PRJNA439181
Gene Identifiaction of rare phenotypes
Two families distantly related each had two fetuses with similar (unique) phenotype. All four affected fetuses presented with severe limb reduction defects distinguishable from AARRS ( Al Awadi Raas Rotschild syndrome ) by radial ray deficiency with humeral involvement, absence of tibiae with or without femoral deficiency, and absence of digits on the pre-axial side. Whole-exome sequencing performed on two probands (F1-II:6 and F1-II:7; as shown in manuscript submitted to Nature,2018), yielded 57 homozygous rare variants with potentially deleterious effects. After filtering and Sanger validation, a single coding mutation in exon 3 of the R-SPONDIN2 gene (RSPO2, MIM 610575) was shown to segregate with the disease phenotype. The resulting missense p.Arg69Cys affects a highly conserved residue found to be invariant in all R-SPONDIN paralogues and homologues.