Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH.

Abstract

Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted. We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions. Among the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other cases (9%; 7/76). Four individuals had a diagnosis of Kabuki syndrome caused by frameshift variants in <i>KMT2D</i>. Putatively deleterious variants in <i>ALG12</i> and <i>EP300</i> were each found in two individuals, supporting their role in CDH development. We also identified individuals with de novo pathogenic variants in <i>FOXP1</i> and <i>SMARCA4</i>, and compound heterozygous pathogenic variants in <i>BRCA2</i>. The role of these genes in CDH development is supported by the expression of their mouse homologs in the developing diaphragm, their high CDH-specific pathogenicity scores generated using a previously validated algorithm for genome-scale knowledge synthesis and previously published case reports. We conclude that ES should be ordered in cases of CDH+ when a specific diagnosis is not suspected and CNV analyses are negative. Our results also provide evidence in favour of phenotypic expansions involving CDH for genes associated with <i>ALG12</i>-congenital disorder of glycosylation, Rubinstein-Taybi syndrome, Fanconi anaemia, Coffin-Siris syndrome and <i>FOXP1</i>-related disorders.