Hirschsprung Disease, Cardiac Defects and Autonomic Dysfunction via the ECE1 Gene

Hirschsprung Disease (HSCR) is characterized by congenital absence of neuronal ganglion cells from a portion of the intestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR, about 15%-20% of cases) when aganglionosis extends proximal to the sigmoid (Amiel et al. 2008). In about 5% of cases, aganglionosis affects the entire large intestine (total colonic aganglionosis). Cases with total colonic aganglionosis and total intestinal HSCR also occur. Affected infants frequently present in the first two months of life with symptoms of impaired intestinal motility such as failure to pass meconium within the first 48 hours of life, constipation, emesis, abdominal pain or distention, and occasionally diarrhea. However, because the initial diagnosis of HSCR may be delayed until late childhood or adulthood, HSCR should be considered in anyone with lifelong severe constipation. HSCR can also be associated with cardiac defects and autonomic dysfunction. Individuals with HSCR are at risk for enterocolitis and/or potentially lethal intestinal perforation (Parisi 2011).

Hirschsprung Disease as a feature of other disorders [Syndromic HSCR]: While HSCR is observed in 10-15% of Down syndrome patients and some cases of MEN2 (Parisi 2011), it occurs as a constant feature of the following syndromes; Waardenburg-Shah Syndrome [OMIM # 277580], Mowat-Wilson Syndrome [OMIM # 235830], Goldberg-Shprintzen Megacolon Syndrome [OMIM # 609460] and Haddad Syndrome [OMIM # 209880].

Hirschsprung Disease demonstrates a multifactorial or polygenic mode of inheritance with an incidence of 1 in 5000 newborns. There is a male predominance of 3:1 to 5:1 in Hirschsprung disease (Lipson et al 1990). Incidence of short-segment disease (80% of HSCR) is four times greater in males than in females; while equal numbers of males and females present with long-segment disease (Badner et al 1990). For L-HSCR cases, the mode of inheritance is compatible with a dominant gene with incomplete penetrance, while for S-HSCR cases, the inheritance pattern is equally likely to be either multifactorial or due to a recessive gene with very low penetrance.

Non-syndromic HSCR has been associated with mutations in at least six genes; RET, EDN3, EDNRB, GDNF, ECE1 and NRTN with mutations in RET accounting for ~50% of cases (Parisi and Kapur 2000). Hirschsprung Disease, Cardiac Defects and Autonomic Dysfunction is caused by heterozygous mutations in ECE1, suggesting an autosomal dominant mode of inheritance (Hofstra et al. 1999). ECE1 (endothelin convertin enzyme-1), is involved in proteolytic processing of endothelin precursors to biologically active peptides.

Mutations in ECE1 are also associated with Essential Hypertension [OMIM#145500].

Mutations in ECE1 are associated with non-syndromic HSCR. The clinical sensitivity of our sequencing assay for this gene is currently unknown. However, since only missense and truncating mutations have been described, we believe that our sequencing assay will be able to identify a significant majority of the causative mutations.

This test provides full coverage of all coding exons of the ECE1 gene 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 full 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).