Array-based molecular karyotyping in fetuses with isolated brain malformations identifies disease-causing CNVs. Issue 1 (December 2016) - Schumann, Madita
Abstract Background The overall birth prevalence for congenital malformations of the central nervous system (CNS) among Europeans may be as high as 1 in 100 live births. The etiological factors remain largely unknown. The aim of this study was to detect causative copy number variations (CNVs) in fetuses of terminated pregnancies with prenatally detected isolated brain malformations. Methods Array-based molecular karyotyping was performed in a cohort of 35 terminated fetuses with isolated CNS malformations. Identified putative disease-causing CNVs were confirmed using quantitative polymerase chain reaction or multiplex ligation-dependent probe amplification. Results Based on their de novo occurrence and/or their established association with congenital brain malformations, we detected five disease-causing CNVs in four fetuses involving chromosomal regions 6p25.1-6p25.3 (FOXC1 ), 6q27, 16p12.3, Xp22.2-Xp22.32 (MID1 ), and Xp22.32-Xp22.33. Furthermore, we detected a probably disease-causing CNV involving chromosomal region 3p26.3 in one fetus, and in addition, we detected 12 CNVs in nine fetuses of unknown clinical significance. All CNVs except for two were absent in 1307 healthy in-house controls (frequency <0.0008). Each of the two CNVs present in in-house controls was present only once (frequency = 0.0008). Furthermore, our data suggests the involvement ofCNTN6 andKLHL15 in the etiology of agenesis of the corpus callosum, the involvement ofRASD1 andPTPRD in Dandy-Walker malformation, and the involvement ofERMARD in ventriculomegaly. Conclusions Our study suggests that CNVs play an important role in the etiology of isolated brain malformations.