PGT-M for spinocerebellar ataxia type 1: development of a STR panel and a report of two clinical cases.

PURPOSE: To present the developed preimplantation genetic testing (PGT) for spinocerebellar ataxia type 1 (SCA1) and the outcomes of IVF with PGT. METHODS: PGT was performed for two unrelated couples from the Republic of Sakha (Yakutia) with the risk of SCA1 in one spouse. We have developed a system for PGT of a monogenic disease (PGT-M) for SCA1, which includes the analysis of a panel of 11 polymorphic STR markers linked to the ATXN1 gene and a pathogenic variant of the ATXN1 gene using nested PCR and fragment analysis. IVF/ICSI programs were performed according to standard protocols. Multiple displacement amplification (MDA) was used for whole genome amplification (WGA) and array comparative genomic hybridization (aCGH) for aneuploidy testing (PGT-A). RESULTS: Eight STRs were informative for the first couple and ten for the second. Similarity of the haplotypes carrying pathogenic variants of the ATXN1 gene was noted. In the first case, during IVF/ICSI-PGT, three embryos reached the blastocyst stage and were biopsied. One embryo was diagnosed as normal by maternal STR haplotype and the ATXN1 allele. PGT-A revealed euploidy. The embryo transfer resulted in a singleton pregnancy, and a healthy boy was born. Postnatal diagnosis confirmed normal ATXN1. In the second case, two blastocysts were biopsied. Both were diagnosed as normal by PGT-M, but PGT-A revealed aneuploidy. CONCLUSION: Birth of a healthy child after PGT for SCA1 was the first case of successful preimplantation prevention of SCA1 for the Yakut couple and the first case of successful PGT for SCA1 in Russia.

Impact of the Polymorphism of the PACRG and CD80 Genes on the Development of the Different Stages of Tuberculosis Infection.

BACKGROUND: Tuberculosis (TB) is one of the most significant health-care problems worldwide. The host's genetics play an important role in the development of TB in humans. The disease progresses through several stages, each of which can be under the control of different genes. The precise genes influencing the different stages of the disease are not yet identified. The aim of the current study was to determine the associations between primary and secondary TB and the polymorphisms of novel candidate genes for TB susceptibility, namely CD79A, HCST, CXCR4, CD4, CD80, CP, PACRG, and CD69. METHODS: A total of 357 patients with TB (130 cases with primary TB and 227 cases with secondary TB) from the Siberian region of Russia as well as 445 healthy controls were studied. The study was performed at the Research Institute of Medical Genetics, Tomsk NRMC, Tomsk, Russia, between July 2015 and November 2016. Genotyping was carried out using MALDI-TOF mass spectrometry and PCR-RFLP. The associations between the single-nucleotide polymorphisms and TB were assessed using logistic regression adjusting for covariates (age and gender). Multiple testing was addressed via the experiment-wise permutation approach. The statistical significance threshold was a P value less than 0.05 for the permutation P values. The analyses were done in R 3.2 statistical software. RESULTS: An association was established between the rs1880661 variant of the CD80 gene and secondary TB and the rs10945890 variant of the PACRG gene and both primary and secondary TB. However, the same allele of PACRG appeared to be both a risk factor for reactivation (secondary TB) and a protector against primary infection. CONCLUSION: The results suggested that the CD80 and PACRG genes were associated with susceptibility to different forms of TB infection in the Russian population.

Molecular Relationships between Bronchial Asthma and Hypertension as Comorbid Diseases.

Comorbidity, a co-incidence of several disorders in an individual, is a common phenomenon. Their development is governed by multiple factors, including genetic variation. The current study was set up to look at associations between isolated and comorbid diseases of bronchial asthma and hypertension, on one hand, and single nucleotide polymorphisms associated with regulation of gene expression (eQTL), on the other hand. A total of 96 eQTL SNPs were genotyped in 587 Russian individuals. Bronchial asthma alone was found to be associated with rs1927914 (TLR4), rs1928298 (intergenic variant), and rs1980616 (SERPINA1); hypertension alone was found to be associated with rs11065987 (intergenic variant); rs2284033 (IL2RB), rs11191582 (NT5C2), and rs11669386 (CARD8); comorbidity between asthma and hypertension was found to be associated with rs1010461 (ANG/RNASE4), rs7038716, rs7026297 (LOC105376244), rs7025144 (intergenic variant), and rs2022318 (intergenic variant). The results suggest that genetic background of comorbidity of asthma and hypertension is different from genetic backgrounds of both diseases manifesting isolated.

Mutations in genes underlying atypical familial mycobacteriosis are not found in tuberculosis patients from Siberian populations.

OBJECTIVES: Atypical familial mycobacteriosis (AFM, OMIM #209950) is caused by mutations in genes regulating IL12/IFNG pathway. Some of the mutations exhibit incomplete penetrance, and they have been proposed to be involved in the common (polygenic) predisposition to tuberculosis (TB). We set out to test this hypothesis in two populations from Siberian region of Russia with high prevalence of TB. MATERIAL AND METHODS: The prevalence of twelve mutations in IL12/IFNG pathway genes of were analysed in 331 Russians and 238 Tuvinians TB patients and in 279 healthy Russians and 265 healthy Tuvinians. A screening for new mutations and rare polymorphisms was carried out in 10 children with severe generalized TB and severe BCG-vaccine complications using Sanger's bidirectional sequencing. RESULTS: Twelve mutations most commonly identified in AFM patients appeared to be "wild-type" monomorphic in the studied groups. No new mutations or rare polymorphisms were identified by sequencing. However, 15 common single nucleotide polymorphisms were found, none of which was associated with TB after correction for multiple testing. CONCLUSION: The results of the study contradict with a hypothesis that mutations underlying AFM syndrome are involved in the predisposition to TB.