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.