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
PAX5 is a transcription factor associated with abnormal posterior midbrain and cerebellum development in mice. PAX5 is highly loss-of-function intolerant and
Fibroblast growth factor receptor‐like 1 (FGFRL1) encodes a transmembrane protein that is related to fibroblast growth factor receptors but lacks an intercellular tyrosine kinase domain. in vitro studies suggest that FGFRL1 inhibits cell proliferation and promotes cell differentiation and cell adhesion. Mice that lack FGFRL1 die shortly after birth from respiratory distress and have abnormally thin diaphragms whose muscular hypoplasia allows the liver to protrude into the thoracic cavity. Haploinsufficiency of FGFRL1 has been hypothesized to contribute to the development of congenital diaphragmatic hernia (CDH) associated with Wolf‐Hirschhorn syndrome. However, data from both humans and mice suggest that disruption of one copy of FGFRL1 alone is insufficient to cause diaphragm defects. Here we report a female fetus with CDH whose 4p16.3 deletion allows us to refine the Wolf‐Hirschhorn syndrome CDH critical region to an approximately 1.9 Mb region that contains FGFRL1. We also report a male infant with isolated left‐sided diaphragm agenesis who carried compound heterozygous missense variants in FGFRL1. These cases provide additional evidence that deleterious FGFRL1 variants may contribute to the development of CDH in humans.
Coffin-Siris syndrome (CSS) is an autosomal dominant neurodevelopmental syndrome that can present with a variety of structural birth defects. Pathogenic variants in 12 genes have been shown to cause CSS. Most of these genes encode proteins that are a part of the mammalian switch/sucrose non-fermentable (mSWI/SNF; BAF) complex. An association between genes that cause CSS and congenital diaphragmatic hernia (CDH) has been suggested based on case reports and the analysis of CSS and CDH cohorts. Here, we describe an unpublished individual with CSS and CDH, and we report additional clinical information on four published cases. Data from these individuals, and a review of the literature, provide evidence that deleterious variants in ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2, DPF2, and SMARCC2, which are associated with CSS types 1-8, respectively, are associated with the development of CDH. This suggests that additional genetic testing to identify a separate cause of CDH in an individual with CSS may be unwarranted, and that comprehensive genetic testing for individuals with non-isolated CDH should include an evaluation of CSS-related genes. These data also suggest that the mSWI/SNF (BAF) complex may play an important role in diaphragm development.
Background
In recent years, therapeutic drug monitoring (TDM) of anti–tumor necrosis factor alpha (anti-TNFα) agents has been commonly utilized. We aimed to investigate its effect on long-term drug retention and clinical outcomes in pediatric patients with Crohn’s disease (CD).
Methods
The medical records of pediatric CD patients receiving anti-TNFα agents from 2007 to 2018 were reviewed retrospectively. Patients were stratified to those who initiated anti-TNFα treatment between 2007 and 2012, an era when TDM was not available (TDM-), and patients who initiated anti-TNFα treatment between 2013 and 2018, with at least 1 TDM during firstline anti-TNFα treatment (TDM+). The main outcome measures included time to first anti-TNFα discontinuation (drug retention), flares, and hospitalizations per year of first anti-TNFα treatment, treatment intensification rate, and surgical resection rate.
Results
One hundred ninety-seven patients were included (n = 98, TDM-; n = 99, TDM+; median [interquartile range] age, 12.6 [10.1–14.2] years; females 68 [35%]). Compared with the TDM- group, the TDM+ group had a longer drug retention time (mean ± SE, 45.0 ± 2.7 vs 33.5 ± 2.4 months; P = 0.001), lower hospitalization rate per patient per year (mean ± SE, 0.51 ± 0.7 vs 0.92 ± 0.81; P < 0.001), and higher treatment intensification rate (70% vs 18%; P < 0.001). Surgical resection rate was not significantly different. Analysis of the entire cohort showed a longer retention time for adalimumab vs infliximab (45.3 ± 2.8 vs 34.8 ± 2.5 months; P = 0.007).
Conclusions
TDM-based treatment enables longer drug retention time, reflecting better utilization of anti-TNFα agents, with several additional favorable outcomes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.