Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A novel CUL4B splice site variant in a young male exhibiting less pronounced features.

ABSTRACT: Patients with variants in CUL4B exhibit syndromic intellectual disability (MIM #300354). A seven-year-old boy presented with intellectual disability, a history of seizure, characteristic facial features, and short stature. Whole-exome sequencing detected a c.974+3A>G variant in CUL4B, which was subsequently confirmed to disrupt mRNA splicing. The current patient showed less pronounced phenotypic features compared with the previously reported cases. This report, therefore, provides evidence of genotype-phenotype correlations in CUL4B-related disorders.

SUBMITTER: Nakamura Y

PROVIDER: S-EPMC6804535 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

A novel CUL4B splice site variant in a young male exhibiting less pronounced features.

Nakamura Yuji Y Okuno Yusuke Y Muramatsu Hideki H Kawai Tomoko T Satou Kazuhito K Ieda Daisuke D Hori Ikumi I Ohashi Kei K Negishi Yutaka Y Hattori Ayako A Takahashi Yoshiyuki Y Kojima Seiji S Saitoh Shinji S

Human genome variation 20190904

Patients with variants in CUL4B exhibit syndromic intellectual disability (MIM #300354). A seven-year-old boy presented with intellectual disability, a history of seizure, characteristic facial features, and short stature. Whole-exome sequencing detected a c.974+3A>G variant in CUL4B, which was subsequently confirmed to disrupt mRNA splicing. The current patient showed less pronounced phenotypic features compared with the previously reported cases. This report, therefore, provides ...[more]

PMID: 31645981

Similar Datasets

Donor splice-site mutation in CUL4B is likely cause of X-linked intellectual disability.

Project description:X-linked intellectual disability is the most common form of cognitive disability in males. Syndromic intellectual disability encompasses cognitive deficits with other medical and behavioral manifestations. Recently, a large family with a novel form of syndromic X-linked intellectual disability was characterized. Eight of 24 members of the family are male and had cognitive dysfunction, short stature, aphasia, skeletal abnormalities, and minor anomalies. To identify the causative gene(s), we performed exome sequencing in three affected boys, both parents, and an unaffected sister. We identified a haplotype consisting of eight variants located in cis within the linkage region that segregated with affected members in the family. Of these variants, two were novel. The first was at the splice-donor site of intron 7 (c.974+1G>T) in the cullin-RING ubiquitin ligase (E3) gene, CUL4B. This variant is predicted to result in failure to splice and remove intron 7 from the primary transcript. The second variant mapped to the 3'-UTR region of the KAISO gene (c.1127T>G). Sanger sequencing validated the variants in these relatives as well as in three affected males and five carriers. The KAISO gene variant was predicted to create a binding site for the microRNAs miR-4999 and miR-4774; however, luciferase expression assays failed to validate increased targeting of these miRNAs to the variant 3'-UTR. This SNP may affect 3'-UTR structure leading to decreased mRNA stability. Our results suggest that the intellectual disability phenotype in this family is caused by aberrant splicing and removal of intron 7 from CUL4B gene primary transcript.

| S-EPMC4404493 | biostudies-literature

A novel splice site variant in CYP11A1 in trans with the p.E314K variant in a male patient with congenital adrenal insufficiency.

Project description:BACKGROUND:The CYP11A1 gene encodes the cytochrome P450 side-chain cleavage enzyme, which is essential for steroid formation. Recessive variants in this gene can lead to impairment of sexual differentiation caused by a complete or partial loss of steroid hormone production. The phenotypic spectrum in affected 46XY males may vary from surgically repairable defects including cryptorchidism and hypospadias to complete feminization of external gonads, accompanied by symptoms of adrenal dysfunction. METHODS:Whole-exome sequencing (WES) of a 12-year-old male proband and his parents was performed after a protracted diagnostic odyssey failed to uncover the cause of his primary adrenal insufficiency. Of note, the proband had early symptomatology and corrective surgery for hypospadias, raising suspicion for a disorder of steroidogenesis. RESULTS:WES identified compound heterozygous variants in CYP11A1 including a novel canonical splice site variant (c.425+1G>A) and a previously reported p.E314K variant, which were consistent with a diagnosis of congenital adrenal insufficiency with partial 46XY sex reversal. CONCLUSION:Congenital adrenal insufficiency with 46XY sex reversal is a rare disorder that is characterized by dysregulation of steroid hormone synthesis, leading to adrenal and gonadal dysfunction. In this report, we describe a patient with adrenal insufficiency, hypospadias, and skin hyperpigmentation who was found to have a novel c.425+1G>A variant in trans with the p.E314K variant in CYP11A1. We performed structural analyses to examine the effect of the p.E314K variant on protein function and show that it falls in the core of the protein may disrupt cholesterol binding in the active site.

| S-EPMC5702577 | biostudies-literature

A novel BRCA2 splice variant identified in a young woman.

Project description:BackgroundBRCA1/2 VUSs represent an important clinical issue in risk assessment for the breast/ovarian cancer families (HBOC) families. Among them, some occurring within the intron-exon boundary may lead to aberrant splicing process by altering or creating de novo splicing regulatory elements or unmasking cryptic splice site. Defining the impact of these potential splice variants at functional level is important to establish their pathogenic role.MethodsGenomic DNA was extracted from peripheral blood sample of a young woman affected with breast cancer belonging to a HBOC family and the entire coding regions of the BRCA1 and BRCA2 genes were amplified using the Ion AmpliSeq BRCA1 and BRCA2 Panel. The BRCA2 c.682-2delA variant has been characterized by RT-PCR analysis performed on mRNA extracted from blood and lymphoblastoid cell line.ResultsWe demonstrated that a novel BRCA2 c.682-2delA variant at the highly conserved splice consensus site in intron 8 disrupts the canonical splice acceptor site generating a truncated protein as predicted by several bioinformatics tools. Segregations analysis in the family and LOH performed on proband breast cancer tissue further confirmed its classification as pathogenic variant.ConclusionCombining different methodologies, we characterized this new BRCA2 variant and provided findings of clinical utility for its classification as pathogenic variant.

| S-EPMC7767566 | biostudies-literature

Structural features of a 3' splice site in influenza a.

Project description:Influenza A is an RNA virus with a genome of eight negative sense segments. Segment 7 mRNA contains a 3' splice site for alternative splicing to encode the essential M2 protein. On the basis of sequence alignment and chemical mapping experiments, the secondary structure surrounding the 3' splice site has an internal loop, adenine bulge, and hairpin loop when it is in the hairpin conformation that exposes the 3' splice site. We report structural features of a three-dimensional model of the hairpin derived from nuclear magnetic resonance spectra and simulated annealing with restrained molecular dynamics. Additional insight was provided by modeling based on (1)H chemical shifts. The internal loop containing the 3' splice site has a dynamic guanosine and a stable imino (cis Watson-Crick/Watson-Crick) GA pair. The adenine bulge also appears to be dynamic with the A either stacked in the stem or forming a base triple with a Watson-Crick GC pair. The hairpin loop is a GAAA tetraloop closed by an AC pair.

| S-EPMC4455060 | biostudies-literature

MYH2-associated myopathy caused by a novel splice-site variant.

Project description:MYH2 encodes MyHCIIa, a myosin heavy chain found in fast type 2A fibers. Pathogenic variants in this gene have previously been implicated in dominant and recessive forms of myopathy. Three individuals reported here are part of a family in which four generations of individuals are affected by a slowly progressive, predominantly proximal myopathy in an autosomal dominant inheritance pattern. Affected individuals in this family lacked classic features of an MYH2-associated myopathy such as congenital contractures and ophthalmoplegia. A novel variant, MYH2 c.5673+1G>C, was detected in the proband and subsequently found to segregate with disease in five additional family members. Further studies demonstrated that this variant affects splicing, resulting in novel transcripts. These data and muscle biopsy findings in the proband, indicate that this family's MYH2 variant is causative of their myopathy, adding to our understanding of the clinical and molecular characteristics of the disease.

| S-EPMC10023425 | biostudies-literature

Atypical Sotos syndrome caused by a novel splice site variant.

Project description:Sotos syndrome is usually caused by haploinsufficiency of NSD1; it is characterized by overgrowth, craniofacial features, and learning disabilities. We describe a boy with Sotos syndrome caused by a splicing variant (c.4378+5G>A). The clinical manifestations included severe connective tissue involvement, including joint hypermobility, progressive scoliosis, pectus deformity, and skin hyperextensibility; no overgrowth was observed.

| S-EPMC9666520 | biostudies-literature

A novel CHD7 variant disrupting acceptor splice site in a patient with mild features of CHARGE syndrome: a case report.

Project description:BackgroundCHARGE syndrome (MIM# 214800)-which is characterised by a number of congenital anomalies including coloboma, ear anomalies, deafness, facial anomalies, heart defects, atresia choanae, genital hypoplasia, growth retardation, and developmental delay-is caused by a heterozygous variant in the CHD7 (MIM# 608892) gene located on chromosome 8q12. We report the identification of a novel c.5535-1G > A variant in CHD7 and provide the evaluation of its effect on pre-mRNA splicing.Case presentationIn this study, we report on a female presenting features of CHARGE syndrome. A novel heterozygous CHD7 variant c.5535-1G > A located in the acceptor splice site of intron 26 was identified in the proband's DNA sample after analysis of whole exome sequencing data. In silico predictions indicating that the variant is probably pathogenic by affecting pre-mRNA splicing were verified by genetic analysis based on reverse transcription of the patient's RNA followed by PCR amplifications performed on synthesised cDNA and Sanger sequencing. Sanger sequencing of cDNA revealed that the c.5535-1G > A variant disrupts the original acceptor splice site and activates a cryptic splice site only one nucleotide downstream of the pathogenic variant site. This change causes the omission of the first nucleotide of exon 27, leading to a frameshift in the mRNA of the CHD7 gene. Our results suggest that the alteration induces the premature truncation of the CHD7 protein (UniProtKB: Q9P2D1), thus resulting in CHARGE syndrome.ConclusionGenetic analysis of novel splice site variant underlines its importance for studying the pathogenic splicing mechanism as well as for confirming a diagnosis.

| S-EPMC6637606 | biostudies-literature

Characterisation of a novel OPA1 splice variant resulting in cryptic splice site activation and mitochondrial dysfunction.

Project description:Autosomal dominant optic atrophy (DOA) is an inherited optic neuropathy that results in progressive, bilateral visual acuity loss and field defects. OPA1 is the causative gene in around 60% of cases of DOA. The majority of patients have a pure ocular phenotype, but 20% have extra-ocular features (DOA +). We report on a patient with DOA + manifesting as bilateral optic atrophy, spastic paraparesis, urinary incontinence and white matter changes in the central nervous system associated with a novel heterozygous splice variant NM_015560.2(OPA1):c.2356-1 G > T. Further characterisation, which was performed using fibroblasts obtained from a skin biopsy, demonstrated that this variant altered mRNA splicing of the OPA1 transcript, specifically a 21 base pair deletion at the start of exon 24, NM_015560.2(OPA1):p.Cys786_Lys792del. The majority of variant transcripts were shown to escape nonsense-mediated decay and modelling of the predicted protein structure suggests that the in-frame 7 amino acid deletion may affect OPA1 oligomerisation. Fibroblasts carrying the c.2356-1 G > T variant demonstrated impaired mitochondrial bioenergetics, membrane potential, increased cell death, and disrupted and fragmented mitochondrial networks in comparison to WT cells. This study suggests that the c.2356-1 G > T OPA1 splice site variant leads to a cryptic splice site activation and may manifest in a dominant-negative manner, which could account for the patient's severe syndromic phenotype.

| S-EPMC9259687 | biostudies-literature

Features generated for computational splice-site prediction correspond to functional elements.

Project description:BackgroundAccurate selection of splice sites during the splicing of precursors to messenger RNA requires both relatively well-characterized signals at the splice sites and auxiliary signals in the adjacent exons and introns. We previously described a feature generation algorithm (FGA) that is capable of achieving high classification accuracy on human 3' splice sites. In this paper, we extend the splice-site prediction to 5' splice sites and explore the generated features for biologically meaningful splicing signals.ResultsWe present examples from the observed features that correspond to known signals, both core signals (including the branch site and pyrimidine tract) and auxiliary signals (including GGG triplets and exon splicing enhancers). We present evidence that features identified by FGA include splicing signals not found by other methods.ConclusionOur generated features capture known biological signals in the expected sequence interval flanking splice sites. The method can be easily applied to other species and to similar classification problems, such as tissue-specific regulatory elements, polyadenylation sites, promoters, etc.

| S-EPMC2241647 | biostudies-literature

Site-specific deacylation by ABHD17a controls BK channel splice variant activity.

Project description:S-Acylation, the reversible post-translational lipid modification of proteins, is an important mechanism to control the properties and function of ion channels and other polytopic transmembrane proteins. However, although increasing evidence reveals the role of diverse acyl protein transferases (zDHHC) in controlling ion channel S-acylation, the acyl protein thioesterases that control ion channel deacylation are very poorly defined. Here we show that ABHD17a (α/β-hydrolase domain-containing protein 17a) deacylates the stress-regulated exon domain of large conductance voltage- and calcium-activated potassium (BK) channels inhibiting channel activity independently of effects on channel surface expression. Importantly, ABHD17a deacylates BK channels in a site-specific manner because it has no effect on the S-acylated S0-S1 domain conserved in all BK channels that controls membrane trafficking and is deacylated by the acyl protein thioesterase Lypla1. Thus, distinct S-acylated domains in the same polytopic transmembrane protein can be regulated by different acyl protein thioesterases revealing mechanisms for generating both specificity and diversity for these important enzymes to control the properties and functions of ion channels.

| S-EPMC7864050 | biostudies-literature