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FHOD1 – Congenital Hypotrichosis with Juvenile Macular Dystrophy

A recent study identified a missense variant, c.1306A>G (p.Arg436Gly), in FHOD1 in a large consanguineous family with congenital hypotrichosis with juvenile macular dystrophy. Twelve affected individuals were reported with this variant segregating in an autosomal recessive pattern, with 18 out of 19 obligate carriers being heterozygous (PMID:31560841). Although bioinformatic predictions supported a damaging effect, the genetic evidence is partially offset by conflicting functional data. Specifically, a CRISPR/Cas knock‑in mouse model harboring the variant failed to recapitulate the disease phenotype (PMID:31560841). These findings illustrate a critical discordance between strong segregation data and negative in vivo functional outcomes.

Further experimental assessments have explored FHOD1’s role in cytoskeletal regulation, notably showing that FHOD1 interacts with Rac1, a key regulator in actin dynamics (PMID:11590143). However, while these biochemical insights may hint at a potential mechanism, they do not clarify the pathogenicity of the FHOD1 variant in the context of congenital hypotrichosis with juvenile macular dystrophy. Overall, the combined genetic and experimental evidence produces a limited evaluation of FHOD1’s involvement. Key take‑home message: Despite robust segregation data, the current evidence for FHOD1’s causative role remains limited, underscoring the need for further functional studies to support clinical decision‑making.

References

  • Molecular genetics & genomic medicine • 2019 • Hypotrichosis with juvenile macular dystrophy: Combination of whole‑genome sequencing and genome‑wide homozygosity mapping identifies a large deletion in CDH3 initially undetected by whole‑exome sequencing-A lesson from next‑generation sequencing PMID:31560841
  • The Journal of biological chemistry • 2001 • The formin/diaphanous‑related protein, FHOS, interacts with Rac1 and activates transcription from the serum response element PMID:11590143

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Twelve affected individuals and segregation in 18/19 obligate carriers support a possible association (PMID:31560841), yet a knock‑in mouse model failed to recapitulate the phenotype (PMID:31560841).

Genetic Evidence

Limited

The FHOD1 variant c.1306A>G (p.Arg436Gly) was observed in 12 affected patients with an autosomal recessive segregation pattern in a consanguineous family (PMID:31560841).

Functional Evidence

Limited

Although FHOD1 biochemically interacts with Rac1 (PMID:11590143), in vivo knock‑in mouse studies did not demonstrate the expected disease phenotype, limiting functional support.