Molecular pathogenesis of congenital diaphragmatic hernia revealed by exome sequencing, developmental data, and bioinformatics

Abstract

Significance Congenital diaphragmatic hernia (CDH) is a common birth defect associated with high morbidity and mortality. Focusing on the coding sequence of 51 genes, discovered in human studies and in mouse models, we studied 275 CDH patients and identified multiple variants in CDH-causing genes. Information on gene expression in embryonic mouse diaphragms and protein interactions allowed us to prioritize additional compelling CDH-associated genes. We believe that an improved understanding of the genetics of CDH will be important to design new therapeutic strategies for patients with diaphragmatic defects.

Unruptured Sinus of Valsalva Aneurysm Presenting with Concurrent Morgagni Hernia

“…While SOVA can be congenital or acquired (8,9), this patient demonstrated no known aortopathy-associated genetic mutations in a specifi c limited aortopathy panel (ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, MYH11, MYLK, PLOD1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFBR1, TGFBR2; aortopathy panel performed by ARUP Laboratories, Salt Lake City, Utah) (10). MH is congenital and is reported to be associated with multiple congenital disorders (11,12). Th is report is the fi rst known case, based on PubMed review, of SOVA and MH occurring simultaneously in the same patient.…”

PBX transcription factors drive pulmonary vascular adaptation to birth

“…Whole-exome and whole-genome sequencing is being performed on an increasing number of patient and family trios and has led to the identification of a number of single-gene variants that are associated with CDH (52)(53)(54). Our research highlights the opportunity to link individual gene mutations to prognosis and indications for specific therapeutic approaches.…”

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

“…Earlier chromosome studies identified several recurrent deletions in patients with CDH, including, e.g., 1q41-42, 8p23.1, and 15q26. Recently, efforts at identifying other genetic causes using large cohorts of patients with CDH have been made [34,35] and several critical CDH genes have been identified such as ZFPM2, GATA4, GATA6 [36,37] and rare variants in other genes, e.g., STAG2 which is implicated in a syndromic form of XLID with microcephaly and a behavioral phenotype [38][39][40]. Complex disorders including CDH with associated LH (and pulmonary hypertension) include Donnai-Barrow syndrome (LRP2), CHARGE syndrome (CHD7), Matthew-Wood syndrome (STRA6), Simpson-Golabi-Behmel syndrome (GPC3), Cornelia de Lange syndrome (NIPBL), and autosomal recessive Fryns Syndrome (PIGN) [32].…”