Identification of Novel Mutations In VACTERL-H Patient via Exome Sequencing

By: Zam Zureena Mohd Rani (zureena@ppukm.ukm.edu.my)

The VATER/VACTERL association refers to sporadic, rare, non-random co-occurrence of the following component features (CFs): vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Although several gene mutations have been reported to cause the disease, these findings have been sparsely replicated to date. In our study, we analyzed the case of a Malay boy with VACTERL with hydrocephalus association (VACTERL-H) based on the presence of five out of six component features. VACTERL-H is inherited as an autosomal recessive or X-linked recessive trait. Whole exome sequencing identified 3 de-novo mutations from the patient: 2 in genes related to vertebra (BP1 and NRK) and 1 in a gene related to trachea (POLI). These 3 mutations were associated with the phenotype of the patient. We further identified 21 and 17 mutations in genes related to VACTERL-H association (autosomal recessive mutation) in the patient’s father and mother, respectively.

Interestingly, we identified BRCA 2 and FANCA (Fanconi Anemia) gene mutations carried by the boy’s healthy parents. These mutations were previously reported to be associated with VACTERL. In summary, we successfully genotyped a VACTERL-H patient and confirmed the diagnosis. We confirmed the patient’s VACTERL-H as an autosomal recessive inheritance. For the first time, BRCA 2 and FANCA mutations was observed in a VACTERL-H patient, with 3 de-novo mutations identified as GBP1 (P.1455M), POLI (P.V54A), NRK (P.Q912H).