Underlying genetic etiologies of congenital diaphragmatic hernia

Abstract

Congenital diaphragmatic hernia (CDH) is often detectable prenatally. Advances in genetic testing have made it possible to obtain a molecular diagnosis in many fetuses with CDH. Here, we review the aneuploidies, copy number variants (CNVs), and single genes that have been clearly associated with CDH. We suggest that array-based CNV analysis, with or without a chromosome analysis, is the optimal test for identifying chromosomal abnormalities and CNVs in fetuses with CDH. To identify causative sequence variants, whole exome sequencing (WES) is the most comprehensive strategy currently available. Whole genome sequencing (WGS) with CNV analysis has the potential to become the most efficient and effective means of identifying an underlying diagnosis but is not yet routinely available for prenatal diagnosis. We describe how to overcome and address the diagnostic and clinical uncertainty that may remain after genetic testing, and review how a molecular diagnosis may impact recurrence risk estimations, mortality rates, and the availability and outcomes of fetal therapy. We conclude that after the prenatal detection of CDH, patients should be counseled about the possible genetic causes of the CDH, and the genetic testing modalities available to them, in accordance with generally accepted guidelines for pretest counseling in the prenatal setting. Key points What's already known about this topic?� Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that is often identified prenatally. A deeper understanding of the genetic causes of CDH, coupled with advances in genetic testing, have made it possible to obtain a molecular diagnosis in an increasing percentage of fetuses with CDH. Practitioners must be prepared to help individuals and families make informed decisions regarding genetic testing and to request the most appropriate genetic tests What does this review add?� We provide a review of chromosomal abnormalities, copy number variants (CNVs), and genes that are clearly associated with the development of CDH in humans. We describe current genetic testing modalities so that practitioners can select the most appropriate genetic test(s). To aid practitioners, we also provide a review of topics that should be discussed with individuals and families so that they can make informed decisions regarding genetic testing

Evidence-Based Genetic Testing for Individuals with Congenital Diaphragmatic Hernia

“…8,9 There is consensus that genetic testing is warranted in individuals complex/syndromic CDH. 4,6 Consistent with this recommendation, genetic testing was diagnostic in 57% (51 out of 89) of infants with complex/syndrome CDH reported by Wild et al Tests leading to a diagnosis in this group included chromosome analysis, CMA, single gene testing, and exome sequencing. Among those in whom a molecular diagnosis was made, a causative chromosomal anomaly or copy number variant was identified in 73% of cases, and a single gene disorder was identified in the other 27%.…”

“…1,2 Over that same period, our understanding of the genetic factors that underlie the development of CDH has improved, and advances in technology have allowed a molecular diagnosis to be made in an increasing number of CDH cases. [3][4][5][6] However, doubts remain regarding the effectiveness of various genetic testing modalities in individuals with isolated/nonsyndromic and complex/syndromic forms of CDH. As a result, individuals and families affected by CDH may not be offered optimal genetic testing despite the potential benefits afforded by a molecular diagnosis.…”

Non-Invasive Detection of a De Novo Frameshift Variant of STAG2 in a Female Fetus: Escape Genes Influence the Manifestation of X-Linked Diseases in Females

“…A genetic etiology for CDH, either pre- or postnatal, was found in about 10% of the cases by conventional/karyotype or CGH/SNP array [ 21 ] whereas WES in 39 trios showed predicted damaging de novo variants in 21% of complex cases and 12% of isolated ones [ 22 , 23 ]. Variants in genes belonging to the cohesion complex were consistently associated with CDH [ 24 ].…”

Use of Prostaglandin E1 in the Management of Congenital Diaphragmatic Hernia–A Review

“…It occurs 70%−75% of the time in the posterolateral aspect of the diaphragm, with over 85% occurring on the left side (2). CDH can also be associated with congenital heart defects (25%−40%), urogenital anomalies (18%), musculoskeletal anomalies (16%) and central nervous system anomalies (10%) (3,4). Despite medical and surgical advances, CDH continues to have high mortality and morbidity rates (5).…”