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Free keywords:
VATER/VACTERL association; CNV analysis; microaberrations; candidate genes; SNP array;
GPR35
Abstract:
The acronym VATER/VACTERL association describes the combination of at least three of the following congenital anomalies:
vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal
atresia (TE), renal malformations (R), and limb defects (L). We aimed to identify highly penetrant
de novo
copy number
variations (CNVs) that contribute to VATER/VACTERL association. Array-based molecular karyotyping was performed in a cohort
of 41 patients with VATER/VACTERL association and 6 patients with VATER/VACTERL-like phenotype including all of the
patients’ parents. Three
de novo
CNVs were identified involving chromosomal regions 1q41, 2q37.3, and 8q24.3 comprising
one (
SPATA17
), two (
CAPN10, GPR35
), and three (
EPPK1
,
PLEC
,
PARP10
) genes, respectively. Pre-existing data from the
literature prompted us to choose
GPR35
and
EPPK1
for mouse expression studies. Based on these studies, we prioritized
GPR35
for sequencing analysis in an extended cohort of 192 patients with VATER/VACTERL association and VATER/VACTERL-
like phenotype. Although no disease-causing mutation was identified, our mouse expression studies suggest
GPR35
to be
involved in the development of the VATER/VACTERL phenotype. Follow-up of
GPR35
and the other genes comprising the
identified duplications is warranted.
