0000000001287629
AUTHOR
Ange-line Bruel
Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
AbstractWhereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene,SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carryingSATB1variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression…
The oculoauriculofrontonasal syndrome: Further clinical characterization and additional evidence suggesting a nontraditional mode of inheritance
IF 2.264; International audience; The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo-auriculo-vertebral spectrum (OAVS)-associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features…
Autosomal recessive truncatingMAB21L1mutation associated with a syndromic scrotal agenesis
We report on a boy with a rare malformative association of scrotum agenesis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global development delay. The reported patient was carrying a homozygous frameshift in MAB21L1 detected by whole-exome sequencing, considered as the most likely disease-causing variant. Mab21l1 knockout mice present a strikingly similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia. We hypothesize that MAB21L1 haploinsufficiency cause a previously undescribed syndrome with scrotal agenesis, ophthalmological anomalies, facial dysmorphism and gross psychomotor delay as remar…
Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature
Item does not contain fulltext Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated wi…
Autosomal recessive IFT57 hypomorphic mutation cause ciliary transport defect in unclassified oral-facial-digital syndrome with short stature and brachymesophalangia
The 13 subtypes of oral-facial-digital syndrome (OFDS) belong to the heterogeneous group of ciliopathies. Disease-causing genes encode for centrosomal proteins, components of the transition zone or proteins implicated in ciliary signaling. A unique consanguineous family presenting with an unclassified OFDS with skeletal dysplasia and brachymesophalangia was explored. Homozygosity mapping and exome sequencing led to the identification of a homozygous mutation in IFT57, which encodes a protein implicated in ciliary transport. The mutation caused splicing anomalies with reduced expression of the wild-type transcript and protein. Both anterograde ciliary transport and sonic hedgehog signaling w…
High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics
ObjectiveTo assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.MethodsSixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) st…
A constitutive BCL2 down-regulation aggravates the phenotype of PKD1-mutant-induced polycystic kidney disease
IF 5.340; International audience; The main identified function of BCL2 protein is to prevent cell death by apoptosis. Mice knock-out for Bcl2 demonstrate growth retardation, severe polycystic kidney disease (PKD), gray hair and lymphopenia, and die prematurely after birth. Here, we report a 40-year-old male referred to for abdominal and thoracic aortic dissection with associated aortic root aneurysm, PKD, lymphocytopenia with a history of T cell lymphoblastic lymphoma, white hair since the age of 20, and learning difficulties. PKD, which was also detected in the father and sister, was related to an inherited PKD1 mutation. The combination of PKD with gray hair and lymphocytopenia was also r…
TBL1XR1 mutations in Pierpont syndrome are not restricted to the recurrent p.Tyr446Cys mutation
IF 2.264; International audience; Pierpont syndrome is a rare and sporadic syndrome, including developmental delay, facial characteristics, and abnormal extremities. Recently, a recurrent de novo TBL1XR1 variant (c.1337A > G; p.Tyr446Cys) has been identified in eight patients by whole‐exome sequencing. A dominant‐negative effect of this mutation is strongly suspected, since patients with TBL1XR1 deletion and other variants predicting loss of function do not share the same phenotype. We report two patients with typical Pierpont‐like syndrome features. Exome sequencing allowed identifying a de novo heterozygous missense TBL1XR1 variant in both patients, different from those already reported: …
Application of whole-exome sequencing to unravel the molecular basis of undiagnosed syndromic congenital neutropenia with intellectual disability
International audience; Neutropenia can be qualified as congenital when of neonatal onset or when associated with extra-hematopoietic manifestations. Overall, 30% of patients with congenital neutropenia (CN) remain without a molecular diagnosis after a multidisciplinary consultation and tedious diagnostic strategy. In the rare situations when neutropenia is identified and associated with intellectual disability (ID), there are few diagnostic hypotheses to test. This retrospective multicenter study reports on a clinically heterogeneous cohort of 10 unrelated patients with CN associated with ID and no molecular diagnosis prior to whole-exome sequencing (WES). WES provided a diagnostic yield o…
BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations
AbstractPurposeHeterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD.MethodsWe performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information.ResultsMolecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splic…
Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants
Next-generation sequencing has revealed the major impact of de novo variants (DNVs) in developmental disorders (DD) such as intellectual disability, autism, and epilepsy. However, a substantial fraction of these predicted pathogenic DNVs remains challenging to distinguish from background DNVs, notably the missense variants acting via nonhaploinsufficient mechanisms on specific amino acid residues. We hypothesized that the detection of the same missense variation in at least two unrelated individuals presenting with a similar phenotype could be a powerful approach to reveal novel pathogenic variants. We looked for variations independently present in both our database of >1200 solo exomes and…
Clinical whole-exome sequencing for the diagnosis of rare disorders with congenital anomalies and/or intellectual disability: substantial interest of prospective annual reanalysis
International audience; PurposeCongenital anomalies and intellectual disability (CA/ID) are a major diagnostic challenge in medical genetics—50% of patients still have no molecular diagnosis after a long and stressful diagnostic “odyssey.” Solo clinical whole-exome sequencing (WES) was applied in our genetics center to improve diagnosis in patients with CA/ID.MethodsThis retrospective study examined 416 consecutive tests performed over 3 years to demonstrate the effectiveness of periodically reanalyzing WES data. The raw data from each nonpositive test was reanalyzed at 12 months with the most recent pipeline and in the light of new data in the literature. The results of the reanalysis for …
Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity
PURPOSE: ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized.METHODS: International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing.RESULTS: We identified 13 individuals with heterozygous…
OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome
Item does not contain fulltext Oral-facial-digital (OFD) syndromes are rare heterogeneous disorders characterized by the association of abnormalities of the face, the oral cavity and the extremities, some due to mutations in proteins of the transition zone of the primary cilia or the closely associated distal end of centrioles. These two structures are essential for the formation of functional cilia, and for signaling events during development. We report here causal compound heterozygous mutations of KIAA0753/OFIP in a patient with an OFD VI syndrome. We show that the KIAA0753/OFIP protein, whose sequence is conserved in ciliated species, associates with centrosome/centriole and pericentrio…
Kosaki overgrowth syndrome: A novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications
Heterozygous activating variants in platelet-derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long-term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contrac…
Expanding the phenotype of ASXL3 ‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3
The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution …
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies
Item does not contain fulltext Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequ…
Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations
PurposeMolecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.MethodsWe performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and …
Severe X-linked chondrodysplasia punctata in nine new female fetuses
ObjectivesConradi-Hunermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. MethodsTo better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. ResultsThe mean age at diagnosis was 22weeks of gestation. The ultrasound features mainly included bon…
The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation
Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia(1,2). How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth(3-5), whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation(6,7). Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, wh…
Secondary findings from whole-exome/genome sequencing evaluating stakeholder perspectives. A review of the literature
IF 2.004 (2017); International audience; With the development of next generation sequencing, beyond identifying the cause of manifestations that justified prescription of the test, other information with potential interest for patients and their families, defined as secondary findings (SF), can be provided once patients have given informed consent, in particular when therapeutic and preventive options are available. The disclosure of such findings has caused much debate. The aim of this work was to summarize all opinion-based studies focusing on SF, so as to shed light on the concerns that this question generate. A review of the literature was performed, focusing on all PubMed articles repo…
Further delineation of a rare recessive encephalomyopathy linked to mutations in GFER thanks to data sharing of whole exome sequencing data
Background Alterations in GFER gene have been associated with progressive mitochondrial myopathy, congenital cataracts, hearing loss, developmental delay, lactic acidosis and respiratory chain deficiency in 3 siblings born to consanguineous Moroccan parents by homozygosity mapping and candidate gene approach (OMIM#613076). Next generation sequencing recently confirmed this association by the finding of compound heterozygous variants in 19-year-old girl with a strikingly similar phenotype, but this ultra-rare entity remains however unknown from most of the scientific community. Materials and methods Whole exome sequencing was performed as part of a "diagnostic odyssey" for suspected mitochon…
Skraban‐Deardorff syndrome: Six new cases of WDR 26 ‐related disease and expansion of the clinical phenotype
International audience; Skraban-Deardorff syndrome (a disease related to variations in the WDR26 gene; OMIM #617616) was first described in a cohort of 15 individuals in 2017. The syndrome comprises intellectual deficiency, severe speech impairment, ataxic gait, seizures, mild hypotonia with feeding difficulties during infancy, and dysmorphic features. Here, we report on six novel heterozygous de novo pathogenic variants in WDR26 in six probands. The patients’ phenotypes were consistent with original publication. One patient displayed marked hypotonia with an abnormal muscle biopsy; this finding warrants further investigation. Gait must be closely monitored, in order to highlight any muscul…
Clinical Delineation Of A Subtype Of Frontonasal Dysplasia With Creased Nasal Ridge And Upper Limb Anomalies: Report Of Six Unrelated Patients
IF 2.259; International audience; Frontonasal dysplasias are rare congenital malformations of frontonasal process-derived structures, characterized by median cleft, nasal anomalies, widely spaced eyes, and cranium bifidum occultum. Several entities of syndromic frontonasal dysplasia have been described, among which, to date, only a few have identified molecular bases. We clinically ascertained a cohort of 124 individuals referred for frontonasal dysplasia. We identified six individuals with a similar phenotype, including one discordant monozygous twin. Facial features were remarkable by nasal deformity with creased ridge and depressed or absent tip, widely spaced eyes, almond-shaped palpebr…
De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.
International audience; Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.Results: Of 20 individuals, 14 showed…
Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency
International audience; PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various ty…
INTU -related oral-facial-digital syndrome type VI: a confirmatory report
Oral-facial-digital (OFD) syndromes are a subgroup of ciliopathies distinguished by the co-occurrence of hamartomas and/or multiple frenula of the oral region and digital anomalies. Several clinical forms of OFD syndromes are distinguished by their associated anomalies and/or inheritance patterns, and at least 20 genetic types of OFD syndromes have been delineated. We describe here a child with preaxial and postaxial polydactyly, lingual hamartoma, a congenital heart defect, delayed development and cerebellar peduncles displaying the molar tooth sign. Whole-exome sequencing and SNP array identified compound heterozygous variants in the INTU gene, which encodes a protein involved in the posi…
New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics.
International audience; Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC.Results: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-ass…
Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility
International audience; Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut dev…
An siRNA-based screen in C2C12 myoblasts identifies novel genes involved in myogenic differentiation
International audience; AbstractMyogenesis is a highly regulated multi-step process involving myoblast proliferation and differentiation. Although studies over the last decades have identified several factors governing these distinct major phases, many of them are not yet known. In order to identify novel genes, we took advantage of the C2C12 myoblastic line to establish a functional siRNA screen combined with quantitative-imaging analysis of a large amount of differentiated myoblasts. We knocked down 100 preselected mouse genes without a previously characterized role in muscle. Using image analysis, we tracked gene-silencing phenotypes by quantitative assessment of cellular density, myotub…
Reducing diagnostic turnaround times of exome sequencing for families requiring timely diagnoses
IF 2.137; International audience; BACKGROUND AND OBJECTIVE:Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to impr…
Loss‐of‐function variants in ARHGEF9 are associated with an X‐linked intellectual disability dominant disorder
ARHGEF9 defects lead to an X-linked intellectual disability disorder related to inhibitory synaptic dysfunction. This condition is more frequent in males, with a few affected females reported. Up to now, sequence variants and gross deletions have been identified in males, while only chromosomal aberrations have been reported in affected females who showed a skewed pattern of X-chromosome inactivation (XCI), suggesting an X-linked recessive (XLR) disorder. We report three novel loss-of-function (LoF) variants in ARHGEF9: A de novo synonymous variant affecting splicing (NM_015185.2: c.1056G>A, p.(Lys352=)) in one female; a nonsense variant in another female (c.865C>T, p.(Arg289*)), that is, a…
Osteo-Oto-Hepato-Enteric Syndrome (O2HE) is caused by loss of function mutations in UNC45A
AbstractDespite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with hitherto unknown syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing and bone fragility, a clinical entity we have termed O2HE (Osteo-Oto-Hepato-enteric) syndrome. Whole exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A), as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss of function paradigm, wherein mutations …
HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans
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…
A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis
International audience; Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgene…