TY - JOUR T1 - Genetic analysis of <em>de novo</em> variants reveals sex differences in complex and isolated congenital diaphragmatic hernia and indicates <em>MYRF</em> as a candidate gene JF - bioRxiv DO - 10.1101/206037 SP - 206037 AU - Hongjian Qi AU - Lan Yu AU - Xueya Zhou AU - Alexander Kitaygorodsky AU - Julia Wynn AU - Na Zhu AU - Gudrun Aspelund AU - Foong Yen Lim AU - Timothy Crombleholme AU - Robert Cusick AU - Kenneth Azarow AU - Melissa Ellen Danko AU - Dai Chung AU - Brad W. Warner AU - George B. Mychaliska AU - Douglas Potoka AU - Amy J. Wagner AU - Mahmoud ElFiky AU - Deborah A. Nickerson AU - Michael J. Bamshad AU - Jay M. Wilson AU - Frances A. High AU - Mauro Longoni AU - Patricia Donahoe AU - Wendy K. Chung AU - Yufeng Shen Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/11/12/206037.abstract N2 - Congenital diaphragmatic hernia (CDH) is one of the most common and lethal birth defects. Previous studies using exome sequencing support a significant contribution of coding de novo variants in complex CDH cases with additional anomalies and likely gene-disrupting (LGD) variants in isolated CDH cases. To further investigate the genetic architecture of CDH, we performed exome or genome sequencing in 283 proband-parent trios. Combined with data from previous studies, we analyzed a total of 357 trios, including 148 complex and 209 isolated cases. Complex and isolated cases both have a significant burden of deleterious de novo coding variants (1.7~fold, p= 1.2×10−5 for complex, 1.5~fold, p= 9.0×10−5 for isolated). Strikingly, in isolated CDH, almost all of the burden is carried by female cases (2.1~fold, p=0.004 for likely gene disrupting and 1.8~fold, p= 0.0008 for damaging missense variants); whereas in complex CDH, the burden is similar in females and males. Additionally, de novo LGD variants in complex cases are mostly enriched in genes highly expressed in developing diaphragm, but distributed in genes with a broad range of expression levels in isolated cases. Finally, we identified a new candidate risk gene MYRF (4 de novo variants, p-value=2×10−10), a transcription factor intolerant of mutations. Patients with MYRF mutations have additional anomalies including congenital heart disease and genitourinary defects, likely representing a novel syndrome. ER -