Ataxia and cerebellar anomalies - narrow panel

Gene: ATOH1

Green List (high evidence)

Comment on list classification: There are 6 unrelated families with heterozygous ATOH1 variants, presenting with hearing loss. Subtle cerebellar symptoms were present in 4/6 patients. In addition, 4 individuals from 3 unrelated families have been reported with biallelic ATOH1 variants, presenting with pontocerebellar hypoplasia. Functional evidence from mouse models supports this gene-disease assiociation - atoh1-/- knockout mice lack cerebellar granule neurons. Based on available evidence, this gene should be promoted to Green on Ataxia and cerebellar anomalies - narrow panel, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 23 Feb 2026, 4:51 p.m. | Last Modified: 23 Feb 2026, 4:58 p.m.

Panel Version: 8.62

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 a lack of cerebellar granule neurons, resulting in hearing impairment, cerebellar and cochlear malformations, and death (PMID: 9367153, Ben-Arie et al., 1997. ATOH1 previously known as MATH1).

ATOH1 is putatively linked to ?Deafness, autosomal dominant 89, MIM:620284 in OMIM (accessed 23rd Feb 2026).

Created: 23 Feb 2026, 4:37 p.m. | Last Modified: 23 Feb 2026, 4:58 p.m.

Panel Version: 8.62

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
?Deafness, autosomal dominant 89 , OMIM:620284; hearing loss, autosomal dominant 89, MONDO:0859528; pontocerebellar hypoplasia, MONDO:0020135

Publications

• 9367153
• 21146598
• 33111345
• 35518571
• 41592563