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

Abstract

PurposeThe 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.ObservationsExome 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 importanceAlthough 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.

The Oculome Panel Test

“…Three of these samples were positive controls from individuals with a known genetic diagnosis including a whole gene deletion in FOXC1, digenic mutations in FOXC1 and PITX2 and a mutation in Here, the variant in GDF3, although previously reported as pathogenic, was detected in the apparently unaffected father. While it cannot be ruled out that the father has a mild subclinical phenotype, our findings were consistent with previous reports of reduced penetrance, 28 as well as variable expressivity (ocular or skeletal phenotypes or both) for this variant. 29 We calculated the diagnostic yield for each sub-panel as the proportion of patients screened within the four phenotypic groups (anterior segment dysgenesis and glaucoma, MAC, early onset retinal dystrophies, congenital cataract) that were detected with a positive class 4 or 5 mutation.…”

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

“…An example of interfamilial variability is provided by a de novo missense variant in GDF6 identified in one patient with bilateral anophthalmia, but also in 3 unrelated cases with coloboma, microphthalmia, post-axial polydactyly and Klippel-Feil syndrome (Asai-Coakwell et al 2009). Beside this clinical variability, nonpenetrance also seems to be a reasonably common occurrence associated with GDF3 and GDF6 variants (Asai-Coakwell et al 2009;Bardakjian et al 2017;Patel et al 2018;Ye et al 2010). This relatively frequent non-penetrance could be due to an additive effect of multiple variants in several BMP ligands contributing to the ocular or skeletal phenotypes (Ye et al 2010).…”

Identifying genetic risk variants associated with brain volumetric phenotypes via K‐sample Ball Divergence method

“…First, APOBEC1 with rs10431307 has an interaction with growth differentiation factor 3 (GDF3) (Levasseur et al, 2008). GDF3 might cause cranial nerve abnormalities because it acts on the cranial nerves and also causes diseases, such as isolated and microphthalmia (Bardakjian et al, 2017; Hexige et al, 2005). Second, ANTXR1, a member of the aldo/keto reductase, has been found to be overexpressed in middle temporal gyrus (MTG) area and MTG plays an important role in AD pathogenesis (Kong et al, 2015).…”