In fact the existence of other genetic factors conferring susceptibility to HSCR in specific populations has been repeatedly reported. For instance, it has been reported that there exist two different RET haplotypes encompassing the enhancer mutation that are over-transmitted to the HSCR offspring in Caucasian populations, while in the Chinese sample only one of those haplotypes was present. A possible explanation was that the enhancer mutation arose on one haplotype which, after the Asian-European split, rearranged to give also the other haplotype, but exclusively in the European part. A similar hypothesis could be forwarded to explain the NRG1 effects in the Chinese population, being this supported by the fact that great differences are observed among the frequencies of the studied variants between both populations. That difference among Caucasian and Asian populations had been recently corroborated by a recent genotyping study in Thai population, where the genetic XAV939 Wnt/beta-catenin inhibitor variation of the RET-protooncogene and NRG1 is involved in the risk of HSCR development in the Thai population. Previous studies had indicated that NRG1 is a signalling protein that mediates cell-cell interactions and it is essential for the development and function of multiple organ systems and its dysregulation has been linked to diseases such as breast cancer, schizophrenia and HSCR. In addition, it has been shown that not only common, but also rare variants of the NRG1 gene contribute to HSCR. Here we report some novel variants located within the non-coding region although after bioinformatic predictions we failed to find that any of those variants would affect neither the splicing process nor the formation or modification of a transcription factor binding site in the DNA sequence. Furthermore, we report three new missense mutations as probably causing mutations for HSCR. Those variants were located on functional domains within the protein and all of them were found totally absent in control population. After functional approaches, we found that M111T, R438H and M139I mutant proteins induced a significant reduction in the quantity of the normal NRG1 protein levels in cells expressing them. In fact, our in silico predictions revealed that M111T and R438H would be probably damaging. Two of the affected residues in the NRG1 protein were located at the extracellular domain and the other one, R438H, was located at the cytoplasmic domain. The Ig-like domain in NRGs proteins could act in the process of attenuation of signalling through ErbB receptors, promoting the internalization and degradation of the complex ligand-receptor. This could be a control mechanism of the NRGs biological activity limiting their ability to diffuse freely and allowing the intracellular accumulation of these proteins to act quickly after being processed. The variant M111T detected at this domain would influence this process of attenuation which would explain the significant reduction of NRG1 level detected in cell lysates and the absence of differences obtained in the conditioned media. In addition, there are two important facts to mention about M111T variant: First, the change of a methionine by a threonine means that it is a non-conservative mutation. This aminoacidic change would alter structures and/or functions of NRG1 protein, as we can guess by functional approaches.