Prioritization of Candidate Genes for Congenital Diaphragmatic Hernia in a Critical Region on Chromosome 4p16 using a Machine-Learning Algorithm

Wolf–Hirschhorn syndrome (WHS) is caused by partial deletion of the short arm of chromosome 4 and is characterized by dysmorphic facies, congenital heart defects, intellectual/developmental disability, and increased risk for congenital diaphragmatic hernia (CDH). In this report, we describe a stillborn girl with WHS and a large CDH. A literature review revealed 15 cases of WHS with CDH, which overlap a 2.3-Mb CDH critical region. We applied a machine-learning algorithm that integrates large-scale genomic knowledge to genes within the 4p16.3 CDH critical region and identified FGFRL1, CTBP1, NSD2, FGFR3, CPLX1, MAEA, CTBP1-AS2, and ZNF141 as genes whose haploinsufficiency may contribute to the development of CDH.