Intronic mutations affecting splicing of INTS12 cause VACTERL-like phenotype in a Palestinian family

Abstract

Background: VACTERAL association involves anal atresia, cardiac defects, renal anomalies, and limb abnormalities. The aim of our study was to identify the genetic causes of this disorder in a Palestinian family affected with similar phenotype which could also be a new syndrome. Methods: Blood samples were collected from five members of a family with VACTERAL association and then DNA was extracted and subjected to Polymerase Chain Reaction (PCR) for suspected genes. Karyotyping analysis was performed. Whole exome sequencing was performed to investigate the causative mutation. Results: Whole exome sequencing revealed a novel splice site mutation in integrator complex subunit 12 (INTS12) gene located on chromosome 4. This SNP (106,629,790 C>G) alteration leads to an inclusion for 66 bp from the intron into the coding sequence resulting in a larger polypeptide chain. 100 control cases were found negative for this INTS12 change. Conclusion: Our results revealed an autosomal recessive association which affects many body systems in the embryo in the early prenatal life. This association results in presence of a cluster of congenital malformations. A splice site mutation in INTS12 that may affect the TGF-B1 pathway which is important in collagen expression and thus affect body tissue formation Keywords: SALL1, SALL4, TOWNS BROCKS, VACTERAL association, INTS12, TGF-B