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. 2011 Oct 13:12:138.
doi: 10.1186/1471-2350-12-138.

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-Torres  1 , Raquel M Fernández, Manuel Jesus Acosta, Maria Del Valle Enguix-Riego, Martina Marbá, Juan Carlos de Agustín, Luis Castaño, Guillermo Antiñolo, Salud Borrego
Affiliations

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-Torres et al. BMC Med Genet. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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Figures

Figure 1
Figure 1
Schematic representation of RET protein. Mutations identified in this study are indicated in the corresponding functional domain. Novel and published mutations are presented in black and grey, respectively.
Figure 2
Figure 2
Allelic distribution frequency of RET enhancer variant rs2435357 in Male and Female subset.
See this image and copyright information in PMC

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