Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome.
Ontology highlight
ABSTRACT:
SUBMITTER: Sparber P
PROVIDER: S-EPMC8686832 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundIntellectual disability with developmental delay is the most common developmental disorder. However, this diagnosis is rarely associated with congenital cardiomyopathy. In the current report, we present the case of a patient suffering from dilated cardiomyopathy and developmental delay.MethodsNeurological pathology in a newborn was diagnosed immediately after birth, and the acquisition of psychomotor skills lagged behind by 3-4 months during the first year of life. WES analysis of the proband did not reveal a causal variant, so the search was extended to trio.ResultsTrio sequencing revealed a de novo missense variant in the CAMK2D gene (p.Arg275His), that is, according to the OMIM database and available literature, not currently associated with any specific inborn disease. The expression of Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIδ) protein is known to be increased in the heart tissues from patients with dilated cardiomyopathy. The functional effect of the CaMKIIδ Arg275His mutant was recently reported; however, no specific mechanism of its pathogenicity was proposed. A structural analysis and comparison of available three-dimensional structures of CaMKIIδ confirmed the probable pathogenicity of the observed missense variant.ConclusionsWe suggest that the CaMKIIδ Arg275His variant is highly likely the cause of dilated cardiomyopathy and neurodevelopmental disorders.
| S-EPMC10298453 | biostudies-literature
Project description:BackgroundMutations in GABRB3 have been identified in subjects with different types of epilepsy and epileptic syndromes, including West syndrome (WS), Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), myoclonic-atonic epilepsy (MAE), and others.Methods and resultsWe herewith report on a girl affected by DS, who has been followed from infancy to the current age of 18 years. Next-generation sequencing (NGS)-based genetic testing for multigene analysis of neurodevelopmental disorders identified two likely de novo pathogenic mutations, a missense variant in GABRB3 gene (c.842 C>T; p.Thr281IIe) and a nonsense variant found in BBS4 gene (c.883 C>T; p.Arg295Ter).ConclusionA likely relationship between the novel GABRB3 gene variant and the clinical manifestations presented by the girl is proposed. Previously, one case of DS and two of DS-like linked with GABRB3 mutations have been reported. To the best of our knowledge, this is the first report of DS associated with this novel variant. A literature review of clinical cases with various types of epileptic encephalopathies (EEs) related to GABRB3 mutations is reported.
| S-EPMC7667356 | biostudies-literature
Project description:BackgroundOsteodysplasia of the oral and maxillofacial bone is generally accompanied by systemic bone abnormalities (such as short stature, joint contracture) or other systemic abnormalities (such as renal, dermatological, cardiovascular, optic, or hearing disorders). However, it does not always present this way. Recent reports have suggested that genome-wide sequencing is an effective method for identifying rare or new disorders. Here, we performed whole-exome sequencing (WES) in a patient with a unique form of acquired, local osteodysplasia of the oral and maxillofacial region.Case presentationA 46-year-old woman presented to our hospital with the complaint of gradually moving mandibular teeth (for 6 months), changing facial appearance, and acquired osteolysis of the oral and maxillofacial bones, showing mandibular hypoplasia without family history. Upon skeletal examination, there were no abnormal findings outside of the oral and maxillofacial area; the patient had a height of 157 cm and bone mineral density (according to dual energy x-ray absorptiometry) of 90%. Results of blood and urine tests, including evaluation of bone metabolism markers and neurological and cardiovascular examinations, were normal. We performed WES of genomic DNA extracted from the blood of this patient and her mother, who did not have the disease, as a negative control. We identified 83 new missense variants in the patient, not detected in her mother, including a candidate single nucleotide variant in exon 14 of PCNT (pericentrin). Critical homozygous or compound heterozygous variants in PCNT are a known cause of microcephalic osteodysplastic primordial dwarfism type II accompanied by mandibular hypoplasia, which is similar to the maxillofacial phenotype in this patient.ConclusionsProtein simulations performed using Polymorphism Phenotyping v2 and Combined Annotation Dependent Depletion software indicated that this missense variant is likely to disrupt the PCNT protein structure. These results suggest that this is a new form of osteolysis related to this PCNT variant.
| S-EPMC6636042 | biostudies-literature
Project description:Febrile-associated epileptic encephalopathy is a large genetically heterogeneous group that is associated with pathogenic variants in SCN1A, PCDH19, SCN2A, SCN8A, and other genes. The disease onset ranges from neonatal or early-onset epileptic encephalopathy to late-onset epilepsy after 18 months. Some etiology-specific epileptic encephalopathies have target therapy which can serve as a clue for the correct genetic diagnosis. We present genetic, clinical, electroencephalographic, and behavioral features of a 4-year-old girl with epileptic encephalopathy related to a de novo intronic variant in the SCN2A gene. Initial NGS analysis revealed a frameshift variant in the KDM6A gene and a previously reported missense variant in SCN1A. Due to lack of typical clinical signs of Kabuki syndrome, we performed X-chromosome inactivation that revealed nearly complete skewed inactivation. Segregation analysis showed that the SCN1A variant was inherited from a healthy father. The proband had resistance to multiple antiseizure medications but responded well to sodium channel inhibitor Carbamazepine. Reanalysis of NGS data by a neurogeneticist revealed a previously uncharacterized heterozygous variant c.1035-7A>G in the SCN2A gene. Minigene assay showed that the c.1035-7A>G variant activates a cryptic intronic acceptor site which leads to 6-nucleotide extension of exon 9 (NP_066287.2:p.(Gly345_Gln346insTyrSer). SCN2A encephalopathy is a recognizable severe phenotype. Its electro-clinical and treatment response features can serve as a hallmark. In such a patient, reanalysis of genetic data is strongly recommended in case of negative or conflicting results of DNA analysis.
| S-EPMC9194094 | biostudies-literature
Project description:Silver-Russell syndrome (SRS, OMIM 180860) is a rare imprinting disorder characterized by intrauterine and postnatal growth restriction, feeding difficulties in early childhood, characteristic facial features, and body asymmetry. The molecular cause most commonly relates to hypomethylation of the imprinted 11p15.5 IGF2/H19 domain but remains unknown in about 40% of the patients. Recently, heterozygous paternally inherited pathogenic variants in IGF2, the gene encoding insulin-like growth factor 2 (IGF2), have been identified in patients with SRS. We report a novel de novo missense variant in IGF2 (c.122T > G, p.Leu41Arg) on the paternally derived allele in a 16-year-old boy with a clinical diagnosis of SRS. The missense variant was identified by targeted exome sequencing and predicted pathogenic by multiple in silico tools. It affects a highly conserved residue on a domain that is important for binding of other molecules. Our finding expands the spectrum of disease-causing variants in IGF2. Targeted exome sequencing is a useful diagnostic tool in patients with negative results of common diagnostic tests for SRS.
| S-EPMC9578642 | biostudies-literature
Project description:Recent studies have indicated that heterozygous loss-of-function variants in fibroblast growth factor receptor 1 (FGFR1) are involved in the development of congenital hypogonadotropic hypogonadism and combined pituitary hormone deficiency (CPHD). We encountered a Japanese boy with short stature and pubertal failure. Endocrine studies showed GH, TSH, and LH/FSH deficiencies, and brain magnetic resonance imaging delineated hypoplastic anterior pituitary and ectopic posterior pituitary. The patient was treated with GH, l-thyroxine, and hCG/rFSH. Next-generation sequencing panel for pituitary dysfunction identified a probably weak disease-associated heterozygous missense variant in FGFR1 (NM_023110.3:c.176A>T:p.(Asp59Val)), together with a probably non-deleterious heterozygous missense variant in KISS1R (NM_032551.5:c.769G>C:p.(Val257Leu)). We also review six previously reported CHPD patients with probably deleterious FGFR1 variants. The data, in conjunction with the previously reported cases, argue for the relevance of FGFR1 variants to the development of CPHD.
| S-EPMC9297172 | biostudies-literature
Project description:RationaleTuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by facial angiofibromas, epilepsy, intellectual disability, and the development of hamartomas in several organs, including the heart, kidneys, brain, and lungs. Mutations in either TSC1 or TSC2 result in dysregulated mTOR activation, leading to the occurrence of TSC.Patient concernsA 44-year-old man was hospitalized for acute lumbago and hematuria.DiagnosisThe patient presented with facial angiofibromas, epilepsy, fibrous plaques, periungual fibroma, renal angiomyolipomas (AML), pulmonary lymphangioleiomyomatosis (LAM), liver hamartomas, and osteosclerosis. A diagnosis of TSC was made based on clinical manifestations.InterventionsNext-generation sequencing (NGS) was performed to screen for potential variants, which were verified using Sanger sequencing. The final variant was analyzed using a minigene assay.OutcomesA potentially pathogenic novel TSC2 variant (NM_000548.4, c.336_336 + 15delGGTAAGGCCCAGGGCG) was identified using NGS and confirmed using Sanger sequencing. The in vitro minigene assay showed that the variant c.336_336 + 15delGGTAAGGCCCAGGGCG caused erroneous integration of a 74 bp sequence into intron 4. This novel variant was not found in his unaffected parents or 100 unrelated healthy controls.LessonsWe identified a novel heterozygous TSC2 variant, c.336_336 + 15delGGTAAGGCCCAGGGCG, in a patient with classical TSC and demonstrated that this variant leads to aberrant splicing using a minigene assay. Our results extend the understanding of the mutational spectrum of TSC2.
| S-EPMC8772658 | biostudies-literature
Project description:BackgroundRAD51D (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development.Case presentationA Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of RAD51D c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3'-end of intron 9 of RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma.ConclusionsWe present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline RAD51D splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production.
| S-EPMC8627011 | biostudies-literature
Project description:BackgroundPapilon-Lefevre syndrome (PLS; OMIM 245000) is a rare autosomal recessive disease characterized by aggressive periodontitis and palmoplantar keratoderma. The prevalence of PLS in the general population is one to four cases per million. Although the etiology and pathogenic mechanisms underlying PLS remain largely unclear, existing evidence shows loss-of-function mutations of the cathepsin C gene (CTSC; OMIM 602365) could cause PLS. Here we found a novel variant of the CTSC gene in a Chinese PLS family and predicted the effect of the variant on the physic-chemical characters and tertiary structure of the protein.MethodsThe 1-7 coding exons and exon-intron boundaries of CTSC gene of the proband and her family were amplified and sequenced directly, and Chromas was used to read sequencing files. Furthermore, the PolyPhen-2, PROVEAN, and Mutation Taster were utilized to predict the pathogenicity of the variant. Besides, the physic-chemical and structural characters of the protein were analyzed by ProtParam, ProtScale, and SWISS-MODEL.ResultsOur study identified a novel homozygous variant c.763T>C (p.Cys255Arg) in exon 6 of the CTSC gene, and it was a likely pathogenic variant as predicted by PolyPhen-2, PROVEAN, and Mutation Taster. Moreover, ProtParam and Protscale revealed the variant increased the isoelectric point and hydrophilicity of the protein, and the SWISS-MODEL analysis suggested the variant was located in a critical domain for protein activity.ConclusionOur study analyzed a Chinese family with PLS and identified a novel missense variant in the CTSC gene. Besides, this study retrospectively summarized 113 variants of CTSC in the world and highlighted the features of 27 CTSC variants in Chinese PLS patients. In addition, this study paid much particular attention to the relationship between CTSC variants and different phenotypes.
| S-EPMC8372118 | biostudies-literature
Project description:A five-year-old girl presented with headache attacks, clumsiness, and a history of transient gait disturbances. She and her father, mother, twin sister, and brother underwent neurological evaluation, neuroimaging, and exome sequencing covering 357 genes associated with movement disorders. Sequencing revealed the new variant KCND3 c.838G>A, p.E280K in the father and sisters, but not in the mother and brother. KCND3 encodes voltage-gated potassium channel D3 (Kv4.3) and mutations have been associated with spinocerebellar ataxia type 19/22 (SCA19/22) and cardiac arrhythmias. SCA19/22 is characterized by ataxia, Parkinsonism, peripheral neuropathy, and sometimes, intellectual disability. Neuroimaging, EEG, and ECG were unremarkable. Mild developmental delay with impaired fluid reasoning was observed in both sisters, but not in the brother. None of the family members demonstrated ataxia or parkinsonism. In Xenopus oocyte electrophysiology experiments, E280K was associated with a rightward shift in the Kv4.3 voltage-activation relationship of 11 mV for WT/E280K and +17 mV for E280K/E280K relative to WT/WT. Steady-state inactivation was similarly right-shifted. Maximal peak current amplitudes were similar for WT/WT, WT/E280K, and E280K/E280K. Our data indicate that Kv4.3 E280K affects channel activation and inactivation and is associated with developmental delay. However, E280K appears to be relatively benign considering it does not result in overt ataxia.
| S-EPMC10341420 | biostudies-literature