GDF6

Chr 8ADAR

growth differentiation factor 6

Also known as: BMP-13, BMP13, CDMP2, KFM, KFS, KFS1, KFSL, SGM1

NCBI Gene: 392255 ENSG00000156466 UniProt: Q6KF10

GDF6 encodes a secreted growth factor of the TGF-beta superfamily that controls proliferation and differentiation in the retina, regulates apoptosis during retinal development, and is required for normal bone and joint formation in the limbs, skull, and axial skeleton. Mutations cause Klippel-Feil syndrome, Leber congenital amaurosis, microphthalmia with or without coloboma, and multiple synostoses syndrome with both autosomal dominant and autosomal recessive inheritance patterns. This gene is highly constrained against loss-of-function variation, reflecting its critical role in skeletal and ocular development.

Summary from RefSeq, OMIM, UniProt

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Primary Disease Associations & Inheritance

Klippel-Feil syndrome 1, autosomal dominantMIM #118100

Leber congenital amaurosis 17MIM #615360

Microphthalmia with coloboma 6, digenicMIM #613703

Microphthalmia, isolated 4MIM #613094

Multiple synostoses syndrome 4MIM #617898

UniProtDeafness, autosomal recessive, 118, with cochlear aplasia

Active trials

Pubs (1 yr)

P/LP submissions

P/LP missense

0.22

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Clinical Summary— GDF6

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 157 VUS of 300 total submissions

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GeneReview available — GDF6

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.22LOEUF

pLI 0.988

Z-score 3.39

OE 0.00 (0.00–0.22)

Highly constrained

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

Missense Constraint

0.93Z-score

OE missense 0.83 (0.74–0.93)

204 obs / 245.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.00 (0.00–0.22)

0≤0.351.4

Missense OE0.83 (0.74–0.93)

0≤0.61.4

Synonymous OE1.05

0≤1.21.6

LoF obs/exp: 0 / 13.4Missense obs/exp: 204 / 245.2Syn Z: -0.39

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGDF6-related oculo-skeletal syndromeOTHERAD

definitiveGDF6-related microphthalmiaOTHERAD

0.3594th %ile

GOF

0.2995th %ile

LOF

0.74top 10%

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.

LOFprediction above median · 1 literature citation · LOEUF 0.22

GOF1 literature citation

Literature Evidence

GOFCollectively, our findings indicate that increased BMP signaling owing to a GDF6 gain-of-function mutation is responsible for loss of joint formation and profound functional impairment in patients with SYNS4.PMID:26643732

LOFEven though the type, range, and severity ofassociated anomalies may have varied between these two families,there was a precise positional correspondence evident between thefull familial range of skeletal anomalies (Table 1), the discretedevelopmental patterns of Gdf6 expression in mice (including tPMID:18425797

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