Human Genome Variation最新文献

Germline loss-of-function mutations in USP9X have been reported to cause a wide spectrum of congenital anomalies. Here, we report a Japanese girl with a novel heterozygous nonsense mutation in USP9X who exhibited intellectual disability with characteristic craniofacial abnormalities, including hypotelorism, brachycephaly, hypodontia, micrognathia, severe dental crowding, and an isolated submucous cleft palate. Our findings provide further evidence that disruptions in USP9X contribute to a broad range of congenital craniofacial abnormalities.

Neurofibromatosis type 1 (NF1) is an autosomal dominant nevus disease characterized by multiple manifestations, primarily café-au-lait macules and neurofibromas. Here, we present the case of an NF1 patient with 47,XYY mosaicism whose diagnosis was prompted by café-au-lait macules on the skin and mandibular neurofibromas. Targeted next-generation sequencing of the patient's blood sample revealed a novel frameshift mutation in NF1 (NM_000267.3:c.6832dupA:p.Thr2278Asnfs*8) that is considered a pathogenic variant.

A 3.5-Mb microdeletion in Xq22 was identified in a female patient with early-onset neurological disease trait (EONDT). The patient exhibited developmental delay but no hypomyelination despite PLP1 involvement in the deletion. However, the clinical features of the patient were consistent with those of TCEAL1 loss-of-function syndrome. The breakpoint junction was analyzed using long-read sequencing, and blunt-end fusion was confirmed.

Short- and long-read sequencing technologies are routinely used to detect DNA variants, including SNVs, indels, and structural variations (SVs). However, the differences in the quality and quantity of variants detected between short- and long-read data are not fully understood. In this study, we comprehensively evaluated the variant calling performance of short- and long-read-based SNV, indel, and SV detection algorithms (6 for SNVs, 12 for indels, and 13 for SVs) using a novel evaluation framework incorporating manual visual inspection. The results showed that indel-insertion calls greater than 10 bp were poorly detected by short-read-based detection algorithms compared to long-read-based algorithms; however, the recall and precision of SNV and indel-deletion detection were similar between short- and long-read data. The recall of SV detection with short-read-based algorithms was significantly lower in repetitive regions, especially for small- to intermediate-sized SVs, than that detected with long-read-based algorithms. In contrast, the recall and precision of SV detection in nonrepetitive regions were similar between short- and long-read data. These findings suggest the need for refined strategies, such as incorporating multiple variant detection algorithms, to generate a more complete set of variants using short-read data.

TNNI3 is a gene that causes hypertrophic cardiomyopathy (HCM). A 14-year-old girl who was diagnosed with nonobstructive HCM presented with cardiopulmonary arrest due to ventricular fibrillation. Genetic testing revealed a novel de novo heterozygous missense variant in TNNI3, NM_000363.5:c.583A>T (p.Ile195Phe), which was determined to be the pathogenic variant. The patient exhibited progressive myocardial fibrosis, left ventricular remodeling, and life-threatening arrhythmias. Genetic testing within families is useful for risk stratification in pediatric HCM patients.

A young patient diagnosed with advanced colon cancer and liver metastasis was found to have familial adenomatous polyposis (FAP) through comprehensive genomic analysis. Whole-genome array comparative genomic hybridization (aCGH) revealed germline deletions at chromosome 5q22.1-22.2 encompassing the entire APC gene. The patient and her son exhibited mild intellectual disability without developmental delay. This case highlights the need for further exploration of the characteristics associated with whole APC deletions. aCGH is a valuable tool for studying FAP and provides a detailed analysis of large deletions.

Autosomal dominant polycystic kidney disease (ADPKD) is commonly caused by PKD1, and mosaic PKD1 variants result in milder phenotypes. We present the case of a 32 year-old male with chronic active Epstein–Barr virus who underwent bone marrow transplantation with chemoradiotherapy at age 9. Despite a low-frequency mosaic splicing PKD1 variant, he developed severe renal cysts and end-stage renal disease in his 30 s. This case highlights how environmental factors may contribute to the genetic predisposition to ADPKD.

Osteogenesis imperfecta is characterized by frequent fractures, bone deformities, and other systemic symptoms. Severe osteogenesis imperfecta may progress to hydrocephalus; however, treatment strategies for this complication remain unclear. Here, we describe severe osteogenesis imperfecta in an infant with symptomatic hydrocephalus treated with ventriculosubgaleal shunt placement. Targeted next-generation sequencing revealed novel compound heterozygous CRTAP variants, i.e., NM_006371.5, c.241 G > T, p.(Glu81*) and NM_006371.5, c.923-2_932del. We suggest that ventriculosubgaleal shunt placement is an effective and safe treatment for hydrocephalus in patients with severe osteogenesis imperfecta.

Recently, heterozygous loss-of-function NFKB1 variants were identified as the primary cause of common variable immunodeficiency (CVID) in the European population. However, pathogenic NFKB1 variants have never been reported in the Japanese population. We present a 29-year-old Japanese woman with CVID. A novel variant, c.136 C > T, p.(Gln46*), was identified in NFKB1. Her mother and daughter carried the same variant, demonstrating the first Japanese pedigree with an NFKB1 pathogenic variant.