Clinical Exome Sequencing Data Reveal High Diagnostic Yields for Congenital Diaphragmatic Hernia Plus (CDH+) and New Phenotypic Expansions Involving CDH

Authors

Tiana M Scott
Ian M Campbell
Andres Hernandez-Garcia
Seema R Lalani
Pengfei Liu
Chad A Shaw
Jill A Rosenfeld
Daryl A Scott

Language

English

Publication Date

3-1-2022

Journal

Journal of Medical Genetics

DOI

10.1136/jmedgenet-2020-107317

PMID

33461977

PMCID

PMC8286264

PubMedCentral® Posted Date

3-1-2022

PubMedCentral® Full Text Version

Post-print

Abstract

Background: 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.

Methods: 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.

Results: 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 KMT2D. Putatively deleterious variants in ALG12 and EP300 were each found in two individuals, supporting their role in CDH development. We also identified individuals with de novo pathogenic variants in FOXP1 and SMARCA4, and compound heterozygous pathogenic variants in BRCA2. 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.

Conclusion: 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 ALG12-congenital disorder of glycosylation, Rubinstein-Taybi syndrome, Fanconi anaemia, Coffin-Siris syndrome and FOXP1-related disorders.

Keywords

Animals, DNA Copy Number Variations, DNA Helicases, Exome, Forkhead Transcription Factors, Frameshift Mutation, Hernias, Diaphragmatic, Congenital, Humans, Mice, Nuclear Proteins, Repressor Proteins, Transcription Factors, Exome Sequencing, Congenital diaphragmatic hernia, exome sequencing, diagnostic yield, EP300, Rubinstein-Taybi syndrome, ALG12-congenital disorder of glycosylation, Fanconi anemia, Coffin-Siris syndrome, FOXP1, Kabuki syndrome

Published Open-Access

no

Recommended Citation

Scott, Tiana M; Campbell, Ian M; Hernandez-Garcia, Andres; et al., "Clinical Exome Sequencing Data Reveal High Diagnostic Yields for Congenital Diaphragmatic Hernia Plus (CDH+) and New Phenotypic Expansions Involving CDH" (2022). Duncan NRI Faculty and Staff Publications. 170.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/170