Human Genome Variation最新文献

Congenital contractual arachnodactyly (CCA) is a genetic connective tissue disorder that is characterized by arachnodactyly, kyphoscoliosis, marfanoid habitus, and crumpled ears. We report a case of a boy with suspected Marfan syndrome. Genetic analysis revealed c.3207_3217+9del in a heterozygote form of the fibrillin-2 (FBN2) gene. This patient was diagnosed with CCA based on his phenotype, and the pathogenicity of this variant was classified according to cDNA analysis and protein modeling.

Leber's hereditary optic neuropathy (LHON) is a mitochondrial hereditary disease in which visual loss affects complex 1 activity of the electron transport chain of mitochondria. It first manifests as painless dulling or blurry in one or even both eyes, and as it develops, sharpness and color perception are lost. In addition to primary mitochondrial DNA (mtDNA) mutations, there are also other environmental and epigenetic factors involved in the pathogenesis of LHON. One of the most common locations for deadly pathogenic mutations in humans is the human complex I accessory NDUFS4 subunit gene. The iron-sulfur clusters of the electron input domain were distorted in the absence of NDUFS4, which reduced complex I function and elevated the production of reactive oxygen species. Therefore, here, we studied the epigenetic alterations of NDUFS4 by focusing on histone activation and repressive markers. We isolated peripheral blood mononuclear cells (PBMCs) from LHON patients and healthy individuals and examined epigenetic modifications in ND4 mutant cells and control cells. Chromatin immunoprecipitation-qRT PCR (ChIP-qRT PCR) assays were performed to investigate the modifications of histones. In comparison to their controls, both LHON patients and ND4 mutant cells exhibited a significant enrichment in activation and repressive markers. This finding indicates that these modifications might mitigate the impact of LHON mutations on complex 1 and aid in elucidating the mechanism underlying the progression of LHON disease.

Congenital tooth agenesis is caused by the impairment of crucial genes related to tooth development, such as Wnt signaling pathway genes. Here, we investigated the genetic causes of sporadic congenital tooth agenesis. Exome sequencing, followed by Sanger sequencing, identified a novel single-nucleotide deletion in WNT10A (NC_000002.12(NM_025216.3):c.802del), which was not found in the healthy parents of the patient. Thus, we concluded that the variant was the genetic cause of the patient's agenesis.

We report the case of a hydrocephalic fetus in which clinical exome sequencing revealed a recurrent synonymous variant of unknown significance, c.453G>T, in the L1CAM gene. This report presents the second case of X-linked hydrocephalus in a fetus with this variant. Since we reproduced the RNA analysis, we were able to reclassify this variant as likely pathogenic. Our results stress the importance of not excluding synonymous variants during prioritization.

Autosomal dominant episodic ataxia type 2 (EA2) is caused by variants in CACNA1A. We examined a 20-year-old male with EA symptoms from a Japanese family with hereditary EA. Cerebellar atrophy was not evident, but single photon emission computed tomography showed cerebellar hypoperfusion. We identified a novel nonsynonymous variant in CACNA1A, NM_001127222.2:c.1805T>G (p.Leu602Arg), which is predicted to be functionally deleterious; therefore, this variant is likely responsible for EA2 in this pedigree.

GJA1 is the causative gene for oculodentodigital dysplasia (ODDD). A novel de novo GJA1 variant, NM 000165:c263C > T [p.P88L], was identified in a mosaic state in a patient with short stature, seizures, delayed myelination, mild hearing loss, and tooth enamel hypoplasia. Although the patient exhibited severe neurodevelopmental delay, other clinical features of ODDD, including limb anomalies, were mild. This may be due to differences in the mosaic ratios in different organs.

DLG4-related synaptopathy is a neurodevelopmental disorder caused by a DLG4 variant. We identified a novel de novo heterozygous frameshift variant, NM_001321075.3(DLG4):c.554_563del, in a Japanese girl. Intellectual regression without motor delay was observed at 2 years of age, and she was diagnosed with autism spectrum disorder and attention-deficit/hyperactivity disorder. Recognizing the possibility of DLG4-related synaptopathy in patients with intellectual regression is important for ensuring an accurate diagnosis.

Neurofibromatosis type 1 (NF1) is one of the most common hereditary neurocutaneous disorders. Here, we report a unique case of a patient with typical NF1 findings and infantile spasms who had three possibly pathogenic de novo variants, c.3586C>T, p.(Leu1196Phe) and c.3590C>T, p.(Ala1197Val) in NF1 located in cis and c.1042G>C, p.(Ala348Pro) in GABBR1. This study contributes to our understanding of the effect of two cis variants on NF1 phenotypes and GABBR1-related neuropsychiatric disorders.

Recessive dystrophic epidermolysis bullosa is a genetic collagen disorder characterized by skin fragility that leads to generalized severe blistering, wounds, and scarring. In this report, we present a patient with a novel COL7A1 homozygous nonsense variant, c.793C>T p.(Gln265*). Although the parents were not consanguineous, both were heterozygous carriers of the variant. Single nucleotide polymorphism (SNP) array analysis revealed an isodisomy area on 3p22.1p21.1, encompassing COL7A1, suggesting that the variant originated from a common ancestor.