Genetic testing for hirschsprung disease (hscr) blueprint genetics electricity voltage in india

Some patients heterozygous for a de novo polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene have isolated or more commonly syndromic Hirschsprung disease in association with with congenital central hypoventilation syndrome (CCHS, PMID 16888290). Repeat expansions are generally difficult to detect via NGS assays and their clinical validation at large scale is impossible due to lack of publicly available control samples with abnormal repeat expansions. So far, we have been able to detect and confirm stretches of 28 alanines instead of normal amount of 20 (genotype “20/28”). However, we do not know exact sensitivity or detection limit of our assay for these alanine repeats.

Some patients heterozygous for a de novo polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene have isolated or more commonly syndromic Hirschsprung disease in association with with congenital central hypoventilation syndrome (CCHS, PMID 16888290). Repeat expansions are generally difficult to detect via NGS assays and their clinical validation at large scale is impossible due to lack of publicly available control samples with abnormal repeat expansions. So far, we have been able to detect and confirm stretches of 28 alanines instead of normal amount of 20 (genotype “20/28”). However, we do not know exact sensitivity or detection limit of our assay for these alanine repeats. ICD codes

Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. Nerve cells are critical to the functioning of the colon as they control the regular muscle contractions that keep food moving through the bowels. In HSCR the aganglionic segment includes the distal rectum and a variable length of contiguous proximal intestine. In 80% of individuals, aganglionosis is restricted to the rectosigmoid colon (short-segment disease), in 15%-20%, it extends proximal to the sigmoid colon (long-segment disease) and in about 5%, aganglionosis affects the entire large intestine (total colonic aganglionosis). Affected infants typically have 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 in the first two months of life. However, in the milder forms the initial diagnosis of HSCR may be delayed until late childhood or adulthood, and therefore HSCR should be considered in anyone with lifelong severe constipation. Individuals with HSCR are at risk for enterocolitis and/or potentially lethal intestinal perforation. HSCR is considered a neurocristopathy, a disorder of cells and tissues derived from the neural crest, and may occur as an isolated finding or as part of a multisystem disorder. Both syndromic and nonsyndromic causes of HSCR are recognized. Roughly a third of children who have Hirschsprung’s disease have other organ system involvement. Examples of monogenic syndromic forms of HSCR (covered by this panel) are Waardenburg syndrome type 4 (autosomal recessive disease due to EDNRB, EDN3 mutations in which HSCR is common and autosomal dominant form with SOX10 mutations in which HSCR is present in almost 100% of cases), Mowat-Wilson syndrome (mutations in ZEB2, HSCR present in 41-71% of cases) and multiple endocrine neoplasia type 2 (MEN 2A and 2B) (mutations in RET). Approximately 50% of familial cases of HSCR are heterozygous for mutations in RET, however the penetrance of these mutations is only 50 to 70%, is gender-dependent, and varies according to the extent of aganglionosis. The incidence of HSCR is approximately 1/ 5,000 live births, but it varies among different populations.

Some patients heterozygous for a de novo polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene have isolated or more commonly syndromic Hirschsprung disease in association with with congenital central hypoventilation syndrome (CCHS, PMID 16888290). Repeat expansions are generally difficult to detect via NGS assays and their clinical validation at large scale is impossible due to lack of publicly available control samples with abnormal repeat expansions. So far, we have been able to detect and confirm stretches of 28 alanines instead of normal amount of 20 (genotype “20/28”). However, we do not know exact sensitivity or detection limit of our assay for these alanine repeats. The strengths of this test include:

Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk ( *) if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above). This test does not detect the following: