22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening / T. L. WENGER in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 27p. Titre : 22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening Type de document : Texte imprimé et/ou numérique Auteurs : T. L. WENGER, Auteur ; J. S. MILLER, Auteur ; L. M. DEPOLO, Auteur ; A. B. DE MARCHENA, Auteur ; Caitlin C. CLEMENTS, Auteur ; B. S. EMANUEL, Auteur ; E. H. ZACKAI, Auteur ; D. M. MCDONALD-MCGINN, Auteur ; Robert T. SCHULTZ, Auteur Article en page(s) : 27p. Langues : Anglais (eng) Mots-clés : Abnormalities, Multiple/diagnosis  Adolescent  Adult  Analysis of Variance  Autism Spectrum Disorder/complications/diagnosis/epidemiology  Child  Child, Preschool  Chromosome Duplication  Chromosomes, Human, Pair 22  DiGeorge Syndrome/complications/diagnosis  Female  Genetic Testing  Humans  Male  Middle Aged  Social Behavior  Surveys and Questionnaires  Young Adult  22q11.2 deletion syndrome  22q11.2 duplication syndrome  Autism spectrum disorder  Developmental delay  Medical characterization  Medical screening  Neuropsychiatric functioning  Syndromic autism  Typically developing controls Index. décimale : PER Périodiques Résumé : BACKGROUND: Widespread use of microarray technology has led to increasing identification of 22q11.2 duplication syndrome (22q11.2DupS), the reciprocal syndrome of the well-characterized 22q11.2 deletion syndrome (22q11.2DS). Individuals with 22q11.2DS have elevated rates of community diagnoses of autism spectrum disorder (ASD), schizophrenia, and a range of medical problems and birth defects that necessitate extensive medical screening. Case reports of 22q11.2DupS include patients with ASD, fewer medical problems, and no schizophrenia; however, no prospective cohort study has been reported. The goals of the study were to (1) characterize the neuropsychiatric functioning of a cohort of individuals with 22q11.2DupS in comparison to large samples of typically developing controls (TDCs), ASD and 22q11.2DS; (2) estimate the prevalence of ASD in 22q11.2DupS; (3) determine whether the indications that prompted the genetic testing in 22q11.2DupS differ from 22q11.2DS and (4) determine whether comprehensive medical screening should be recommended for those diagnosed with 22q11.2DupS. METHODS: Medical characterization was done by parental questionnaire and medical chart review of individuals with 22q11.2DupS (n = 37) and 22q11.2DS (n = 101). Neuropsychiatric characterization of children with 22.11.2DupS, 22q11.2DS, TDCs, and ASD was done by parent-report questionnaires; in addition, the ASD and 22q11.2DupS groups received the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. RESULTS: Individuals with 22q11.2DupS, 22q11.2DS, and ASD had significantly impaired social interaction and adaptive behavior skills compared to TDCs. Overall, 38% of children aged 2-18 with 22q11.2DupS had community diagnoses of ASD, but fewer (14-25%) met on the basis of best clinical judgment that included ADI-R and ADOS data. Indications for genetic testing were significantly different for 22q11.2DupS and 22q11.2DS, with the deletions more commonly tested because of birth defects or medical problems, and the duplications because of developmental delay. However, when the screening protocol for 22q11.2DS was applied to the 22q11.2DupS sample, several medical problems were identified that would pose significant risk if left undetected. CONCLUSIONS: 22q11.2DupS has a high rate of ASD at 14-25%, among the highest of any genetic disorder. Prospective medical screening should be done for all patients with 22q11.2DupS, including those diagnosed due to developmental delays and ASD alone. En ligne : http://dx.doi.org/10.1186/s13229-016-0090-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] 22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening [Texte imprimé et/ou numérique] / T. L. WENGER, Auteur ; J. S. MILLER, Auteur ; L. M. DEPOLO, Auteur ; A. B. DE MARCHENA, Auteur ; Caitlin C. CLEMENTS, Auteur ; B. S. EMANUEL, Auteur ; E. H. ZACKAI, Auteur ; D. M. MCDONALD-MCGINN, Auteur ; Robert T. SCHULTZ, Auteur . - 27p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 27p. Mots-clés : Abnormalities, Multiple/diagnosis  Adolescent  Adult  Analysis of Variance  Autism Spectrum Disorder/complications/diagnosis/epidemiology  Child  Child, Preschool  Chromosome Duplication  Chromosomes, Human, Pair 22  DiGeorge Syndrome/complications/diagnosis  Female  Genetic Testing  Humans  Male  Middle Aged  Social Behavior  Surveys and Questionnaires  Young Adult  22q11.2 deletion syndrome  22q11.2 duplication syndrome  Autism spectrum disorder  Developmental delay  Medical characterization  Medical screening  Neuropsychiatric functioning  Syndromic autism  Typically developing controls Index. décimale : PER Périodiques Résumé : BACKGROUND: Widespread use of microarray technology has led to increasing identification of 22q11.2 duplication syndrome (22q11.2DupS), the reciprocal syndrome of the well-characterized 22q11.2 deletion syndrome (22q11.2DS). Individuals with 22q11.2DS have elevated rates of community diagnoses of autism spectrum disorder (ASD), schizophrenia, and a range of medical problems and birth defects that necessitate extensive medical screening. Case reports of 22q11.2DupS include patients with ASD, fewer medical problems, and no schizophrenia; however, no prospective cohort study has been reported. The goals of the study were to (1) characterize the neuropsychiatric functioning of a cohort of individuals with 22q11.2DupS in comparison to large samples of typically developing controls (TDCs), ASD and 22q11.2DS; (2) estimate the prevalence of ASD in 22q11.2DupS; (3) determine whether the indications that prompted the genetic testing in 22q11.2DupS differ from 22q11.2DS and (4) determine whether comprehensive medical screening should be recommended for those diagnosed with 22q11.2DupS. METHODS: Medical characterization was done by parental questionnaire and medical chart review of individuals with 22q11.2DupS (n = 37) and 22q11.2DS (n = 101). Neuropsychiatric characterization of children with 22.11.2DupS, 22q11.2DS, TDCs, and ASD was done by parent-report questionnaires; in addition, the ASD and 22q11.2DupS groups received the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. RESULTS: Individuals with 22q11.2DupS, 22q11.2DS, and ASD had significantly impaired social interaction and adaptive behavior skills compared to TDCs. Overall, 38% of children aged 2-18 with 22q11.2DupS had community diagnoses of ASD, but fewer (14-25%) met on the basis of best clinical judgment that included ADI-R and ADOS data. Indications for genetic testing were significantly different for 22q11.2DupS and 22q11.2DS, with the deletions more commonly tested because of birth defects or medical problems, and the duplications because of developmental delay. However, when the screening protocol for 22q11.2DS was applied to the 22q11.2DupS sample, several medical problems were identified that would pose significant risk if left undetected. CONCLUSIONS: 22q11.2DupS has a high rate of ASD at 14-25%, among the highest of any genetic disorder. Prospective medical screening should be done for all patients with 22q11.2DupS, including those diagnosed due to developmental delays and ASD alone. En ligne : http://dx.doi.org/10.1186/s13229-016-0090-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Critical region within 22q11.2 linked to higher rate of autism spectrum disorder / Caitlin C. CLEMENTS in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 58p. Titre : Critical region within 22q11.2 linked to higher rate of autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Caitlin C. CLEMENTS, Auteur ; T. L. WENGER, Auteur ; A. R. ZOLTOWSKI, Auteur ; Jennifer R. BERTOLLO, Auteur ; J. S. MILLER, Auteur ; A. B. DE MARCHENA, Auteur ; L. M. MITTEER, Auteur ; J. C. CAREY, Auteur ; B. E. YERYS, Auteur ; E. H. ZACKAI, Auteur ; B. S. EMANUEL, Auteur ; D. M. MCDONALD-MCGINN, Auteur ; Robert T. SCHULTZ, Auteur Article en page(s) : 58p. Langues : Anglais (eng) Mots-clés : 22q11.2 deletion syndrome  22q11.2 duplication syndrome  Atypical  Autism spectrum disorder  Face processing  Nested  Prosopagnosia  Ranbp1  Screening  Syndromic autism Index. décimale : PER Périodiques Résumé : BACKGROUND: Previous studies have reported no clear critical region for medical comorbidities in children with deletions or duplications of 22q11.2. The purpose of this study was to evaluate whether individuals with small nested deletions or duplications of the LCR-A to B region of 22q11.2 show an elevated rate of autism spectrum disorder (ASD) compared to individuals with deletions or duplications that do not include this region. METHODS: We recruited 46 patients with nested deletions (n = 33) or duplications (n = 13) of 22q11.2, including LCR-A to B (ndel = 11), LCR-A to C (ndel = 4), LCR-B to D (ndel = 14; ndup = 8), LCR-C to D (ndel = 4; ndup = 2), and smaller nested regions (n = 3). Parent questionnaire, record review, and, for a subset, in-person evaluation were used for ASD diagnostic classification. Rates of ASD in individuals with involvement of LCR-B to LCR-D were compared with Fisher's exact test to LCR-A to LCR-B for deletions, and to a previously published sample of LCR-A to LCR-D for duplications. The rates of medical comorbidities and psychiatric diagnoses were determined from questionnaires and chart review. We also report group mean differences on psychiatric questionnaires. RESULTS: Individuals with deletions involving LCR-A to B showed a 39-44% rate of ASD compared to 0% in individuals whose deletions did not involve LCR-A to B. We observed similar rates of medical comorbidities in individuals with involvement of LCR-A to B and LCR-B to D for both duplications and deletions, consistent with prior studies. CONCLUSIONS: Children with nested deletions of 22q11.2 may be at greater risk for autism spectrum disorder if the region includes LCR-A to LCR-B. Replication is needed. En ligne : http://dx.doi.org/10.1186/s13229-017-0171-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Critical region within 22q11.2 linked to higher rate of autism spectrum disorder [Texte imprimé et/ou numérique] / Caitlin C. CLEMENTS, Auteur ; T. L. WENGER, Auteur ; A. R. ZOLTOWSKI, Auteur ; Jennifer R. BERTOLLO, Auteur ; J. S. MILLER, Auteur ; A. B. DE MARCHENA, Auteur ; L. M. MITTEER, Auteur ; J. C. CAREY, Auteur ; B. E. YERYS, Auteur ; E. H. ZACKAI, Auteur ; B. S. EMANUEL, Auteur ; D. M. MCDONALD-MCGINN, Auteur ; Robert T. SCHULTZ, Auteur . - 58p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 58p. Mots-clés : 22q11.2 deletion syndrome  22q11.2 duplication syndrome  Atypical  Autism spectrum disorder  Face processing  Nested  Prosopagnosia  Ranbp1  Screening  Syndromic autism Index. décimale : PER Périodiques Résumé : BACKGROUND: Previous studies have reported no clear critical region for medical comorbidities in children with deletions or duplications of 22q11.2. The purpose of this study was to evaluate whether individuals with small nested deletions or duplications of the LCR-A to B region of 22q11.2 show an elevated rate of autism spectrum disorder (ASD) compared to individuals with deletions or duplications that do not include this region. METHODS: We recruited 46 patients with nested deletions (n = 33) or duplications (n = 13) of 22q11.2, including LCR-A to B (ndel = 11), LCR-A to C (ndel = 4), LCR-B to D (ndel = 14; ndup = 8), LCR-C to D (ndel = 4; ndup = 2), and smaller nested regions (n = 3). Parent questionnaire, record review, and, for a subset, in-person evaluation were used for ASD diagnostic classification. Rates of ASD in individuals with involvement of LCR-B to LCR-D were compared with Fisher's exact test to LCR-A to LCR-B for deletions, and to a previously published sample of LCR-A to LCR-D for duplications. The rates of medical comorbidities and psychiatric diagnoses were determined from questionnaires and chart review. We also report group mean differences on psychiatric questionnaires. RESULTS: Individuals with deletions involving LCR-A to B showed a 39-44% rate of ASD compared to 0% in individuals whose deletions did not involve LCR-A to B. We observed similar rates of medical comorbidities in individuals with involvement of LCR-A to B and LCR-B to D for both duplications and deletions, consistent with prior studies. CONCLUSIONS: Children with nested deletions of 22q11.2 may be at greater risk for autism spectrum disorder if the region includes LCR-A to LCR-B. Replication is needed. En ligne : http://dx.doi.org/10.1186/s13229-017-0171-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Erratum to: 22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening / T. L. WENGER in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 34p. Titre : Erratum to: 22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening Type de document : Texte imprimé et/ou numérique Auteurs : T. L. WENGER, Auteur ; J. S. MILLER, Auteur ; L. M. DEPOLO, Auteur ; A. B. DE MARCHENA, Auteur ; Caitlin C. CLEMENTS, Auteur ; B. S. EMANUEL, Auteur ; E. H. ZACKAI, Auteur ; D. M. MCDONALD-MCGINN, Auteur ; Robert T. SCHULTZ, Auteur Article en page(s) : 34p. Langues : Anglais (eng) Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1186/s13229-016-0097-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Erratum to: 22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening [Texte imprimé et/ou numérique] / T. L. WENGER, Auteur ; J. S. MILLER, Auteur ; L. M. DEPOLO, Auteur ; A. B. DE MARCHENA, Auteur ; Caitlin C. CLEMENTS, Auteur ; B. S. EMANUEL, Auteur ; E. H. ZACKAI, Auteur ; D. M. MCDONALD-MCGINN, Auteur ; Robert T. SCHULTZ, Auteur . - 34p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 34p. Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1186/s13229-016-0097-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

A Novel Approach to Dysmorphology to Enhance the Phenotypic Classification of Autism Spectrum Disorder in the Study to Explore Early Development / S. K. SHAPIRA in Journal of Autism and Developmental Disorders, 49-5 (May 2019)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 49-5 (May 2019) . - p.2184-2202 Titre : A Novel Approach to Dysmorphology to Enhance the Phenotypic Classification of Autism Spectrum Disorder in the Study to Explore Early Development Type de document : Texte imprimé et/ou numérique Auteurs : S. K. SHAPIRA, Auteur ; L. H. TIAN, Auteur ; Arthur S. AYLSWORTH, Auteur ; E. R. ELIAS, Auteur ; J. E. HOOVER-FONG, Auteur ; N. J. L. MEEKS, Auteur ; M. C. SOUDERS, Auteur ; A. C. TSAI, Auteur ; E. H. ZACKAI, Auteur ; A. A. ALEXANDER, Auteur ; M. YEARGIN-ALLSOPP, Auteur ; Laura A. SCHIEVE, Auteur Article en page(s) : p.2184-2202 Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Birth defects  Dysmorphic features  Dysmorphology  Genetic disorders  Morphologic anomalies  Phenotypic classification  Race/ethnicity Index. décimale : PER Périodiques Résumé : The presence of multiple dysmorphic features in some children with autism spectrum disorder (ASD) might identify distinct ASD phenotypes and serve as potential markers for understanding causes and prognoses. To evaluate dysmorphology in ASD, children aged 3-6 years with ASD and non-ASD population controls (POP) from the Study to Explore Early Development were evaluated using a novel, systematic dysmorphology review approach. Separate analyses were conducted for non-Hispanic White, non-Hispanic Black, and Hispanic children. In each racial/ethnic group, ~ 17% of ASD cases were Dysmorphic compared with ~ 5% of POP controls. The ASD-POP differential was not explained by known genetic disorders or birth defects. In future epidemiologic studies, subgrouping ASD cases as Dysmorphic vs. Non-dysmorphic might help delineate risk factors for ASD. En ligne : http://dx.doi.org/10.1007/s10803-019-03899-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=393 [article] A Novel Approach to Dysmorphology to Enhance the Phenotypic Classification of Autism Spectrum Disorder in the Study to Explore Early Development [Texte imprimé et/ou numérique] / S. K. SHAPIRA, Auteur ; L. H. TIAN, Auteur ; Arthur S. AYLSWORTH, Auteur ; E. R. ELIAS, Auteur ; J. E. HOOVER-FONG, Auteur ; N. J. L. MEEKS, Auteur ; M. C. SOUDERS, Auteur ; A. C. TSAI, Auteur ; E. H. ZACKAI, Auteur ; A. A. ALEXANDER, Auteur ; M. YEARGIN-ALLSOPP, Auteur ; Laura A. SCHIEVE, Auteur . - p.2184-2202. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 49-5 (May 2019) . - p.2184-2202 Mots-clés : Autism spectrum disorder  Birth defects  Dysmorphic features  Dysmorphology  Genetic disorders  Morphologic anomalies  Phenotypic classification  Race/ethnicity Index. décimale : PER Périodiques Résumé : The presence of multiple dysmorphic features in some children with autism spectrum disorder (ASD) might identify distinct ASD phenotypes and serve as potential markers for understanding causes and prognoses. To evaluate dysmorphology in ASD, children aged 3-6 years with ASD and non-ASD population controls (POP) from the Study to Explore Early Development were evaluated using a novel, systematic dysmorphology review approach. Separate analyses were conducted for non-Hispanic White, non-Hispanic Black, and Hispanic children. In each racial/ethnic group, ~ 17% of ASD cases were Dysmorphic compared with ~ 5% of POP controls. The ASD-POP differential was not explained by known genetic disorders or birth defects. In future epidemiologic studies, subgrouping ASD cases as Dysmorphic vs. Non-dysmorphic might help delineate risk factors for ASD. En ligne : http://dx.doi.org/10.1007/s10803-019-03899-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=393

De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures / B. ROYER-BERTRAND in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 69 p. Titre : De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures Type de document : Texte imprimé et/ou numérique Auteurs : B. ROYER-BERTRAND, Auteur ; M. JEQUIER GYGAX, Auteur ; K. CISAROVA, Auteur ; J. A. ROSENFELD, Auteur ; J. A. BASSETTI, Auteur ; O. MOLDOVAN, Auteur ; E. O'HEIR, Auteur ; L. C. BURRAGE, Auteur ; J. ALLEN, Auteur ; L. T. EMRICK, Auteur ; E. EASTMAN, Auteur ; C. KUMPS, Auteur ; S. ABBAS, Auteur ; G. VAN WINCKEL, Auteur ; Nadia CHABANE, Auteur ; E. H. ZACKAI, Auteur ; S. LEBON, Auteur ; B. KEENA, Auteur ; E. J. BHOJ, Auteur ; M. UMAIR, Auteur ; D. LI, Auteur ; K. A. DONALD, Auteur ; A. SUPERTI-FURGA, Auteur Article en page(s) : 69 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Cacna1e  Developmental regression  Epilepsy  Exome sequencing  Global developmental delay  Intellectual disability  Neurodevelopmental disorders  Seizures  Topiramate  receives revenue from clinical genetic testing completed at Baylor Genetics  Laboratories. Index. décimale : PER Périodiques Résumé : BACKGROUND: De novo variants in the voltage-gated calcium channel subunit ?1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. METHODS: Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. RESULTS: We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype-phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. LIMITATIONS: The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. CONCLUSIONS: Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate. En ligne : http://dx.doi.org/10.1186/s13229-021-00473-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures [Texte imprimé et/ou numérique] / B. ROYER-BERTRAND, Auteur ; M. JEQUIER GYGAX, Auteur ; K. CISAROVA, Auteur ; J. A. ROSENFELD, Auteur ; J. A. BASSETTI, Auteur ; O. MOLDOVAN, Auteur ; E. O'HEIR, Auteur ; L. C. BURRAGE, Auteur ; J. ALLEN, Auteur ; L. T. EMRICK, Auteur ; E. EASTMAN, Auteur ; C. KUMPS, Auteur ; S. ABBAS, Auteur ; G. VAN WINCKEL, Auteur ; Nadia CHABANE, Auteur ; E. H. ZACKAI, Auteur ; S. LEBON, Auteur ; B. KEENA, Auteur ; E. J. BHOJ, Auteur ; M. UMAIR, Auteur ; D. LI, Auteur ; K. A. DONALD, Auteur ; A. SUPERTI-FURGA, Auteur . - 69 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 69 p. Mots-clés : Autism spectrum disorder  Cacna1e  Developmental regression  Epilepsy  Exome sequencing  Global developmental delay  Intellectual disability  Neurodevelopmental disorders  Seizures  Topiramate  receives revenue from clinical genetic testing completed at Baylor Genetics  Laboratories. Index. décimale : PER Périodiques Résumé : BACKGROUND: De novo variants in the voltage-gated calcium channel subunit ?1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. METHODS: Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. RESULTS: We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype-phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. LIMITATIONS: The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. CONCLUSIONS: Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate. En ligne : http://dx.doi.org/10.1186/s13229-021-00473-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

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