Human Heredity最新文献

Background: Voltage-gated sodium channels are protein complexes composed of 2 subunits, namely, pore-forming α- and regulatory β-subunits. A β-subunit consists of 5 proteins encoded by 4 genes (i.e., SCN1B-SCN4B).

Summary: β1-Subunits regulate sodium ion channel functions, including gating properties, subcellular localization, and kinetics. Key Message: Sodium channel β1- and its variant β1B-subunits are encoded by SCN1B. These variants are associated with many human diseases, such as epilepsy, Brugada syndrome, Dravet syndrome, and cancers. On the basis of previous research, we aimed to provide an overview of the structure, expression, and involvement of SCN1B in physiological processes and focused on its role in diseases.

Objectives: Nonsyndromic hearing loss (NSHL) is the most frequent type of hereditary hearing impairment. Here, we explored the underlying genetic cause of NSHL in a three-generation family using whole-exome sequencing. The proband had concomitant NSHL and rare 48,XXYY Klinefelter syndrome.

Material and methods: Genomic DNA was extracted from the peripheral blood of the proband and their family members. Sanger sequencing and pedigree verification were performed on the pathogenic variants filtered by whole-exome sequencing. The function of the variants was analyzed using bioinformatics software.

Results: The proband was digenic heterozygous for p.V37I in the GJB2 gene and p.L347I in the MYO7A gene. The proband's mother had normal hearing and did not have any variant. The proband's father and uncle both had NSHL and were compound for the GJB2 p.V37I and MYO7A p.L347I variants, thus indicating a possible GJB2/MYO7A digenic inheritance of NSHL. 48,XXYY Klinefelter syndrome was discovered in the proband after the karyotype analysis, while his parents both had normal karyotypes.

Conclusions: Our findings reported a putative GJB2/MYO7A digenic inheritance form of hearing loss, expanding the genotype and phenotype spectrum of NSHL. In addition, this is the first report of concomitant NSHL and 48,XXYY syndrome.

Introduction: Auditory neuropathy is a hearing disorder where outer hair cell function within the cochlea is normal, but inner hair cell and/or the auditory nerve function is disrupted. It is a heterogeneous disorder, which can have either congenital or acquired causes.

Methods: We found a disease-segregating mutation in the X-linked AIFM1 gene through whole-exome sequencing, encoding the apoptosis-inducing factor mitochondrion-associated 1.

Results: The impact of the c.1045A>G; p.(Ser349Gly) mutation on the AIFM1 protein was predicted using different bioinformatics tools. The pedigree analysis in the examined family was consistent with X-linked dominant inheritance.

Discussion/conclusion: To our knowledge, this is the first study that identifies a mutation in the AIFM1 gene in Moroccan patients suffering from X-linked auditory neuropathy.

Weighted burden analysis has been used in exome-sequenced case-control studies to identify genes in which there is an excess of rare and/or functional variants associated with phenotype. Implementation in a ridge regression framework allows simultaneous analysis of all variants along with relevant covariates, such as population principal components. In order to apply the approach to a quantitative phenotype, a weighted burden score is derived for each subject and included in a linear regression analysis. The weighting scheme is adjusted in order to apply differential weights to rare and very rare variants and a score is derived based on both the frequency and predicted effect of each variant. When applied to an ethnically heterogeneous dataset consisting of 49,790 exome-sequenced UK Biobank subjects and using body mass index as the phenotype, the method produces a very inflated test statistic. However, this is almost completely corrected by including 20 population principal components as covariates. When this is done, the top 30 genes include a few which are quite plausibly associated with the phenotype, including LYPLAL1 and NSDHL. This approach offers a way to carry out gene-based analyses of rare variants identified by exome sequencing in heterogeneous datasets without requiring that data from ethnic minority subjects be discarded. This research has been conducted using the UK Biobank Resource.

Introduction: Breast cancer is a heterogeneous and multifactorial disease. TP53 and PAI-1 as important tumor suppressor genes are involved in the development, invasion, and metastasis of many cancers. This study's objective was to demonstrate the combined genotype effects of these 2 genes by investigating their single nucleotide polymorphisms.

Methods: In this case-control study, 200 individuals with breast cancer and 179 healthy individuals were studied. The genotypes were determined using the tetra-ARMS method. For data analysis, MDR, online javstat statistics package, and SPSS v.24 software were used. Also, in silico studies on the estimated effects of each of these polymorphisms were performed.

Results: We showed a novel gene-gene interaction of these 2 genes and demonstrated a strong synergistic interaction for TP53/PAI-1, moderate synergistic interaction for PAI-1/age, and correlation for TP53/age. On the other hand, there was no association between the allelic and genotype frequency alone and in combination, with case-control status, using the parametric method, between TP53 and PAI-1.

Discussion/conclusion: Our findings suggest that the polymorphism of codon 72 of the TP53 gene was significantly associated with tumor stage (p < 0.023). In conclusion, we showed a gene-gene interaction between TP53 and PAI-1, in combination, using the MDR method.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is caused by one or more mutations in the G6PD gene on chromosome X. This study aimed to characterize the G6PD gene variant distribution in Shenzhen of Guangdong province.

Methods: A total of 33,562 individuals were selected at the hospital for retrospective analysis, of which 1,213 cases with enzymatic activity-confirmed G6PD deficiency were screened for G6PD gene variants. Amplification refractory mutation system PCR was first used to screen the 6 dominant mutants in the Chinese population (c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, c.392G>T, and c.871G>A). If the 6 hotspot variants were not found, next-generation sequencing was then performed. Finally, Sanger sequencing was used to verify all the mutations.

Results: The incidence of G6PD deficiency in this study was 3.54%. A total of 26 kinds of mutants were found in the coding region, except for c.-8-624T>C, which was in the noncoding region. c.1376G>T and c.1388G>A, both located in exon 12, were the top 2 mutants, accounting for 68.43% of all individuals. The 6 hotspot mutations had a cumulative proportion of 94.02%.

Conclusions: This study provided detailed characteristics of G6PD gene variants in Shenzhen, and the results would be valuable to enrich the knowledge of G6PD deficiency.