Congenital Diaphragmatic Hernia Panel

Congenital diaphragmatic hernia (CDH) is a relatively common and severe developmental defect of the diaphragm that affects around 1 in 3,000 live births (Pober. 2008. PubMed ID: 18510546; Wang et al. 2011. PubMed ID: 21960515; Wright et al. 2011. PubMed ID: 21281327; Wynn et al. 2014. PubMed ID: 25447988; Burgos and Frenckner. 2017. PubMed ID: 27745705; Shanmugam et al. 2017. PubMed ID: 28925604). It is characterized by incomplete formation of the diaphragm that results in either absence or deficiency of the entire diaphragm or a portion of the diaphragm (Longoni et al. 1993. PubMed ID: 20301533).

CDH may be classified into several types depending on where the herniation occurs. Posterolateral hernias, or Bochdalek hernias, are posterior defects of the diaphragm and comprise ~80-90% of all CDH (Longoni et al. 1993. PubMed ID: 20301533). Due to the location of the hernia these types often include herniation of the stomach, liver, and/or spleen into the chest cavity. Posterolateral hernias may occur on the left side (~85%) or right side (~10%), or may be bilateral (~5%) (Longoni et al. 1993. PubMed ID: 20301533).

Non-posterolateral hernias, or non-Bochdalek hernias, are anterior defects of the diaphragm and comprise ~2% of all CDH (Longoni et al. 1993. PubMed ID: 20301533). These types of hernias may also occur on the left or right side or may be midline defects. Diaphragmatic eventration occurs when there is incomplete muscularization of the diaphragm, which results in a thin membranous sheet of tissue, and is also included within the spectrum of CDH (Wynn et al. 2014. PubMed ID: 25447988).

About 50-60% of CDH cases occur as isolated defects, however ~40-50% are complex cases that are associated with other congenital anomalies (Longoni et al. 1993. PubMed ID: 20301533). These complex cases may be associated with a readily identifiable genetic syndrome or chromosome anomaly; however other complex cases are not attributed to a recognized genetic syndrome. CDH typically presents in the neonatal period with severe respiratory distress, however ~5-10% of affected individuals present after the neonatal period with respiratory or gastrointestinal distress (Longoni et al. 1993. PubMed ID: 20301533).

Additional clinical manifestations may accompany CDH and are often dependent on the severity of the CDH. These additional manifestations may include pulmonary hypertension, failure to thrive, neurodevelopmental complications, musculoskeletal anomalies, and sensorineural hearing loss (Longoni et al. 1993. PubMed ID: 20301533). Of note, ~1% of individuals are asymptomatic and the CDH is discovered incidentally on imaging studies in later childhood or adulthood (Bagłaj and Dorobisz. 2005. PubMed ID: 15778858).

The mortality rates associated with CDH range from 20-60% due to the variation in patient population and data collection techniques (Longoni et al. 1993. PubMed ID: 20301533; Colvin et al. 2005. PubMed ID: 16140678). Different prognostic indicators of CDH may be considered and include whether the CDH is isolated or complex, the size of the defect, the degree of pulmonary hypoplasia, the presence of liver herniation, the severity of the pulmonary hypertension in the perinatal period, and whether the hernia is right-sided, left-sided, or bilateral (Longoni et al. 1993. PubMed ID: 20301533).

Treatment for CDH varies based on the severity of the hernia and if the hernia is isolated or complex. Therapy focuses on respiratory support to prevent additional lung injury, including the use of extracorporeal membrane oxygenation (ECMO). However, the use of ECMO treatment is complex and includes numerous complications (Cairo et al. 2018. PubMed ID: 30080776).

CDH are associated with a group of clinically and genetically heterogeneous disorders; therefore the differential diagnoses are numerous. Genetic testing may aid in determining a diagnosis in ~15-20% of cases, which in turn would provide valuable information on prognosis, management, and recurrence risk (Pober et al. 2005. PubMed ID: 16094667; Pober. 2008. PubMed ID: 18510546; Wynn et al. 2014. PubMed ID: 25447988).

This test includes genes identified through literature, Online Mendelian Inheritance in Man (OMIM), and Human Gene Mutation Database (HGMD) searches that have a reported associated with congenital diaphragmatic hernia.

Congenital diaphragmatic hernias are genetically heterogeneous disorders that may result from chromosome anomalies, a single gene disorder, or a complex disorder resulting from interactions involving multiple genes. Of note, environmental risk factors may also contribute to the development of CDH; however most human cases are unexplained by known environmental factors (Yu et al. 2020. Pubmed ID: 31443905). A great majority of CDH cases, ~80%, are idiopathic (Wynn et al. 2014. PubMed ID: 25447988).

Chromosome anomalies such as complete or mosaic chromosome aneuplodies, large chromosome deletions or duplications, and complex chromosome rearrangements are identified in 10-35% of CDH cases (Wynn et al. 2014. PubMed ID: 25447988). Additionally, smaller structural variants such as microdeletions or microduplications may be identified in ~3.5-13% of CDH cases (Wynn et al. 2014. PubMed ID: 25447988). Chromosome anomalies involving almost every chromosome have been reported in association with CDH (Holder et al. 2007. PubMed ID: 17436238).

Pathogenic variants involving a single or just a few nucleotides have been reported in cases of syndromic and non-syndromic CDH (Longoni et al. 1993. PubMed ID: 20301533; Wynn et al. 2014. PubMed ID: 25447988). These Mendelian forms of CDH may be inherited in an autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL manner), or may arise de novo. CDH has been reported to show incomplete penetrance and variable expressivity in individuals with a heterozygous pathogenic variant in an AD form of CDH (Yu et al. 2013. PubMed ID: 23138528; Longoni et al. 2015. PubMed ID: 24702427).

CDH genes include transcription factors and genes involved in cell migration or formation of the extracellular matrix. However, some genetic causes, particularly structural variants, are not consistently associated with CDH, and this suggests the presence of additional interacting genetic or non-genetic factors (Yu et al. 2020. Pubmed ID: 31443905).

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of CDH, the clinical sensitivity of this specific grouping of genes is difficult to estimate. Genetic testing may aid in determining a diagnosis in ~15-20% of cases (Pober et al. 2005. PubMed ID: 16094667; Pober. 2008. PubMed ID: 18510546). Of note, ~80% of CDH cases are idiopathic, which demonstrates the limited understanding of the genetic etiologies of CDH as well as suggests additional non-genetic, non-Mendelian, or multifactorial etiologies for CDH (Wynn et al. 2014. PubMed ID: 25447988).

Large chromosome anomalies including complete or mosaic chromosome aneuploidies, large chromosome deletions or duplications, and complex chromosome rearrangements are identified in 10-35% of CDH cases (Wynn et al. 2014. PubMed ID: 25447988). Additionally, smaller structural variants such as microdeletions or microduplications have been reported in ~3.5-13% of CDH cases (Wynn et al. 2014. PubMed ID: 25447988).

Another study analyzed whole exome sequencing data from individuals with isolated or complex CDH and their unaffected parents (trio analyses) (Longoni et al. 2017. PubMed ID: 28303347). These data were combined with a previous study looking at a similar cohort with the aim of increasing the sample size and power of the study (Yu et al. 2015. PubMed ID: 26034137). Taken together, these studies identified de novo variants that were likely gene disrupting or predicted deleterious missense in 12% of isolated cases of CDH and in 21% of complex cases of CDH (Longoni et al. 2017. PubMed ID: 28303347). Several of the identified genes identified in these studies have also been associated with congenital heart disease or neurodevelopmental conditions.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.2% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom panels).