FHL1

Chr X

four and a half LIM domains 1

Also known as: FCMSU, FHL-1, FHL1A, FHL1B, FLH1A, KYOT, RBMX1A, RBMX1B

NCBI Gene: 2273 ENSG00000022267 UniProt: Q13642

The FHL1 protein is a member of the four-and-a-half-LIM-only protein family containing zinc finger domains that function in various cellular processes. Mutations cause a spectrum of X-linked muscle disorders including Emery-Dreifuss muscular dystrophy, reducing body myopathy, scapuloperoneal myopathy, and myopathy with postural muscle atrophy, as well as autosomal recessive familial hemophagocytic lymphohistiocytosis. The pathogenic mechanism involves loss of function of this cytoplasmic protein.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the four-and-a-half-LIM-only protein family. Family members contain two highly conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. Expression of these family members occurs in a cell- and tissue-specific mode and these proteins are involved in many cellular processes. Mutations in this gene have been found in patients with Emery-Dreifuss muscular dystrophy. Multiple alternately spliced transcript variants which encode different protein isoforms have been described.[provided by RefSeq, Nov 2009]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtEmery-Dreifuss muscular dystrophy 6, X-linked

UniProtScapuloperoneal myopathy, X-linked dominant

UniProtMyopathy, X-linked, with postural muscle atrophy

UniProtReducing body myopathy, X-linked 1A, severe, with infantile or early childhood onset

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.28

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — FHL1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

0.28LOEUF

pLI 0.970

Z-score 3.05

OE 0.00 (0.00–0.28)

Highly constrained

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

Missense Constraint?

0.89Z-score

OE missense 0.78 (0.67–0.92)

105 obs / 134.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.28)

0≤0.351.4

Missense OE?0.78 (0.67–0.92)

0≤0.61.4

Synonymous OE?0.77

0≤1.21.6

LoF obs/exp: 0 / 10.8Missense obs/exp: 105 / 134.0Syn Z: 1.32

Background carrier burden — how many people carry a rare variant somewhere in FHL1?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 300

269 rare PASS variants

Rare truncating (LoF)

1 in 8,700

19 rare PASS variants

Rare synonymous (reference)

1 in 450

101 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FHL1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 400	1 in 5,900
South Asian	~36k	1 in 280	none seen
Remaining (unassigned)	~31k	1 in 270	≈ 1 in 31,000
European (Finnish)	~27k	1 in 660	none seen
Admixed American	~23k	1 in 300	none seen
African / African American	~21k	1 in 180	none seen
East Asian	~20k	1 in 320	none seen
Ashkenazi Jewish	~13k	1 in 970	none seen
Middle Eastern	~2,758	≈ 1 in 1,300	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓