DIAPH1

Chr 5ADAR

diaphanous related formin 1

Also known as: DFNA1, DIA1, DRF1, LFHL1, SCBMS, hDIA1, mDia1

NCBI Gene: 1729 ENSG00000131504 UniProt: O60610 OMIM: 602121

DIAPH1 encodes a formin protein that nucleates and elongates actin filaments, particularly in hair cells of the inner ear, and also regulates microtubule stabilization and cell shape. Mutations cause autosomal dominant progressive low-frequency sensorineural hearing loss (often with thrombocytopenia) and autosomal recessive seizures with cortical blindness and microcephaly syndrome. The gene is highly constrained against loss-of-function variants (pLI 0.92, LOEUF 0.32), reflecting its essential cellular functions.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.322 OMIM phenotypes

Clinical Summary— DIAPH1

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Gene-Disease Validity (ClinGen)

DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.32LOEUF

pLI 0.915

Z-score 5.80

OE 0.20 (0.13–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

1.65Z-score

OE missense 0.82 (0.76–0.88)

535 obs / 653.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.20 (0.13–0.32)

0≤0.351.4

Missense OE0.82 (0.76–0.88)

0≤0.61.4

Synonymous OE1.05

0≤1.21.6

LoF obs/exp: 12 / 60.8Missense obs/exp: 535 / 653.8Syn Z: -0.65

0.4388th %ile

GOF

0.5367th %ile

LOF

0.56top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.32

GOF1 literature citation

Literature Evidence

GOFHere, we report the first cases of DIAPH1-related disorder in Australia caused by the autosomal dominant gain-of-function DIAPH1 R1213X variant formed by truncation of the protein within the diaphanous auto-regulatory domain (DAD) with loss of regulatory motifs responsible for autoinhibitory interacPMID:34223798

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.