A three generation family with VACTERL association is found to have a rare form of diamond-blackfan anaemia

The spectrum of congenital malformations in VACTERL association varies among patients and can be differentially diagnosed with CHARGE syndrome, Fanconi anaemia, and others (reviewed in Solomon 2011). Despite overlapping clinical findings, the genetic causes of these diseases are distinct. In this context, unbiased whole genome sequencing can assist in differential diagnoses, as well as identify new gene-disease associations. In this report, we demonstrate that whole genome sequencing of a proband with suspected VACTERL association revealed two gene variants in the ribosomal genes RPL18 (NM_000979.4 c.397 G > C p.(Gly133Arg)) and RPS6 (NM_001010.3: c.370 C > G p.(Leu124Val)). Mutations in ribosomal genes are associated with Diamond-Blackfan anaemia, a condition that shares phenotypic similarities with Fanconi anaemia. Our modelling and functional assessment of the identified variants strongly indicate pathogenicity of the RPL18:p.(G133R) variant as it is novel, displays reduced expression and stability and abnormal intracellular distribution, and interferes with protein synthesis in cultured cells. The RPS6:p.(L124V) variant reduced protein expression and altered cytoplasmic distribution but does not interfere with protein synthesis in cultured cells. Overall, our study indicates the significant advantage of using unbiased whole genome sequencing for the examination of patients with complex congenital malformations.