Digenic Inheritance of Heterozygous FANCA and BRCA2 mutations in a VACTERL-H patient
VACTERL with hydrocephalus (VACTERL-H) is a subtype of VACTERL. Clinically, VACTERL-H is diagnosed based on the presence of 3 or more congenital anomalies affecting the vertebrae, anus, heart, trachea, oesophagus, kidneys or limbs with hydrocephalus. VACTERL-H is an autosomal recessive or X-linked genetic disease and accounts for about 5-10% of Fanconi anaemia cases. We performed whole exome sequencing analysis of a 2-year-old boy with VACTERL-H and his unaffected parents. The exome data was analysed using Torrent Suite software and annotated using ANNOVAR. Polymorphisms with allele frequency > 0.01 were excluded and the remaining variants were filtered based on de novo mutations and autosomal recessive, X-linked and digenic inheritance traits. We found that the patient harboured heterozygous mutations in BRCA2 (ENST00000380152: c.C7052G, p.Ala2351Gly) and FANCA (ENST00000389301: c.C397T, p.His133Tyr), which were inherited from his father and mother, respectively. The candidate mutations were confirmed by Sanger sequencing. Combined heterozygous mutations of FANCA and BRCA2 may be causative of VACTERL-H and it is heritable through a digenic inheritance. As FANCA and BRCA2 are linked to Fanconi anaemia (FA), clinical follow-up of the patient is crucial in determining the risk for FA and for future management.