Open Access Highly Accessed Research article

Comprehensive analysis of RET common and rare variants in a series of Spanish Hirschsprung patients confirms a synergistic effect of both kinds of events

Rocio Núñez-Torres12, Raquel M Fernández12, Manuel Jesus Acosta12, Maria del Valle Enguix-Riego12, Martina Marbá3, Juan Carlos de Agustín4, Luis Castaño5, Guillermo Antiñolo12 and Salud Borrego12*

Author affiliations

1 Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal. Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain

2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Sevilla, Spain

3 Departamento de Genómica y Bioinformática. Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain

4 Unidad de Gestión Clínica de Cirugía Infantil, Hospital Universitario Virgen del Rocío, Sevilla, Spain

5 Grupo de investigación en Endocrinología y Diabetes, Hospital de Cruces, Vizcaya, Spain

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Citation and License

BMC Medical Genetics 2011, 12:138  doi:10.1186/1471-2350-12-138

Published: 13 October 2011



RET is the major gene associated to Hirschsprung disease (HSCR) with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. In the present study, we have performed a comprehensive study of our HSCR series evaluating the involvement of both RET rare variants (RVs) and common variants (CVs) in the context of the disease.


RET mutational screening was performed by dHPLC and direct sequencing for the identification of RVs. In addition Taqman technology was applied for the genotyping of 3 RET CVs previously associated to HSCR, including a variant lying in an enhancer domain within RET intron 1 (rs2435357). Statistical analyses were performed using the SPSS v.17.0 to analyze the distribution of the variants.


Our results confirm the strongest association to HSCR for the "enhancer" variant, and demonstrate a significantly higher impact of it in male versus female patients. Integration of the RET RVs and CVs analysis showed that in 91.66% of cases with both kinds of mutational events, the enhancer allele is in trans with the allele bearing the RET RV.


A gender effect exists on both the transmission and distribution of rare coding and common HSCR causing mutations. In addition, these RET CVs and RVs seem to act in a synergistic way leading to HSCR phenotype.