ATOH1 – Intellectual Disability

This summary reviews the association between ATOH1 and intellectual disability, focusing on a report of a biallelic missense variant found in a family with two affected siblings. The index case identified a homozygous variant, c.481C>G (p.Arg161Gly), that segregated with a phenotype including intellectual disability, pontocerebellar hypoplasia, and hearing loss (PMID:35518571).

In the reported case, the autosomal recessive inheritance pattern is supported by segregation analysis, where the variant was identified in both siblings, indicating that an affected family member harbors this change (PMID:35518571). Though the evidence is derived from a single family, it provides an important clue towards the pathogenic role of ATOH1 in this patient subset.

Further support comes from a multi‐patient study of intellectual disability where ATOH1 was highlighted among candidate genes. In this larger cohort analysis, while many genes were evaluated, ATOH1 emerged as a rare variant in the context of recessive inheritance, thereby complementing the case report data (PMID:27431290).

Genetic evidence for this association is based on the identification of the c.481C>G (p.Arg161Gly) variant that disrupts the evolutionarily conserved DNA-binding bHLH domain. Although the total number of unrelated probands remains limited, the segregation data in the reported family and candidate hits in larger studies provide a preliminary genetic link between ATOH1 and intellectual disability.

Functional studies support the gene’s role in neurodevelopment. Structural modeling of the p.Arg161Gly variant indicates disruption of a critical salt bridge with the DNA backbone, which likely compromises the transcription factor activity of ATOH1. Additional experimental studies in animal models and cellular assays have demonstrated that alterations in ATOH1 can impair normal neural and inner ear development, which may contribute to the complex neurodevelopmental phenotype observed (PMID:19011097, PMID:25412697).

No major conflicting evidence has been reported; however, the available data are limited by the small number of affected individuals. Further case series and functional validation will be required to definitively establish this association beyond the candidate gene status.

In summary, ATOH1 shows emerging evidence for its role in intellectual disability based on a combination of genetic and functional data. While the association is currently classified as limited by ClinGen criteria, it provides a useful diagnostic consideration and lays the foundation for further investigation.

Key Take‑home sentence: Despite limited case numbers, the integrated genetic and functional evidence underscores the clinical utility of ATOH1 in the diagnostic evaluation of patients with intellectual disability.

References

• Neurology. Genetics • 2022 • Biallelic ATOH1 Gene Variant in Siblings With Pontocerebellar Hypoplasia, Developmental Delay, and Hearing Loss PMID:35518571
• Molecular Psychiatry • 2017 • Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield PMID:27431290
• Proceedings of the National Academy of Sciences of the United States of America • 2008 • Sox2 signaling in prosensory domain specification and subsequent hair cell differentiation in the developing cochlea PMID:19011097
• Biology of the Cell • 2015 • Molecular cloning and functional characterisation of chicken Atonal homologue 1: a comparison with human Atoh1 PMID:25412697

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