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Genetic testing has variable diagnostic yield in congenital diaphragmatic hernia

By Eleanor McDermid, medwireNews Reporter

Genetic testing can identify an underlying cause in more than half of complex/syndromic infants with congenital diaphragmatic hernia (CDH), but factors underlying isolated cases remain elusive, say researchers.

The study by K Taylor Wild (Perelman School of Medicine at University of Pennsylvania, Philadelphia, USA) and colleagues is published in The Journal of Pediatrics.

In an editorial accompanying the paper, Yoel Gofin and Daryl Scott, both from Baylor College of Medicine in Houston, Texas, USA, note that the single-centre study of 411 infants contributes “one of the largest clinical CDH cohorts published to date”.

They believe the findings “may prove beneficial in on-going and future studies aimed at identifying genes that contribute to the development of CDH.”

But noting the large proportion of infants who remained without an identified underlying cause, they highlight “the need for further investigations aimed at identifying additional genetic, epigenetic, and environmental factors that contribute to the development of CDH”.

The infants in the study, who were born between 2011 and 2021, were 58% boys and 42% girls, and the majority (79%) had left-sided CDH. Most (78%) were classed as having isolated CDH, with 22% having complex/syndromic CDH. Just three infants had a family history of CDH.

The overall survival rate was 78%, but mortality rates were significantly higher in the complex/syndromic group, at 35% versus 17% in the isolated CDH group. In addition, 73% of the surviving children with complex/syndromic CDH had developmental delay, compared with 34% of those with isolated CDH.

The most common associated anomalies identified in the infants with complex/syndromic CDH were congenital heart defects, in 39%, followed by renal anomalies in 19%, neurologic anomalies in 18% and cleft palate in 10%.

Almost all (97%) of the infants had microarray testing performed, either pre- or postnatally, with or without karyotype, and this produced a diagnostic result in 9%. Among these, prenatal testing was diagnostic for 27% of 59 tested and produced an abnormal result of unclear significance in 46%, while postnatal testing was diagnostic for 5% of 340 tested.

In addition, 47 infants underwent sequencing of either a single target gene or a gene panel, or exome sequencing, resulting in a diagnosis for 47%. This comprised a diagnostic result in 38% of 39 who underwent exome sequencing, 2% of seven with a single gene analysed and none of the 13 in whom a gene panel (most commonly for Noonan syndrome) was sequenced.

Of note, genetic testing produced a diagnostic result in 57% of infants with complex/syndromic CDH, compared with just 2% of those with isolated CDH.

However, the researchers stress that gene sequencing was often triggered because of clinical suspicion of a syndrome, contributing to the low diagnosis rate in the isolated cases, and that patients born in later years of the study had access to more advanced genetic testing.

The most frequent syndromic diagnoses were trisomy 18, identified in seven infants, tetrasomy 12p/Pallister Killian syndrome in five and Emmanuel syndrome in four. In addition, the researchers identified Simpson-Golabi-Behmel syndrome, Coffin Siris syndrome, coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities and ear abnormalities syndrome, each in two children, and a number of other conditions that each affected just one child.

“Although it is likely that there are many more genetic contributors yet to be identified that contribute to CDH, it is also possible that a significant number of isolated/nonsyndromic CDH cases result from nongenetic (environmental) causes or, more likely, represent a complex trait that requires both genetic and environmental interactions”, says the team.

“The relatively low yield among isolated/nonsyndromic cases also suggests a need for more studies using expanded genetic/genomic testing modalities (eg, genome sequencing, RNA sequencing, and tissue-specific molecular testing) in infants with CDH to improve our understanding of the genetic contributors to CDH and improve our ability to develop individualized management and counseling for affected infants and their families.”

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

J Pediatr 2022; doi:10.1016/j.jpeds.2022.04.012

J Pediatr 2022; doi:10.1016/j.jpeds.2022.05.059