A novel pathogenic variant in OSBPL2 linked to hereditary late-onset deafness in a Mongolian family.

BACKGROUND: To investigate the clinical features and the underlying causal gene of a family with hereditary late-onset deafness in Inner Mongolia of China, and to provide evidence for the early genetic screening and diagnosis of this disease. METHODS: Family data were collected to draw a pedigree. Audiological testing and physical examination of the family members were conducted following questionnaire. Genomic DNA was extracted from peripheral blood of 5 family members (3 patients and 2 normal control) and subjected to whole genome sequencing for identifying deafness casual genes. The pathogenic variant in the deafness gene was further confirmed by Sanger sequencing. RESULTS: The family is composed of a total of 6 generations, with 53 traceable individuals. In this family,19 of them were diagnosed with post lingual deafness with the age of onset between 10 and 40 years, displaying delayed and progressive hearing loss. Patients with hearing loss showed bilateral symmetry and mild to severe sensorineural deafness. The pattern of deafness inheritance in this family is autosomal dominant. Whole genome sequencing identified a novel pathogenic frameshift mutation, c.158_159delAA (p.Gln53Arg fs*100) in the gene OSBPL2 (Oxysterol-binding protein-related protein 2, NM_144498.2), which is absent from genomic data of 201 unrelated normal subjects. This pathogenic variant was further validated by Sanger sequencing, and was found to co-segregate in this family. CONCLUSIONS: Whole genome sequencing identified a two-nucleotide deletion in OSBPL2 (c.158_159delAA) as the pathogenic variant for deafness in the family. Our finding expands the mutational spectrum of OSBPL2 and contributes to the pathogenic variant list in genetic counseling for deafness screening.

Bidirectional causal link between inflammatory bowel disease and celiac disease: A two-sample mendelian randomization analysis.

Background: Observational research has shown a correlation between inflammatory bowel disease (IBD) [comprising ulcerative colitis (UC) and Crohn's disease (CD)] and celiac disease. However, the relationship between these two diseases remains uncertain. Methods: We utilized two-sample Mendelian randomization (MR) to estimate the bidirectional causal relationships between IBD and celiac disease. This study utilized data on single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWASs). Heterogeneity, pleiotropy, and sensitivity analyses were also performed to evaluate the MR results. Results: There was a significant causal relationship between IBD and CD and celiac disease (e.g., IBD and celiac disease, inverse variance weighting (IVW) odds ratio (OR) = 1.0828, 95% CI = 1.0258-1.1428, p = 0.0039; CD and celiac disease, IVW OR = 1.0807, 95% CI = 1.0227-1.1420, p = 0.0058). However, in the reverse direction, we found only suggestive positive causality between celiac disease and CD (e.g., IVW OR = 1.0366, 95% CI = 1.0031-1.0711, p = 0.0319). No evidence of heterogeneity between genetic variants was found (e.g., IBD vs. celiac disease, MR-Egger Q = 47.4391, p = 0.6159). Horizontal pleiotropy hardly influenced causality (e.g., IBD vs. celiac disease, MR-Egger test: p = 0.4340). Leave-one-out analysis showed that individual SNPs did not influence the general results. Conclusion: Our MR analysis revealed a positive causal link between IBD and celiac disease in the European population. In addition, several recommendations for disease prevention and clinical management have been discussed.

Identification of a HOXD13 variant in a Mongolian family with incomplete penetrance syndactyly by exon sequencing.

BACKGROUND: Syndactyly (SD) refers to a deformity caused by the fusion and limb differentiation disorder of soft tissues and/or skeletons to varying extents between adjacent fingers (toes). The main features of this disease are phenotypic heterogeneity and genetic heterogeneity. In this study, we examined four generations of a Chinese Mongolian with different phenotypes of syndactylia and analysed and identified the pathogenic genetic variants of SD by exon sequencing. METHODS: The clinical phenotypes of patients were analysed, and the hands and feet were examined by X-ray. The pedigree was drawn, and the family data were analysed. Peripheral blood was collected from the family members, and genomic DNA was extracted. The candidate genes of SD were identified by exon sequencing, and the mutation sites of the captured candidate genes were amplified by PCR and verified by Sanger sequencing. RESULTS: The family has congenital syndactyly, which is an autosomal dominant disease. At present, this condition has been passed down for 4 generations and was identified in 9 patients, including 4 males and 5 females. Five patients, I2, II4, III5, III,7 and III10, had unilateral syndactyly, and four patients, III16, IV3, IV6 and IV7, had bilateral finger syndactyly. All of their toes were unaffected. The proband and the other patients in this family had a c.917G > A (p.R306Q) mutation, which is located at position 917 of the second exon of the HOXD13 gene. This mutation results in a change in the amino acid at position 306, in which arginine is changed to glutamine. This mutation cosegregates in unaffected individuals and affected patients in this family. Moreover, 201 Mongolian genome databases and a thousand human genome databases were referenced to further confirm that the pathogenic genetic variant that causes syndactyly in this family is found in HOXD13. CONCLUSION: This study found that the mutation site of the pathogenic gene in this family was HOXD13, c.917G > A (p.R306Q). The phenotype of the family member III12 was normal, but this member was also a carrier of the pathogenic genetic variant. This indicates that the disease of this family has incomplete penetrance characteristics. Our results further enrich the expression profile of the HOXD13 gene.