Human Genome Variation最新文献

Spastic paraplegia (SPG)10 is an autosomal dominant SPG caused by kinesin family member 5A (KIF5A) gene variants. We describe a Japanese patient with SPG whose deceased mother and maternal uncle also exhibited SPG. Exome analysis identified a rare KIF5A nonsense variant (NM_004984.4:c.2590C>T (p.Arg864Ter)) in the patient, regarded as pathogenic. As KIF5A mRNA expression was significantly decreased compared with that of a healthy control, the variant was deemed causative of SPG.

Here we report a patient with holoprosencephaly (HPE) associated with 45, XY,der(18)t(18;21)(p11.2;q21.3),-21 derived from a paternal balanced reciprocal translocation. Array comparative genomic hybridization analysis revealed 18p11.32-p11.21 and 21q11.2-q21.3 deletions. So far, nine cases of monosomy 18p with an unbalanced translocation (18;21) have been reported, four of which presented with HPE. Our case provides a detailed long-term clinical course and helps us to better understand these rare genetic events.

Beckwith-Wiedemann spectrum (BWSp) is a genomic imprinting disorder characterized by a wide range of clinical features. Here we report an infant with BWSp and atypical features, for whom long-read sequencing confirmed a de novo CDKN1C variant that occurred on the maternally inherited allele and excluded other genetic etiologies. These findings not only expand the BWSp concept but also highlight the potential value of allelic origin analysis in cases with atypical presentations.

Maturity-onset diabetes of the young type 4 (MODY4, PDX1-MODY) is a monogenic diabetes caused by the PDX1 gene. Here we detected two novel heterozygous missense variants, NM_000209.4(NP_000200.1):c.443G>T, p.(Arg148Leu) and c.442C>G p.(Arg148Gly), in two Japanese patients. Pathogenicity testing revealed a loss of function in both variants. Family members had severe diabetic complications, including proliferative retinopathy and overt nephropathy such as end-stage renal disease. Laboratory testing indicated persistently high glucose levels, at least partially caused by reduced postprandial insulin secretion.

Here we report the first successful birth after preimplantation genetic testing for m.10197G>A mutation, a rare variant responsible for Leigh encephalopathy. Preimplantation genetic testing diagnosed the embryo with a mutant load of <5%, and transfer resulted in a live birth. The mutant load of embryos diagnosed in this case was skewed to the extremes. Skewed segregation patterns have been observed in common mutations, but this case suggests that the same phenomenon may be seen in this rare mutation.

Variable copy number variations (CNVs) in the short arm of chromosome 17 are associated with many neurodevelopmental disorders, including Charcot-Marie-Tooth disease type 1A, Potocki-Lupski syndrome and Yuan-Harel-Lupski syndrome. Here we examined CNVs in two sporadic cases of developmental abnormalities, brain impairment and peripheral neuropathy. We identified novel duplications of approximately 14.1 Mb at 17p11.2-p13.1 (containing PMP22 and RAI1) and 17.6 Mb at 17p11.2-p13.3 (YWHAE, PAFAH1B and PMP22) in each patient. Both duplications were suggested to be produced by de novo mutations of paternal origin. This study suggests that CNVs at 17p should be examined in patients with peripheral neuropathy as well as developmental and brain abnormalities.

Adrenoleukodystrophy (ALD), an X-linked leukodystrophy caused by pathogenic variants in ABCD1, exhibits a broad range of phenotypes from childhood-onset cerebral forms to adult-onset adrenomyeloneuropathy (AMN). We report a rare in-frame ABCD1 deletion c.1469_71delTGG (p.Val490del) in a man with AMN. Although this variant has been interpreted as 'uncertain significance' in ClinVar, biochemical analysis along with clinical evaluation confirmed the pathogenicity of this variant, underscoring the importance of functional assessment of in-frame deletions.

Jakun, a Proto-Malay subtribe from Peninsular Malaysia, is believed to have inhabited the Malay Archipelago during the period of agricultural expansion approximately 4 thousand years ago (kya). However, their genetic structure and population history remain inconclusive. In this study, we report the genome structure of a Jakun female, based on whole-genome sequencing, which yielded an average coverage of 35.97-fold. We identified approximately 3.6 million single-nucleotide variations (SNVs) and 517,784 small insertions/deletions (indels). Of these, 39,916 SNVs were novel (referencing dbSNP151), and 10,167 were nonsynonymous (nsSNVs), spanning 5674 genes. Principal Component Analysis (PCA) revealed that the Jakun genome sequence closely clustered with the genomes of the Cambodians (CAM) and the Metropolitan Malays from Singapore (SG_MAS). The ADMIXTURE analysis further revealed potential admixture from the EA and North Borneo populations, as corroborated by the results from the F3, F4, and TreeMix analyses. Mitochondrial DNA analysis revealed that the Jakun genome carried the N21a haplogroup (estimated to have occurred ~19 kya), which is commonly found among Malays from Malaysia and Indonesia. From the whole-genome sequence data, we identified 825 damaging and deleterious nonsynonymous single-nucleotide polymorphisms (nsSNVs) affecting 720 genes. Some of these variants are associated with age-related macular degeneration, atrial fibrillation, and HDL cholesterol level. Additionally, we located a total of 3310 variants on 32 core adsorption, distribution, metabolism, and elimination (ADME) genes. Of these, 193 variants are listed in PharmGKB, and 21 are nsSNVs. In summary, the genetic structure identified in the Jakun individual could enhance the mapping of genetic variants for disease-based population studies and further our understanding of the human migration history in Southeast Asia.

UBA1 is an E1 ubiquitin-activating enzyme that initiates the ubiquitylation of target proteins and is thus a key component of the ubiquitin signaling pathway. Three disorders are associated with pathogenic variants of the UBA1 gene: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, lung cancer in never smokers (LCINS), and X-linked spinal muscular atrophy (XL-SMA, SMAX2). We here report a case of infantile respiratory distress syndrome followed by continuing neuromuscular symptoms. We identified a de novo hemizygous mutation, c.1660 C > T (p.Pro554Ser), in exon 15 of the UBA1 gene in this baby. This missense mutation was located with the AAD (active adenylation domain) of the protein, a known hotspot of SMAX2 mutations. This case lends support to the genotype-phenotype correlation regarding the UBA1 mutation and its related diseases.

Two ERLIN2 variants (NM_007175.8:c.660delA and NM_007175.8:c.869C>T) were detected in a Spanish patient with hereditary spastic paraplegia via whole-exome sequencing and software-based pathogenic variant selection. Segregation analysis revealed that the patient's two affected siblings carried both variants, whereas their offspring, carrying only one variant, were asymptomatic, indicating the autosomal recessive nature of the disease. These findings suggest that the identified variants can be classified as pathogenic when they are present as compound heterozygous variants.