Evaluation Of Gene Variants Research Articles

Evaluation of Gene Variants in TGFB1, SERPINF1 and MEPE in a Spanish Family Affected by Otosclerosis and Tinnitus

Otosclerosis (OTSC) is a common type of deafness affecting up to 0.4 % of Caucasians. Its familial form is inherited in an autosomal dominant fashion, although to this date, no definitive cause for OTSC has been found. In the development of OTSC, three recent genetic association studies have suggested the participation of particular point mutations and small indels in the TGFB1, SERPINF1, and MEPE genes. Consequently, replicative studies are needed to confirm the role of the proposed mutations in OTSC patients. The goal of this study was to test the presence of the candidate variants described in the genes TGFB1, SERPINF1, and MEPE in a new case of familial OTSC with seven affected individuals. DNA was extracted from saliva samples of a Spanish family with several members affected by OTSC. PCR amplified target regions of some candidate genes, and the products were purified, Sanger-sequenced, and analyzed in silico. The family subject of the study did not carry the candidate variants for OTSC described in the genes TGFB1, SERPINF1, and MEPE, although it cannot be ruled out the involvement of other mutations in genes related to their same signaling pathways. This result highlights the importance of performing replicative studies for complex diseases, such as OTCS, in families of diverse origins. Additionally, a significant association of subjective tinnitus with OTSC has been found in this family, although the link between the two pathologies should be studied further.

Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole-exome next generation sequencing.

IntroductionVitamin D (VD) deficiency has been associated with multiple sclerosis (MS) and other autoimmune diseases (AIDs). However, the effect of the genetics of VD on the risk of MS is subject to debate. This study focuses on genes linked to the VD signaling pathway in families with MS. The evaluation of gene variants in all the members of families could contribute to an additional knowledge on the information obtained from case‐control studies that use nonrelated healthy people.Material and MethodsWe studied 94 individuals from 15 families including at least two patients with MS. We performed whole‐exome next generation sequencing on all individuals and analyzed variants of the DHCR7, CYP2R1, CYP3A4, CYP27A1, GC, CYP27B1, LRP2, CUBN, DAB2, FCGR, RXR, VDR, CYP24A1, and PDIA3 genes. We also studied PTH, FGF23, METTL1, METTL21B, and the role of the linkage disequilibrium block on the long arm of chromosome 12, through analysis of the CDK4, TSFM, AGAP2, and AVIL genes. We compared patients with MS, other AIDs and unaffected members from different family types.ResultsThe study described the variants in the VD signaling pathway that appear in families with at least two patients with MS. Some infrequent variants were detected in these families, but no significant difference was observed between patients with MS and/or other AIDs and unaffected family members in the frequency of these variants. Variants previously associated with MS in the literature were not observed in these families or were distributed similarly in patients and unaffected family members.ConclusionThe study of genes involved in the VD signaling pathway in families that include more than one patient with MS did not identify any variants that could explain the presence of the disease, suggesting that VD metabolism could probably play a role in MS more as an environmental factor rather than as a genetic factor. Our study also supports the analysis of cases and unaffected individuals within families in order to determine the influence of genetic factors.