomatic family members had the deletion nor was it detected in 55 healthy controls.

PMID: 11835375 - Boerkoel et al 2002 - screened PMP22, GJB1, and MPZ in 159 unrelated patients with primary peripheral demyelinating neuropathy or a primary peripheral axonal neuropathy and report 5 which have heterozygous variants in PMP22, 1 of which had a clinical diagnosis of CMT1 + deafness (variant 82T>C W28R). An affected sibling had the same variant.

PMID: 10330345 - Kovach et al 1999 - analysis of a 7 generation family from central Illinois with autosomal dominant CMT and deafness. In the 31 affected family members, hearing loss ranged from borderline normal to profound hearing loss, with all having at least mild bilateral hearing loss by adulthood. Following haplotype analysis they sequenced PMP22 and a point mutation was found in affected individuals G->C at position 248 in exon 4 in the heterozygous state (p.Ala67Pro).

PMID: 8355122 - Hamiel et al 1993 - Abstract only accessed. Describe a family with hereditary motor-sensory neuropathy with sensorineural deafness is described; the neurologic features and deafness were apparent in early childhood and infancy.

Summary: 3 cases in which hearing loss is reported in CMT patients with PMP22 variants. In all cases a limited number of genes were sequenced.
Monogenic hearing loss v2.96 PMP22 Eleanor Williams changed review comment from: Associated with Charcot-Marie-Tooth disease, type 1E #118300 (AD) in which hearing loss is listed as a clinical feature

PMID: 12578939 - Sambuughin et al 2003 - report deafness associated with a demyelinating neuropathy in three individuals of a family in whom a novel 12bp deletion resulting in the deletion of four-amino acid deletion (115-118) in the PMP22 gene was identified. No asymptomatic family members had the deletion nor was it detected in 55 healthy controls.

PMID: 11835375 - Boerkoel et al 2002 - screened PMP22, GJB1, and MPZ contained 159 unrelated patients with primary peripheral demyelinating neuropathy or a primary peripheral axonal neuropathy and report 5 which have heterozygous variants in PMP22, 1 of which had a clinical diagnosis of CMT1 + deafness (variant 82T>C W28R). An affected sibling had the same variant.

PMID: 10330345 - Kovach et al 1999 - analysis of a 7 generation family from central Illinois with autosomal dominant CMT and deafness. In the 31 affected family members, hearing loss ranged from borderline normal to profound hearing loss, with all having at least mild bilateral hearing loss by adulthood. A point mutation was found in affected individuals G->C at position 248 in exon 4 in the heterozygous state (p.Ala67Pro).

PMID: 8355122 - Hamiel et al 1993 - Abstract only accessed. Describe a family with hereditary motor-sensory neuropathy with sensorineural deafness is described; the neurologic features and deafness were apparent in early childhood and infancy.

Summary: 3 cases in which hearing loss is reported in CMT patients with PMP22 variants.; to: Associated with Charcot-Marie-Tooth disease, type 1E #118300 (AD) in which hearing loss is listed as a clinical feature

PMID: 12578939 - Sambuughin et al 2003 - report deafness associated with a demyelinating neuropathy in three individuals of a family in whom a novel 12bp deletion resulting in the deletion of four-amino acid deletion (115-118) in the PMP22 gene was identified (targeted sequencing of PMP22). No asymptomatic family members had the deletion nor was it detected in 55 healthy controls.

PMID: 11835375 - Boerkoel et al 2002 - screened PMP22, GJB1, and MPZ contained 159 unrelated patients with primary peripheral demyelinating neuropathy or a primary peripheral axonal neuropathy and report 5 which have heterozygous variants in PMP22, 1 of which had a clinical diagnosis of CMT1 + deafness (variant 82T>C W28R). An affected sibling had the same variant.

PMID: 10330345 - Kovach et al 1999 - analysis of a 7 generation family from central Illinois with autosomal dominant CMT and deafness. In the 31 affected family members, hearing loss ranged from borderline normal to profound hearing loss, with all having at least mild bilateral hearing loss by adulthood. Following haplotype analysis they sequenced PMP22 and a point mutation was found in affected individuals G->C at position 248 in exon 4 in the heterozygous state (p.Ala67Pro).

PMID: 8355122 - Hamiel et al 1993 - Abstract only accessed. Describe a family with hereditary motor-sensory neuropathy with sensorineural deafness is described; the neurologic features and deafness were apparent in early childhood and infancy.

Summary: 3 cases in which hearing loss is reported in CMT patients with PMP22 variants. In all cases a limited number of genes were sequenced.
Monogenic hearing loss v2.14 SLC52A2 Eleanor Williams commented on gene: SLC52A2: Associated with Brown-Vialetto-Van Laere syndrome 2 #614707 (AR) in OMIM. Early childhood onset of sensorineural deafness is a feature along with bulbar dysfunction, and severe diffuse muscle weakness and wasting of the upper and lower limbs and axial muscles, resulting in respiratory insufficiency.

Numerous cases have been reported with variants in the SLC52A2 gene and Brown-Vialetto-Van Laere syndrome 2:

PMID: 22740598 Johnson et al 2012 - used linkage and exome sequencing to identify a novel mutation (p.G306R (c.916G>A)) in SLC52A2 in an extended Lebanese Brown-Vialetto-Van Laere kindred. The same homozygous mutation was identified in one additional subject from the UK, from 44 screened.

PMID: 22864630 Haack et al 2012 - exome sequencing of a single case with Brown-Vialetto-Van Laere syndrome showed compound heterozygosity for two pathogenic mutations in the SLC52A2 gene. Overexpression studies confirmed that the gene products of both mutant alleles have reduced riboflavin transport activities.

PMID: 23243084 Ciccolella et al 2013 - 1 case of a severe BVVL patient with two novel compound heterozygous mutations in SLC52A2 (c.155C>T, p.S52F and c.1255G>A, p.G419S). Functional studies show that these variants impair the gene expression of the corresponding transporter, resulting in a significant reduction of riboflavin transport.

PMID: 24253200 Foley et al 2014 - using exome and sanger sequencing identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy, hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression.
Monogenic hearing loss v2.4 SIX5 Zornitza Stark reviewed gene: SIX5: Rating: RED; Mode of pathogenicity: None; Publications: 17357085, 24429398, 21280147, 14704431, 17357085, 11950062; Phenotypes: Branchiootorenal syndrome 2, MIM#610896; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted