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 OMIM: 601147

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein is required for normal formation of some bones and joints in the limbs, skull, and axial skeleton. Mutations in this gene are associated with Klippel-Feil syndrome, microphthalmia, and Leber congenital amaurosis. [provided by RefSeq, Sep 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.225 OMIM phenotypes

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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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 OE?0.00 (0.00–0.22)

0≤0.351.4

Missense OE?0.83 (0.74–0.93)

0≤0.61.4

Synonymous OE?1.05

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

This gene — mechanism propensity

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 SYNS4.1

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 t2

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

References