Journal of Human Genetics最新文献

Next-generation sequencing (NGS) offers a fast, cost-effective, and scalable solution for pharmacogenomic allele assignment but faces challenges in accurately identifying variants and haplotypes in regions with high sequence similarity. This study aimed to evaluate the performance of three NGS-compatible genotyping tools - PyPGx, Stargazer, and Aldy - for CYP2D6 annotation and investigated the CYP2D6 genetic distribution in 1008 whole-genome sequences from the 1000 Vietnamese Genome Project (VN1K) data. A benchmark dataset was constructed using 8556 diverse CYP2D6 alleles and 122 samples with complex structural variations. Tools were then assessed for haplotype, diplotype, and phenotype concordance across sequencing coverages of 8x, 30x, and 60x. Then, all three tools were subsequently applied to genotype CYP2D6 in the VN1K dataset. Overall, Aldy outperformed others, achieving haplotype and phenotype accuracies of 89.56% and 96.59%, respectively, even at low coverage (8x). In comparison, Stargazer and PyPGx achieved diplotype concordance rates of 51.33% and 47.77% under the same coverage level. According to the output of Aldy - the best performance tool in analysing the CYP2D6 genetic distribution in VN1K data, the results revealed a predominance of reduced-function alleles and a high prevalence of intermediate metabolizer phenotypes, underscoring the need for population-specific pharmacogenomic strategies and highlighting Aldy's potential in advancing precision medicine.

Tubulin proteins form microtubules, which are critical for neuronal cell migration. In humans, there are at least 27 tubulin genes. Pathogenic variants in these genes cause tubulinopathies, which are characterized by diverse neurodevelopmental symptoms and brain malformations. This study analyzed the genetic variants and clinical characteristics of 12 patients (3 males, 9 females) with confirmed β-tubulinopathies. A retrospective chart review indicated that diagnoses were made via exome, genome, or targeted next-generation panel sequencing. Most patients (11/12) showed significant developmental delay and hypotonia. Other neurological symptoms included ocular motility disorders (7/12), ataxia (6/12), seizures (3/12), and microcephaly (2/12). The median age at symptom onset was 10 months (range 0 - 24). Corpus callosum abnormalities were the most common brain malformation, present in 10 patients, including one case of complete agenesis. Basal ganglia abnormalities and cerebellar hypoplasia were each observed in 9 patients. Cortical abnormalities, white matter changes, and brainstem hypoplasia were each present in 8 patients. Severe lissencephaly was not observed. Ten pathogenic or likely pathogenic missense variants were identified in five β-tubulin genes (TUBB2A, TUBB2B, TUBB3, TUBB4A, and TUBB5). Most variants were de novo, but one was a maternally inherited variant, c.211 G > A in TUBB3, which was associated with milder features. A novel variant in TUBB2A, c.1234 G > A p.(Glu412Lys), was also identified. These genetic variations were associated with a broad phenotypic spectrum of β-tubulinopathies, including complex brain malformations and neurodevelopmental disorders. Despite its rarity, tubulinopathy may be considered in the differential diagnosis for patients presenting with developmental delay and brain malformations.

Congenital heart disease and ectodermal dysplasia syndrome (CHDED syndrome) (MIM: 617364) is an autosomal dominant disorder cause by PRKD1 gene pathogenic variants, characterised mainly by congenital heart defects (CHD) and ectodermal dysplasia, along with other variable clinical features (including skeletal defects). Whole exome sequencing was performed on a 7-year-old male proband with CHD, born of non-consanguineous Asian Indian origin couple with affected father and unaffected mother. We identified a novel heterozygous splice variant in PRKD1 (c.1906-1 G > T) in the proband, inherited from the affected father. Transcript analysis confirmed that the PRKD1 splice variant caused the complete skipping of exon 14. Interestingly, the proband exhibited a novel extended phenotype, which include CHD - TOF, and sagittal craniosynostosis, thus broadening the phenotypic spectrum of CHDED syndrome. Affected father showed CHD (septal defects) and no craniosynostosis. Further functional studies are required to elucidate the association of PRKD1 sequence variants with craniosynostosis observed in the proband.

The m.3243 A > G mitochondrial DNA variant is a major pathogenic variant associated with various clinical phenotypes, including hearing impairment and diabetes. This study retrospectively analyzed clinical data from 37 patients with the m.3243 A > G variant to clarify the relationship between clinical characteristics and hearing loss. Most patients developed post-lingual, late-onset sensorineural hearing loss (SNHL), with flat-type audiometric configurations being the most common. Blood heteroplasmy levels were negatively correlated with age at genetic testing (R² = 0.6303), and age-adjusted heteroplasmy levels were inversely associated with age at onset of hearing loss (p = 0.029). A significant difference in clinical characteristics was observed between patients with hearing loss and/or diabetes alone and those with multiple organ involvement, with the latter group showing a lower BMI (p = 0.031) and more severe hearing loss (p < 0.001). Two cases initially presenting with maternally inherited deafness and diabetes progressed to MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), demonstrating the importance of early systemic evaluation. Cochlear implantation was considered for advanced hearing loss, although systemic complications were a challenge. Our findings suggest that hearing loss may be an early risk factor of systemic mitochondrial disease, particularly in lean individuals. Comprehensive assessment, including BMI and genetic testing, may aid in the early diagnosis and management of patients with m.3243 A > G variant.

Single nucleotide polymorphisms in microRNA genes (miRNA-SNPs) can alter miRNA maturation or target mRNA recognition, resulting in gain- or loss-of-function, and are associated with various diseases. This study aimed to identify miRNA-SNPs or somatic mutations in miRNA gens that could serve as biomarkers for the onset or progression of adult T-cell lymphoma-leukemia (ATLL), using next-generation sequencing (NGS) targeting 1809 pre-miRNA genes. Genomic DNA extracted from peripheral blood samples from 31 ATLL patients with low human T-cell leukemia virus type-1 (HTLV-1) proviral loads and 28 healthy subjects was analyzed. Fourteen miRNA-SNPs with significantly different allele frequencies were between the two groups were identified. To determine whether the observed variants were germline or somatic, miRNA-SNPs detected in blood-derived DNA were compared with those from saliva-derived DNA in 6 out of 31 patients. Concordant results between the two sources suggested the variants were germline SNPs. Furthermore, comparison of blood-derived DNA samples from 10 ATLL patients collected during low and high HTLV-1 proviral load periods revealed 10 somatic mutations in pre-miRNA genes, including pre-mir-142, present only in high proviral load samples. These somatic mutations may serve as markers of ATLL progression. In conclusion, out comprehensive NGS analysis identified both germline miRNA-SNPs and somatic mutations that may act as biomarkers for the onset or progression of ATLL. Future studies with larger cohorts will be essential to validate their clinical utility.

Early-onset hippocampal sclerosis is a major cause of focal epilepsy, yet many genetic contributors remain unknown. We investigate a 12-year-old girl with recurrent focal seizures, progressive memory impairment, and MRI evidence of left hippocampal atrophy with ipsilateral parietal gliosis. Singleton exome sequencing revealed a novel homozygous NOL10 variant (NM_024894.4: c.682 A > C; p.Asn228His), absent from population and clinical databases; both parents were heterozygous carriers. The variant alters a highly conserved residue within the WD-repeat domain. Proband fibroblasts maintained normal NOL10 transcript levels but exhibited nucleoplasmic mislocalization and loss of interaction with AATF and NGDN, key partners in small ribosomal subunit biogenesis. Structural modeling and ΔΔG calculations predicted that N228H is strongly destabilizing. Functionally, proband cells showed specific impairment of 40S maturation with reduced 40S, 80S and polysome content, accompanied by G₀/G₁ arrest and increased cell death. Network and expression analyses place NOL10 at the center of nucleolar rRNA processing and ribosome assembly, with substantial expression across hippocampal subfields, supporting selective vulnerability of hippocampal neurons. Collectively, our data implicate biallelic NOL10:c.682 A > C as a novel, likely pathogenic cause of neurodevelopmental disorder characterized by hippocampal sclerosis and gliosis, and highlight disrupted ribosome biogenesis as a plausible disease mechanism.