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Hirschsprung disease, associated syndromes and genetics: a review

¹ Université Paris 5-Descartes, Faculté de Médecine; INSERM U-781; AP-HP, Hôpital Necker-Enfant Malades, Paris, France
² McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA
³ Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine of the University of Hong Kong, Hong Kong SAR, China
⁴ Laboratorio di Genetica Molecolare, Istituto G. Gaslini, L.go G. Gaslini 5, Italy
⁵ Dipartimento di Scienze della Salute, Sezione Biostatistica, Universitè degli Studi di Genova, Genova, Italy
⁶ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
⁷ Unidad Clinica de Genetica y Reproduccion. Hospitales Universitarios Virgen del Rocio and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Sevilla, Spain
⁸ Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands

Correspondence to:
Dr Jeanne Amiel, INSERM U781 et Département de Génétique, Hôpital Necker-Enfants Malades, 149, rue de Sèvres 75743 Paris Cedex 15, France; amiel{at}necker.fr]

ABSTRACT
Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.

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