Contribution of rare and common variants determine complex diseases—Hirschsprung disease as a model

Abstract

Finding genes for complex diseases has been the goal of many genetic studies. Most of these studies have been successful by searching for genes and mutations in rare familial cases, by screening candidate genes and by performing genome wide association studies. However, only a small fraction of the total genetic risk for these complex genetic diseases can be explained by the identified mutations and associated genetic loci. In this review we focus on Hirschsprung disease (HSCR) as an example of a complex genetic disorder. We describe the genes identified in this congenital malformation and postulate that both common 'low penetrant' variants in combination with rare or private 'high penetrant' variants determine the risk on HSCR, and likely, on other complex diseases. We also discuss how new technological advances can be used to gain further insights in the genetic background of complex diseases. Finally, we outline a few steps to develop functional assays in order to determine the involvement of these variants in disease development.

Contrasting genetic architectures in different mouse reference populations used for studying complex traits

“…Affected individuals lack enteric neurons along the gastrointestinal tract, leading to constipation or intestinal obstruction. The penetrance and severity of Hirschsprung's disease is often determined by interactions between genes within the GDNF/RET and EDNRB pathways, including an interaction between RET and NRG1 (Gabriel et al 2002;Garcia-Barcelo et al 2009;Wallace and Anderson 2011;Alves et al 2013). The key to success for these genetic studies lies in the important but limited genetic heterogeneity of each disorder.…”

Functional Loss of Semaphorin 3C and/or Semaphorin 3D and Their Epistatic Interaction with Ret Are Critical to Hirschsprung Disease Liability

“…Genetic studies have identified rare high-penetrance mutations in , cumulatively explaining only a modest number of cases (<10%) and often involving syndromic forms. 2,3 Surprisingly, significantly greater phenotypic variation is explained by two common low-penetrance non-coding variants at RET (rs2435357) 4 and NRG1 (MIM 142445) (rs4541858), 5 respectively. Of these, rs2435357 disrupts function of a GI-tract-specific enhancer in RET intron 1 through abrogation of SOX10 binding, thereby reducing RET expression.…”

Familial hirschsprung’s disease: a systematic review

“…HSCR is a multi-genetic condition with complex aetiology [5]. Mutations in RET proto-oncogene and endothelin receptor B (ENDRB) are the most frequent genetic insults [6].…”