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Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.
Moutton, S; Bruel, A-L; Assoum, M; Chevarin, M; Sarrazin, E; Goizet, C; Guerrot, A-M; Charollais, A; Charles, P; Heron, D; Faudet, A; Houcinat, N; Vitobello, A; Tran-Mau-Them, F; Philippe, C; Duffourd, Y; Thauvin-Robinet, C; Faivre, L.
Afiliación
  • Moutton S; Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, France.
  • Bruel AL; INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon, France.
  • Assoum M; INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon, France.
  • Chevarin M; INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon, France.
  • Sarrazin E; INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon, France.
  • Goizet C; Caribbean Reference Center for Rare Neurological and Neuromuscular Diseases, Fort de France University Hospital, Fort de France, France.
  • Guerrot AM; Reference Center for Developmental Anomalies, Medical Genetics Department, CHU Bordeaux and Laboratoire MRGM, INSERM U1211, University of Bordeaux, Bordeaux, France.
  • Charollais A; Department of Genetics, Rouen University Hospital, Rouen, France.
  • Charles P; Department of Neonatal Medicine and Intensive Care, Neuropediatrics and Reference Centre for Learning Disabilities, Rouen University Hospital, Rouen, France.
  • Heron D; Reference Center for Rare Intellectual Disability Disorders, AP-HP, Pitié-Salpêtrière Hospital, Paris, France and Clinical Research Group "intellectual disability and autism", UPMC, Paris, France.
  • Faudet A; Reference Center for Rare Intellectual Disability Disorders, AP-HP, Pitié-Salpêtrière Hospital, Paris, France and Clinical Research Group "intellectual disability and autism", UPMC, Paris, France.
  • Houcinat N; Reference Center for Rare Intellectual Disability Disorders, AP-HP, Pitié-Salpêtrière Hospital, Paris, France and Clinical Research Group "intellectual disability and autism", UPMC, Paris, France.
  • Vitobello A; Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, France.
  • Tran-Mau-Them F; INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon, France.
  • Philippe C; INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon, France.
  • Duffourd Y; Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, France.
  • Thauvin-Robinet C; INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon, France.
  • Faivre L; Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, France.
Clin Genet ; 93(6): 1172-1178, 2018 06.
Article en En | MEDLINE | ID: mdl-29460436
Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in known disease-causing genes and non-disease-causing genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes post-synaptic density protein 95 (PSD-95), a protein expressed in various tissues, including the brain. In neurons, PSD-95 is located at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one patient carried a a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients exhibited mild-to-moderate ID, similar marfanoid features, including a long face, high-arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Homólogo 4 de la Proteína Discs Large / Síndrome de Marfan / Discapacidad Intelectual / Mutación Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adolescent / Adult / Child / Female / Humans / Male / Middle aged Idioma: En Revista: Clin Genet Año: 2018 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Dinamarca
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Homólogo 4 de la Proteína Discs Large / Síndrome de Marfan / Discapacidad Intelectual / Mutación Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adolescent / Adult / Child / Female / Humans / Male / Middle aged Idioma: En Revista: Clin Genet Año: 2018 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Dinamarca