GDF6 – Microphthalmia

Growth differentiation factor 6 (GDF6) is a bone morphogenetic protein critical for ocular morphogenesis. Heterozygous variants in GDF6 have been reported in individuals with microphthalmia and other ocular anomalies, suggesting an autosomal dominant contribution to reduced globe size. Functional studies further support a role for GDF6 perturbation in eye development.

Two unrelated patients with renal hypodysplasia and extrarenal manifestations including microphthalmos were found to carry rare heterozygous missense variants in GDF6: c.112G>C (p.Gly38Arg) and c.746C>A (p.Ala249Glu) (PMID:32737436). A separate individual with combined GDF3 and GDF6 alterations harbored the variant c.595G>A (p.Ala199Thr), identified in a cohort screened for ocular and skeletal anomalies (PMID:19864492). No additional familial segregation has been reported, and all variants are novel or extremely rare in population databases.

The inheritance pattern for GDF6-related microphthalmia is autosomal dominant. The known variant spectrum consists exclusively of missense changes, with no recurrent or founder alleles described. No loss-of-function or splice variants have yet been implicated. Phenotypic spectrum spans bilateral microphthalmos (HP:0007633) and may include coloboma or syndromic findings when other genes are involved.

Experimental evidence demonstrates that GDF6 perturbation disrupts BMP signaling during eye development. Morpholino-mediated knockdown of the zebrafish gdf6 ortholog recapitulates microphthalmia and coloboma, and in vitro luciferase reporter assays show substantially reduced BMP pathway activation for patient-derived GDF6 variants (PMID:19864492). These data support a loss-of-function mechanism, likely via haploinsufficiency.

No conflicting reports have been published to date. Although the number of affected individuals is limited, the concordance of heterozygous missense variants with ocular phenotypes and the reproducible functional defects in model systems strengthen the association. Additional studies will be required to establish segregating families and to define the full phenotypic range.

Key Take-home: Rare heterozygous missense variants in GDF6 cause autosomal dominant microphthalmia through impaired BMP signaling, supporting diagnostic testing in individuals with unexplained reduced globe size.

References

• Human molecular genetics • 2010 • Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies. PMID:19864492
• European journal of human genetics : EJHG • 2020 • Rare heterozygous GDF6 variants in patients with renal anomalies. PMID:32737436

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