Congenital Anomalies of the Gastrointestinal Tract Panel

Congenital anomalies (sometimes described as congenital malformations, congenital abnormalities, or birth defects) are the fifth leading cause of death globally in children less than five years of age (Wright. 2019. PubMed ID: 31481373). The most common life-threatening congenital anomalies involve the gastrointestinal tract and may include malformations, dysplasias, disruptions, or deformations of one or more organs such as the esophagus, stomach, small and large intestines, anus and rectum, pancreas, and hepato-billiary system. Collectively, congenital anomalies of the gastrointestinal tract affect 10 in 10,000 births (or 0.1%). Up to 40% of emergency neonatal surgeries aim to correct these gastrointestinal anomalies (Stanescu et al. 2017. PubMed ID: 28601177; Wright. 2019. PubMed ID: 31481373).

Intestinal atresia and stenosis result in complete or partial blockage of the digestive tract, respectively. Clinical manifestations of intestinal atresia and stenosis vary depending on the type of defect and location within the digestive tract, but may include polyhydramnios in the prenatal period, distended abdomen, constipation, vomiting, jaundice, and feeding intolerance. Malrotation, most often occurring in the small intestine, happens when an organ fails to rotate properly into its final position during fetal development and is often asymptomatic. Symptomatic malrotation often occurs with volvulus, a severe life-threatening complication where blood flow becomes restricted or the digestive tract is completely blocked, and may present with abdominal pain, constipation, diarrhea, failure to thrive, distended abdomen, and vomiting. Hirschsprung disease, characterized by the complete absence of neuronal ganglion cells from a portion of the intestinal tract, may present with constipation, diarrhea, fatigue, distended abdomen, and vomiting. Other congenital anomalies of the gastrointestinal tract include duplication cysts, congenital diaphragmatic hernia, pancreatic agenesis, heterotaxy involving the gastrointestinal tract, and abdominal wall defects including omphalocele and gastroschisis (Wilson et al. 2020. PubMed ID: 31424831; https://www.niddk.nih.gov/).

While the majority of congenital anomalies of the gastrointestinal tract may be isolated occurrences, they could be a component of a monogenic disease or a chromosomal syndrome. A molecular diagnosis is not likely to aid in surgical treatment of the gastrointestinal defect, but patients and their families may benefit from a molecular diagnosis for prognostic information, symptom management, and reproductive planning.

This test includes genes known to be monogenic causes of disorders in which an association with a congenital anomaly of the gastrointestinal tract is well-established, genes for which there is suggestive evidence for an association with gastrointestinal defects, and genes associated with disorders that may be difficult to distinguish phenotypically. These genes were identified through literature, OMIM, and HGMD searches.

Congenital anomalies of the gastrointestinal tract represent a group of phenotypically and etiologically diverse developmental defects  that may result from a single gene disorder, a chromosomal abnormality, a complex polygenic disorder, or gestational exposure to environmental risk factors (Zwink et al. 2011. PubMed ID: 21586115; Neves et al. 2018. PubMed ID: 29174094; Heuckeroth. 2018. PubMed ID: 29300049; Sigmon et al. 2020. PubMed ID: 29261981). Mendelian forms may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner, or may arise de novo.

Chromosomal abnormalities, including trisomies and other abnormalities such as large deletions and unbalanced translocations, may be the most common genetic risk factor associated with congenital malformations of the gastrointestinal tract (Nicolaides et al. 1992. PubMed ID: 1386985; Bishop et al. 2020. PubMed ID: 31167209). For example, up to 40% of infants with duodenal atresia have trisomy 21, and 2-3% of all patients with trisomy 21 have duodenal atresia (Sigmon et al. 2020. PubMed ID: 29261981). However, some monogenic disorders are also associated with congenital anomalies of the gastrointestinal tract. For example, pathogenic variants in ZIC3 cause X-linked heterotaxy syndrome, which may feature duodenal atresia due to defects in left-right axis formation during development (Bellchambers and Ware. 2018. PubMed ID: 29442328; Bishop et al. 2020. PubMed ID: 31167209). Biallelic pathogenic variants in TTC7A cause autosomal recessive gastrointestinal defects and immunodeficiency syndrome, which may feature multiple intestinal atresia and combined immunodeficiency due to defects in intestinal epithelial cell structure and function, though the molecular mechanism remains incompletely understood (Neves et al. 2018. PubMed ID: 29174094; Jardine et al. 2018 PubMed ID: 30553809). 

A wide variety of causative variants in genes associated with congenital anomalies of the gastrointestinal tract have been reported including missense, nonsense, splicing, small insertions and deletions, large deletions and duplications, and complex rearrangements (Human Gene Mutation Database). See individual gene summaries for information about the molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of the disorders tested in this panel, and the etiological diversity of gastrointestinal defects, the clinical sensitivity of this specific grouping of genes is difficult to estimate. Clinical sensitivity may vary depending on the type of gastrointestinal defect, the presentation (isolated vs syndromic), and family history. For example, up to 40% of infants with duodenal atresia have a chromosomal abnormality, primarily trisomy 21 (Sigmon et al. 2020. PubMed ID: 29261981). Approximately 8% of infants with a congenital anomaly of the gastrointestinal tract have Hirschsprung disease (Asindi et al. 2002. PubMed ID: 12370716), and 10-50% of patients with Hirschsprung disease have causative variants in the RET, EDNRB, or EDN3 genes (Kusafuka et al. 1996. PubMed ID: 8852658; Svensson et al. 1999. PubMed ID: 10231870; Sancandi et al. 2000. PubMed ID: 10646792).

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

This panel typically provides 98.8% 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).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).