Tilghman JM, et al. - Samples from 190 patients with Hirschsprung’s disease were genotyped and exome-sequenced in order to determine the genetic burden in these patients. DNA sequence variants, large copy-number variants, and karyotype variants in probands, when significantly correlated with Hirschsprung’s disease or another neurodevelopmental disorder, were considered to be pathogenic. A widespread risk of Hirschsprung’s disease was defined with the presence of five or more variants in four noncoding elements (48.4% of patients and 17.1% of controls). Hirschsprung’s disease was initiated from common noncoding variants, rare coding variants, and copy-number variants impacting genes involved in enteric neural-crest cell fate that intensify the widespread genetic susceptibility linked with receptor tyrosine kinase, among the studied patients. For individual patients, variation by a factor of around 67 was noted in the genotype-specific odds ratios, which affords a basis for risk stratification and genetic counseling.