SYNE4

Chr 19AR

spectrin repeat containing nuclear envelope family member 4

ENSG00000181392 UniProt: Q8N205 OMIM: 615535

The protein functions as a component of the LINC complex that connects the nuclear lamina to the cytoskeleton, transmits mechanical forces across the nuclear envelope, and serves as a kinesin cargo to promote proper cellular organization in secretory epithelial cells. Mutations cause autosomal recessive deafness (DFNB76), indicating a critical role in inner ear function. The gene shows low constraint to loss-of-function variation, consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from OMIM, UniProt

MultiplemechanismARLOEUF 1.291 OMIM phenotype

Clinical Summary— SYNE4

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.29LOEUF

pLI 0.000

Z-score 0.51

OE 0.88 (0.61–1.29)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

0.49Z-score

OE missense 0.91 (0.81–1.02)

208 obs / 229.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.88 (0.61–1.29)

0≤0.351.4

Missense OE0.91 (0.81–1.02)

0≤0.61.4

Synonymous OE1.13

0≤1.21.6

LoF obs/exp: 19 / 21.5Missense obs/exp: 208 / 229.0Syn Z: -0.97

0.6356th %ile

GOF

0.76top 25%

LOF

0.3647th %ile

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

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.