Human Genome Variation最新文献

Here, we report the case of a 29-year-old male with classic Pelizaeus-Merzbacher disease (PMD) harboring the PLP1 variant NM_000533.5:c.62 C > T, leading to an NP_000524.3:p.(Ala21Val) alteration in the first transmembrane domain of the protein. He presented with developmental delays, nystagmus, spastic paraparesis, optic atrophy, dysphagia, appendicular ataxia, and progressive head tremor. Brain MRI revealed hypomyelination, diffuse white matter hyperintensity, and atrophy of the corpus callosum and cerebellum, expanding the known clinical spectrum of PMD.

DSG2, encoding desmoglein-2, is one of the causative genes of arrhythmogenic cardiomyopathy. We previously identified a homozygous DSG2 p.Arg119Ter stop-gain variant in a patient with juvenile-onset cardiomyopathy and advanced biventricular heart failure. However, the pathological significance and prevalence of the heterozygous DSG2 p.Arg119Ter variant remains uncertain. Here, we identified four unrelated patients with cardiomyopathy with heterozygous DSG2 p.Arg119Ter variants among 808 patients with nonischemic cardiomyopathy; the allele frequency was 0.0037, which is more than 50-fold greater than that reported in the general Japanese population. These patients were clinically diagnosed with arrhythmogenic right ventricular cardiomyopathy (Pt-1), dilated cardiomyopathy (DCM) after ventricular septum defect closure surgery (Pt-2), DCM (Pt-3), and end-stage hypertrophic cardiomyopathy (Pt-4). The patients also exhibited reduced left ventricular contractile function and varying clinical courses. Genetic analysis identified additional possible causative variants, DSG2 p.Arg292Cys in Pt-1 and BAG3 p.His166SerfsTer6 in Pt-3. Immunohistochemical analysis of endomyocardial biopsy samples revealed that the expression of not only desmoglein-2 but also desmoplakin was markedly reduced. Transmission electron microscopy revealed pale and fragmented desmosomes and widened gaps between intercalated discs in the myocardium. A microforce test using human cardiomyocytes differentiated from induced pluripotent stem cells (iPSC-CMs) demonstrated reduced contractility in iPSC-CMs carrying a heterozygous truncating variant in DSG2. These data suggest that the DSG2 p.Arg119Ter variant is concealed in patients with cardiomyopathy with heart failure, and desmosome impairment may be a latent exacerbating factor of contractile dysfunction and disease progression.

Bryant-Li-Bhoj syndrome (BLBS; OMIM # 619720, 619721), caused by germline H3F3A and H3F3B variants encoding histone H3.3, is characterized by mild to severe developmental delay, intellectual disability, failure to thrive, muscle tone abnormalities, and dysmorphic facial features. Here, we present a Japanese patient with a novel heterozygous p.A48G variant in H3F3A, displaying previously unrecognized symptoms of neonatal myoclonus. This case helps broaden the phenotypic spectrum of BLBS.

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by germline variants in the APC gene, leading to the development of numerous colorectal polyps and significantly increases the risk of colorectal cancer. A diagnosis is typically made using colonoscopy, and genetic testing can assist in patient surveillance and carrier identification. Recent advances include the use of whole-genome array comparative genomic hybridization (a-CGH), which provides better resolution of genetic imbalances. We aimed to explore the specific features of FAP patients with whole APC gene deletions using high-resolution a-CGH and to compare patient characteristics. Two polyposis patients with whole APC deletions were identified, and the lost genetic sizes ranged from 0.3-1.1 Mb. Nervous abnormalities were a characteristic symptom in a patient with a 1.1 Mb loss. A patient with an approximately 0.3 Mb loss, which included the entire APC gene, presented a polyposis phenotype without intellectual disability. The comparison of genetic losses, with or without intellectual disability, revealed 7 genetic changes. Consequently, EPB41L4A is a candidate gene associated with the neurogenic phenotype.

We report a case of a fetus with short-rib thoracic dysplasia (SRTD) with polydactyly that also presented with atypical severe acro-mesomelic ossification defects. Genetic analysis using massively parallel sequencing of a skeletal dysplasia panel revealed compound heterozygous variants in DYNC2H1. This clinical report highlights the challenges associated with diagnosing the diverse phenotypes in the SRTD group and emphasizes the importance of genetic surveillance with a targeted gene panel for accurate diagnosis.

Genetic testing identified novel compound heterozygous missense variants in the HEXA gene (NM_00520.6: c.775A>C and NM_000520.6: c.508C>T) in a 16-month-old girl diagnosed with Tay‒Sachs disease. The patient gradually became unable to consume food orally. She suffered severe aspiration pneumonia and underwent gastrostomy and laryngotracheal separation at 2 years and 4 months of age. Despite an initially good prognosis, she died at 3 years of age.

Neurofibromatosis type 1 (NF1) presents with a broad spectrum of clinical manifestations, including an increased risk of tumor development and hypertension. Comprehensive data on genotype‒phenotype correlations in patients with NF1 are limited. Therefore, in this study, we aimed to elucidate the detailed genetic and clinical characteristics of NF1 in a hereditary tumor cohort. We performed sequencing and copy number assays in a clinical laboratory and analyzed the clinical data of 44 patients with suspected NF1. Germline pathogenic variants were detected in 36 patients (81.8%), and 20.7% of the variants were novel. Notably, 40.0% of adult patients presented with malignancies; female breast cancer occurred in 20.0% of patients, which was a higher rate than that previously reported. Hypertension was observed in 30.6% of the adult patients, with one patient experiencing sudden death and another developing pheochromocytoma. Three patients with large deletions in NF1 exhibited prominent cutaneous, skeletal, and neurological manifestations. These results highlight the importance of regular surveillance, particularly for patients with malignancies and hypertension. Our findings provide valuable insights for genetic counseling and clinical management, highlighting the multiple health risks associated with NF1 and the need for comprehensive and multidisciplinary care.

We describe a case of RAS-associated autoimmune leukoproliferative disease with primary ciliary dyskinesia (PCD)-like symptoms, such as recurrent pneumonia, sinusitis, and otitis media, that occurred 7 years after hematopoietic cell transplantation. Whole-exome sequencing revealed a heterozygous CFAP43 nonsense variant. Environmental factors related to hematopoietic cell transplantation may have led to PCD symptoms in this patient with this variant. Genetic screening can help avoid subsequent complications during patient management.

We present a case of suspected CDKL5 deficiency disorder (CDD) in which a novel intragenic multi-exonic duplication in the CDKL5 gene was identified using next-generation sequencing and multiple ligation-dependent probe amplification. This duplication was assumed to result in a shift of the reading frame and the introduction of a premature stop codon. This case highlights the importance of careful phenotyping and comprehensive genetic testing to detect rare structural variants in CDD patients.

Cockayne syndrome (CS) is a progressive multisystem disorder characterized by growth failure, microcephaly, developmental delay, and photosensitivity. The characteristic symptoms appear during early childhood in most patients with CS. Herein, we report a mild case of CS with a novel start-loss variant in ERCC8 that did not show the characteristic symptoms of CS during early childhood and exhibited sudden growth failure after the age of 10 years.