Search results for "Exome"

Commonalities and distinctions between two neurodevelopmental disorder subtypes associated with SCN2A and SCN8A variants and literature review.

2022

This study was aimed to analyze the commonalities and distinctions of voltage-gated sodium channels, Nav1.2, Nav1.6, in neurodevelopmental disorders. An observational study was performed including two patients with neurodevelopmental disorders. The demographic, electroclinical, genetic, and neuropsychological characteristics were analyzed and compared with each other and then with the subjects carrying the same genetic variants reported in the literature. The clinical features of one of them argued for autism spectrum disorder and developmental delay, the other for intellectual disability, diagnoses confirmed by the neuropsychological assessment. The first patient was a carrier of SCN2A (p.…

DETECTION OF NEW GENES RESPONSIBLE OF FAMILIAL RECESSIVE HYPERCHOLESTEROLEMIA: PRELIMINARY DATA FROM AN EXOME SEQUENCING APPROACH

2014

HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans

2019

The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth ind…

Identification of molecular and physiopathologic basis in oral-facial-digital syndromes

2016

Oral-facial-digital syndromes (OFDS) are characterized by the association of oral, facial and digital anomalies. The different modes of inheritance and additional features lead to clinically delineate 13 subtypes. For a long time, only the OFD1 gene, responsible for OFDI subtype and coding for a centrosomal protein, has been known, suggesting the involvement of the primary cilium in OFDS. Mutations have recently been reported in the TMEM216, DDX59, SCLT1, TBC1D32 and TCTN3 genes in anecdotic cases. To identify new genes involved in OFDS, we performed whole-exome sequencing in 24 patients. In 14/24 cases, we identified 5 novel genes (C2CD3, TMEM107, INTU, KIAA0753, IFT57), enlarged the clini…

Capacity building in clinical and molecular characterization of rare neurodegenerative diseases through the development of a local register and impro…

2020

Neurodegenerative diseases (NDs) are very polymorphic and affect people of all ages. They concern both rare diseases and more common diseases. Improving knowledge of NDs in the French Caribbean region requires special attention because of the unique environmental and genetic background of its populations. In Martinique, there is a huge need for scientific research on rare NDs. While epidemiological and clinical research has increased over the past decade in the French West Indies, there is still little or no data on the genetics of NDs in these regions. The advent of Next Generation Sequencing (NGS) on a global scale has the potential to make a difference in this field, provided that techno…

De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

2014

Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387)(1-3). Here we report that individuals with MPPH lacking upstream PI3K-AKT pathway mutations carry de novo mutations in CCND2 (encoding cyclin D2) that are clustered around a residue that can be phosphorylated by glycogen synthase kinase 313 (GSK-3 beta)(4). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3 beta activity(4), and cells from individuals with PIK3CA, PIK3R2 or AKT3 mutations showed similar CCND2 accumulation. CCND…

Novel Mutations in the Asparagine Synthetase Gene (ASNS) Associated With Microcephaly

2018

Microcephaly is a devastating condition defined by a small head and small brain compared to the age- and sex-matched population. Mutations in a number of different genes causative for microcephaly have been identified, e.g., MCPH1, WDR62, and ASPM. Recently, mutations in the gene encoding the enzyme asparagine synthetase (ASNS) were associated to microcephaly and so far 24 different mutations in ASNS causing microcephaly have been described. In a family with two affected girls, we identified novel compound heterozygous variants in ASNS (c.1165G > C, p.E389Q and c.601delA, p.M201Wfs∗28). The first mutation (E389Q) is a missense mutation resulting in the replacement of a glutamate residue …

Filamin C variants are associated with a distinctive clinical and immunohistochemical arrhythmogenic cardiomyopathy phenotype.

2020

Background: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level. Methods: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry. Results: Novel or rare FLNC variants, four null and five variants of unknown significance, were id…

LARP7 variants and further delineation of the Alazami syndrome phenotypic spectrum among primordial dwarfisms: 2 sisters.

2019

Abstract Alazami syndrome (AS) (MIM# 615071 ) is an autosomal recessive microcephalic primordial dwarfism (PD) with recognizable facial features and severe intellectual disability due to depletion or loss of function variants in LARP7. To date, 15 patients with AS have been reported. Here we describe two consanguineous Algerian sisters with Alazami PD due to LARP7 homozygous pathogenic variants detected by whole exome sequencing. By comparing these two additional cases with those previously reported, we strengthen the key features of AS: severe growth restriction, severe intellectual disability and some distinguishing facial features such as broad nose, malar hypoplasia, wide mouth, full li…

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenital

2022

BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index pati…