Digenic Inheritance of Heterozygous FANCA and BRCA2 mutations in a VACTERL-H patient

  • Nor Azian Abdul Murad
  • Chow Yock Ping
  • Zam Zureena Mohd Rani
  • Siti Nurmi Nasir
  • Salwati Shuib
  • Dayang Anita A. Aziz
  • Hana Azhari
  • Sharifah Azween Syed Omar
  • Zarina Abdul Latiff
  • Ang Mia Yang
  • Rahman Jamal


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.

How to Cite
Abdul Murad, N. A., Yock Ping, C., Mohd Rani, Z. Z., Nasir, S. N., Shuib, S., A. Aziz, D. A., Azhari, H., Syed Omar, S. A., Abdul Latiff, Z., Mia Yang, A., & Jamal, R. (2019). Digenic Inheritance of Heterozygous FANCA and BRCA2 mutations in a VACTERL-H patient. Asian Journal of Medicine and Biomedicine, 3(2), 35-45. Retrieved from https://journal.unisza.edu.my/ajmb/index.php/ajmb/article/view/302