Journal of Human Genetics

The human SET nuclear proto-oncogene (SET) gene is a protein-coding gene that encodes proteins that affects chromatin remodeling and gene transcription. Mutations in the SET gene have been reported to cause intellectual disability (ID) and epilepsy. In this study, we collected and analyzed clinical, genetic, and transcript features of two unrelated Chinese patients with ID. Both patients were characterized by moderate intellectual disability. Whole-exome sequencing identified two novel heterozygous mutations in the SET gene: NM_001122821...

Numerous variants of unknown significance (VUSs) exist in hereditary breast and ovarian cancers. Although multiple methods have been developed to assess the significance of BRCA1/2 variants, functional discrepancies among these approaches remain. Therefore, a comprehensive functional evaluation system for these variants should be established. We performed conventional homologous recombination (HR) assays for 50 BRCA1 and 108 BRCA2 VUSs and complementarily predicted VUSs using a statistical logistic regression prediction model that integrated six in silico functional prediction tools...

Heterozygous deleterious variants in SKI cause Shprintzen-Goldberg Syndrome, which is mainly characterized by craniofacial features, neurodevelopmental disorder and thoracic aorta dilatations/aneurysms. The encoded protein is a member of the transforming growth factor beta signaling. Paucity of reported studies exploring the SGS molecular pathogenesis hampers disease recognition and clinical interpretation of private variants. Here, the unpublished c.349G>A, p.[Gly117Ser] and the recurrent c.539C>T, p...

tRNA-histidine guanyltransferase 1-like protein (THG1L), located in the mitochondria, plays a crucial role in the tRNA maturation process. Dysfunction of THG1L results in abnormal mitochondrial tRNA modification and neurodevelopmental disorders. To date, few studies have focused on THG1L-related cerebellar ataxia. Whole-exome sequencing revealed compound heterozygous variants NM_017872.5: [c.224A > G]; [c.369-8T > G] in THG1L in a 6-year-old boy with moderate cerebellar ataxia...

This study aims to investigate the correlations between islet function/ insulin resistance and serum lipid levels, as well as to assess whether the strength of such correlations is affected by the GCKR rs1260326 variant in healthy and T2D individuals. We performed an oral glucose tolerance test (OGTT) on 4889 middle-aged adults, including 3135 healthy and 1754 T2D individuals from the REACTION population study in the Nanjing region. We also measured their serum lipid levels and genotyped for rs1260326. We found that serum high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels were independently correlated with indexes of islet function (HOMA-β and IGI [insulinogenic index]) and insulin resistance (HOMO-IR and ISIMatsuda ) in both healthy and T2D individuals...

No abstract text is available yet for this article.

OBJECTIVES: Genome-wide association studies (GWAS) have successfully revealed numerous susceptibility loci for obesity. However, identifying the causal genes, pathways, and tissues/cell types responsible for these associations remains a challenge, and standardized analysis workflows are lacking. Additionally, due to limited treatment options for obesity, there is a need for the development of new pharmacological therapies. This study aimed to address these issues by performing step-wise utilization of knowledgebase for gene prioritization and assessing the potential relevance of key obesity genes as therapeutic targets...

Hereditary tumor syndromes have garnered substantial attention due to their adverse effects on both the physical and psychological health of patients, as well as the elevated risk of transmission to subsequent generations. This has prompted a growing interest in exploring preimplantation genetic testing (PGT) as a treatment option to mitigate and eliminate these impacts. Several studies have demonstrated that de novo variants have become a great cause of many hereditary tumor syndromes, which introduce certain difficulties to PGT...

Benign adult familial myoclonic epilepsy type 1 (BAFME1) is an autosomal dominant, adult-onset neurological disease caused by SAMD12 repeat expansion. In BAFME1, anticipation, such as the earlier onset of tremor and/or seizures in the next generation, was reported. This could be explained by intergenerational repeat instability, leading to larger expansions in successive generations. We report a four-generation BAFME1-affected family with anticipation. Using Nanopore long-read sequencing, detailed information regarding the sizes, configurations, and compositions of the expanded SAMD12 repeats across generations was obtained...

Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis...

Neurogenetic diseases are rare genetic diseases in which neurological findings are prominent. Whole exome sequencing (WES) has led to great advances in the understanding of the causes of neurogenetic diseases. Etiological research ends with the WES method in many patients. This etiological research is called a "diagnostic odyssey" for many families. Here, we present the results of 168 patients who were previously undiagnosed and underwent WES with the suspicion of neurogenetic disease. A total of 168 cases, 94 males and 74 females, with suspected undiagnosed neurogenetic disease were included in the study...

Acute necrotizing encephalopathy (ANE) is a rare disease that predominantly affects children and is associated with a high mortality rate. Here we report three cases of COVID-19-related ANE in children, with the mutation detection in two genes associated with mitochondrial dysfunction. The cases exhibited common ANE symptoms, such as fever, impaired consciousness, positive pathological reflex, increased cerebrospinal fluid protein, and multifocal and symmetric brain lesions identified through MRI. Using genotype-phenotype correlation analysis in trio-whole exome sequencing (WES), four potential pathogenic variants were identified in two genes associated with mitochondrial function (RANBP2 and MCCC2)...

BACKGROUND: GEMIN5 is an RNA-binding protein that regulates multiple molecular functions, including splicing, localisation, translation, and mRNA stability. GEMIN5 mutations present a syndrome centred on cerebellar dysplasia, including motor dysfunction, developmental delay, cerebellar atrophy, and hypotonia. CASES: We report three patients from two families with novel compound heterozygous mutations in the tetratricopeptide repeat-like domain of the GEMIN5 gene who presented with motor dysfunction, developmental delay, and ataxia syndrome...

The Ryukyu Islands are located in the southernmost part of the Japanese Archipelago and consist of several island groups. Each island group has its own history and culture, which differ from those of mainland Japan. People of the Ryukyu Islands are genetically subdivided; however, their detailed demographic history remains unclear. We report the results of a whole-genome sequencing analysis of a total of 50 Ryukyu islanders, focusing on genetic differentiation between Miyako and Okinawa islanders. We confirmed that Miyako and Okinawa islanders cluster differently in principal component analysis and ADMIXTURE analysis and that there is a population structure among Miyako islanders...

The mechanism of chromosomal rearrangement associated with inverted-duplication-deletion (INV-DUP-DEL) pattern formation has been investigated by many researchers, and several possible mechanisms have been proposed. Currently, fold-back and subsequent dicentric chromosome formation has been established as non-recurrent INV-DUP-DEL pattern formation mechanisms. In the present study, we analyzed the breakpoint junctions of INV-DUP-DEL patterns in five patients using long-read whole-genome sequencing and detected 2...

Resistin is mainly expressed in human monocytes/macrophages and is associated with insulin resistance, inflammation, and atherosclerosis. Serum resistin is strongly correlated with the G-A haplotype defined by single nucleotide polymorphisms (SNPs) c.-420 C>G (SNP-420) (rs1862513) and c.-358 G>A (SNP-358) (rs3219175) in the promoter region of the human resistin gene (RETN). Smoking is also associated with insulin resistance. We investigated the association between smoking and serum resistin and the effect of the G-A haplotype on this association...

Germline double heterozygosity (GDH) is rarely reported in cases of inherited cancer syndromes, and GDH of a mismatch repair gene and BRCA has never been reported in Japan. Nonetheless, the current report demonstrates a case of ovarian mucinous adenocarcinoma with initiated Lynch syndrome (LS)-related surveillance because of a known germline MSH2 variant. Six and a half years after oophorectomy, multiple tumors developed in the patient's lungs, bones, and lymph nodes, and histology results confirmed mucinous adenocarcinoma...

No abstract text is available yet for this article.

Mutations in the TTN gene have been reported to be responsible for a range of neuromuscular disorders, including recessive distal myopathy and congenital myopathy (CM). Only five splicing mutations have been identified to induce aberrant mRNA splicing in TTN-related neuromuscular disorders. In our study, we described detailed clinical characteristics, muscle pathology and genetic analysis of two probands with TTN-related autosomal recessive neuromuscular disorders. Besides, we identified two novel intronic mutations, c...

Carrier screening can identify people at risk of conceiving pregnancies affected with inherited genetic disorders or who have a genetic disorder with late or variable onset. Carrier screening based on whole exome sequencing (WES) data can offer more comprehensive assessment than on-target carrier screening tests. A total of 224 Chinese adult patients WES data was analyzed, except positive variants associated with the patients' major complaint, 378 pathogenic (P) and "likely pathogenic" (LP) variants from 175 adult patients were identified...