Hirschsprung, RET-SOX and beyond: the challenge of examining non-mendelian traits (Review).
Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a common hereditary disorder causing intestinal obstruction, thereby showing considerable phenotypic variation in conjunction with complex inheritance. Moreover, phenotypic assessment of the disease has been complicated since a subset of the observed mutations is also associated with several additional syndromic anomalies. Coding sequence mutations in e.g. RET, GDNF, EDNRB, EDN3, and SOX10 lead to long-segment (L-HSCR) as well as syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). Furthermore, mutations in the RET gene are responsible for approximately half of the familial and some sporadic cases, strongly suggesting, on the one hand, the importance of non-coding variations and, on the other hand, that additional genes involved in the development of the enteric nervous system still await their discovery. For almost all of the identified HSCR genes incomplete penetrance of the HSCR phenotype has been reported, probably due to modifier loci. Therefore, HSCR has become a model for a complex oligo-/polygenic disorder in which the relationship between different genes creating a non-mendelian inheritance pattern still remains to be elucidated.
Pusch
Carsten M
CM
Division of Molecular Genetics, University of Tübingen, 72074 Tubingen, Germany.
Sasiadek
Maria M
MM
Blin
Nikolaus
N
D004268:DNA-Binding Proteins / Q000235:genetics*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006609:High Mobility Group Proteins / Q000235:genetics*; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D020412:Multifactorial Inheritance / Q000235:genetics*; D009414:Nerve Growth Factors / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics; D055757:SOXE Transcription Factors; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006609:High Mobility Group Proteins; D009414:Nerve Growth Factors; D015513:Oncogene Proteins; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; D014157:Transcription Factors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases