Abstract
Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract. The HSCR phenotype is highly variable with respect to gender, length of aganglionosis, familiality and the presence of additional anomalies. By molecular genetic analysis, a minimum of 11 neuro-developmental genes (RET, GDNF, NRTN, SOX10, EDNRB, EDN3, ECE1, ZFHX1B, PHOX2B, KIAA1279, TCF4) are known to harbor rare, high-penetrance mutations that confer a large risk to the bearer. In addition, two other genes (RET, NRG1) harbor common, low-penetrance polymorphisms that contribute only partially to risk and can act as genetic modifiers. To broaden this search, we examined whether a set of 67 proven and candidate HSCR genes harbored additional modifier alleles. In this pilot study, we utilized a custom-designed array CGH with ∼33,000 test probes at an average resolution of ∼185 bp to detect gene-sized or smaller copy number variants (CNVs) within these 67 genes in 18 heterogeneous HSCR patients. Using stringent criteria, we identified CNVs at three loci (MAPK10, ZFHX1B, SOX2) that are novel, involve regulatory and coding sequences of neuro-developmental genes, and show association with HSCR in combination with other congenital anomalies. Additional CNVs are observed under relaxed criteria. Our research suggests a role for CNVs in HSCR and, importantly, emphasizes the role of variation in regulatory sequences. A much larger study will be necessary both for replication and for identifying the full spectrum of small CNV effects.
Highlights
Among newborns, the most frequent cause of a functional intestinal obstruction is Hirschsprung disease (HSCR: MIM# 142623), or congenital aganglionosis, a neuro- developmental defect associated with the lack of intramural ganglion cells in the myenteric and sub-mucosal plexuses along varying segments of the gastrointestinal tract [1]
HSCR is a multifactorial disorder where multiple rare and common mutations exist within each patient
Any single HSCR gene is expected to be mutant in only a subset of patients implying that the number of genes involved and their mutational types are numerous
Summary
The most frequent cause of a functional intestinal obstruction is Hirschsprung disease (HSCR: MIM# 142623), or congenital aganglionosis, a neuro- developmental defect associated with the lack of intramural ganglion cells in the myenteric and sub-mucosal plexuses along varying segments of the gastrointestinal tract [1]. HSCR usually occurs as an isolated trait in ,70% of cases: the remainder comprises those with a recognized chromosomal abnormality, a recognized syndrome or additional congenital anomalies [2] This birth defect is not uncommon and shows population incidences of 15, 28 and 21 cases per 100,000 live births among Europeans, Asians and Africans, respectively [1]. Numerous molecular genetic studies have identified rare highpenetrance mutations in 11 genes (RET, GDNF, NRTN, SOX10, EDNRB, EDN3, ECE1, ZFHX1B, PHOX2B, KIAA1279, TCF4) in HSCR [1,2]. Cumulatively, these mutations explain only a minority (,5%) of cases. Additional phenotypic variation is explained by two common low-penetrance polymorphic variants at RET [4] and NRG1 [5], but the vast majority (,80%) of HSCR heritability is still hidden or missing [6]
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