Hirschsprung Disease (HSCR) via the RET Gene

Hirschsprung disease (HSCR) (OMIM# 142623), aka congenital intestinal aganglionosis, is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract (Eng & Mulligan. Hum Mutat 9:97-109, 1997). In 80% of individuals, aganglionosis is restricted to the rectosigmoid colon (S-HSCR); in 15%-20%, aganglionosis extends beyond the sigmoid colon (L-HSCR); in about 5%, aganglionosis affects the entire large intestine (total colonic aganglionosis). HSCR is the main genetic cause of functional intestinal obstruction in infants and children. 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, HSCR should be considered in anyone with lifelong severe constipation.

Hirschsprung disease (HSCR) has an estimated incidence of 1 in 5,000 births, varying among different ethnic groups. About 70% of affected individuals have the nonsyndromic form (isolated HSCR), and the remaining 30% have the syndromic form with multiple congenital abnormalities. At least six different genes are associated with isolated HSCR, with different inheritance patterns (Parisi GeneReview 2006). RET is the primary gene underlying HSCR, and RET-related HSCR is inherited in an autosomal dominant manner with reduced and sex-dependent penetrance (Passarge Nat Genet 31:11-12, 2002). Loss-of-function variants in RET have been identified in 50% familial and 10-35% of sporadic HSCR cases. The RET proto-oncogene is one of the receptor tyrosine kinases, cell-surface molecules that transduce signals for cell growth and differentiation. This gene plays a crucial role in neural crest development. RET interacts with the glial-derived neurotropic factor (GDNF) family of ligands: GDNF, neurturin, persephin, and artemin. Formation of a complex containing two RET protein molecules leads to RET autophosphorylation and intracellular signaling (Santoro et al. Endocrinology 145:5448-5451, 2004).

This test is predicted to detect disease variants in 50% of familial HSCR cases and up to 35% of sporadic HSCR cases (Attie et al. Hum Mol Genet 4:1381-1386, 1995; Eng & Mulligan. Hum Mutat 9:97-109, 1997, Hofstra et al. Hum Mutat 15:418-429, 2000; Bolk Gabriel et al. Nature Genet 31:89-93, 2002). Among individuals with L-HSCR, a RET variant can be detected in as high as 80% of cases (Angrist et al. Hum Mol Genet 4:821-830, 1995, Seri et al. Hum Mutat 9:243-249, 1997).

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