FHIP2A and Intellectual Disability

This summary details the limited but emerging evidence linking FHIP2A (HGNC:29320) to intellectual disability (MONDO:0001071). A case report in a consanguineous family described a 38‐year‑old patient with severe intellectual disability, microcephaly, ataxia, behavioral abnormalities, and speech problems, in whom a homozygous early truncating variant, c.115G>T (p.Glu39Ter) (PMID:31353455), was identified. A second report described a homozygous missense change in a similarly affected 7‑year‑old, further supporting a link between loss‑of‑function alleles in FHIP2A and a syndromic intellectual disability phenotype.

The genetic evidence shows an autosomal recessive inheritance pattern with two affected probands harboring biallelic variants. The identification of a truncating variant, c.115G>T (p.Glu39Ter), in one family and a missense change in another aligns with a loss‐of‐function mechanism. However, the total number of probands and lack of extensive segregation data limit the overall evidence to a limited strength tier (PMID:31353455).

Multi‐patient genomic studies have also flagged FHIP2A as a candidate gene among a broad panel associated with intellectual disability (PMID:27431290). Although these larger cohort studies add weight to the association, the specific evidence for FHIP2A remains scarce and does not yet reach the threshold for a strong classification.

Functional evidence directly supporting the pathogenic mechanism of FHIP2A in neurodevelopment is currently lacking. No experimental studies or animal/cellular models have been reported that clarify how loss of FHIP2A function disrupts nervous system development. As such, functional evidence is considered absent at this time.

In summary, while the genetic data from two independent probands and supportive cohort analyses point to a role for FHIP2A in intellectual disability, the limited number of cases and absence of experimental validation confine the association to a limited evidence tier. Future studies, including segregation analyses and functional assays, are required to substantiate and refine this association.

Key take‑home sentence: FHIP2A represents a promising candidate in the etiology of intellectual disability, but further genetic and functional evidence is needed to establish its clinical utility.

References

• Clinical Genetics • 2019 • FAM160B1 deficit associated with microcephaly, severe intellectual disability, ataxia, behavioral abnormalities and speech problems PMID:31353455
• Molecular Psychiatry • 2017 • Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield PMID:27431290

Evidence Based Scoring (AI generated)