A recurrent, non-penetrant sequence variant, p.Arg266Cys in Growth/Differentiation Factor 3 ( GDF3 ) in a female with unilateral anophthalmia and skeletal anomalies.

Purpose: The genetic causes of anophthalmia, microphthalmia and coloboma remain poorly understood. Missense mutations in Growth/Differentiation Factor 3 ( GDF3 ) gene have previously been reported in patients with microphthalmia, iridial and retinal colobomas, Klippel-Feil anomaly with vertebral fusion, scoliosis, rudimentary 12th ribs and an anomalous right temporal bone. We used whole exome sequencing with a trio approach to study a female with unilateral anophthalmia, kyphoscoliosis and additional skeletal anomalies.

Observations: Exome sequencing revealed that the proposita was heterozygous for c.796C > T, predicting p.Arg266Cys, in GDF3 . Sanger sequencing confirmed the mutation and showed that the unaffected mother was heterozygous for the same missense substitution.

Conclusions and importance: Although transfection studies with the p.Arg266Cys mutation have shown that this amino acid substitution is likely to impair function, non-penetrance for the ocular defects was apparent in this family and has been observed in other families with sequence variants in GDF3 . We conclude p.Arg266Cys and other GDF3 mutations can be non-penetrant, making pathogenicity more difficult to establish when sequence variants in this gene are present in patients with structural eye defects.