title: Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease.
abstract: Several genes have been implicated in Rett syndrome (RTT) in its typical and variant forms. We applied next-generation sequencing (NGS) to evaluate for mutations in known or new candidate genes in patients with variant forms of Rett or Rett-like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett-like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile-onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT-like phenotypes. Moreover, we report the first familial case of CDKL5-related disease.
authors.affiliation: Laboratoire de génétique médicale, CHU de Nancy - Hôpital de Brabois, Nancy, France.|Development and Disease Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Allou
authors.affiliation: Service de génétique médicale, Pôle de biologie, CHU de Toulouse - Hôpital Purpan, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: Julia
authors.affiliation: Service de pédiatrie 1, CHRU de Besançon - Hôpital Jean Minjoz, Besançon, France.
authors.forename: D
authors.initials: D
authors.lastname: Amsallem
authors.affiliation: Service de génétique médicale, CHU de Strasbourg - Hôpital de Hautepierre, Strasbourg, France.
authors.forename: S
authors.initials: S
authors.lastname: El Chehadeh
authors.affiliation: UF de génétique médicale, CHU de Nancy - Maternité régionale, Nancy, France.|Service de Médecine Infantile et Génétique Clinique - Hôpital d'Enfants, CHU de Nancy - Hôpital de Brabois, Nancy, France.
authors.forename: L
authors.initials: L
authors.lastname: Lambert
authors.affiliation: Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Inter région Est, Pôle Pédiatrie, CHU de Dijon - Complexe du Bocage, Dijon, France.|Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
authors.forename: J
authors.identifier: 0000-0001-9271-3961
authors.initials: J
authors.lastname: Thevenon
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Duffourd
authors.affiliation: Laboratoire de génétique médicale, CHU de Nancy - Hôpital de Brabois, Nancy, France.
authors.forename: A
authors.initials: A
authors.lastname: Saunier
authors.affiliation: Laboratoire de génétique médicale, CHU de Nancy - Hôpital de Brabois, Nancy, France.
authors.forename: P
authors.initials: P
authors.lastname: Bouquet
authors.affiliation: Laboratoire de génétique médicale, CHU de Nancy - Hôpital de Brabois, Nancy, France.
authors.forename: S
authors.initials: S
authors.lastname: Pere
authors.affiliation: Laboratoire de génétique médicale, CHU de Nancy - Hôpital de Brabois, Nancy, France.
authors.forename: A
authors.initials: A
authors.lastname: Moustaïne
authors.affiliation: Service de pédiatrie 1, CHRU de Besançon - Hôpital Jean Minjoz, Besançon, France.
authors.forename: L
authors.initials: L
authors.lastname: Ruaud
authors.affiliation: Laboratoire de génétique médicale, CHU de Nancy - Hôpital de Brabois, Nancy, France.
authors.forename: V
authors.initials: V
authors.lastname: Roth
authors.affiliation: Laboratoire de génétique médicale, CHU de Nancy - Hôpital de Brabois, Nancy, France.|Inserm U954 Nutrition-Genetics-Environmental Risk Exposure, Medical Faculty, Université de Lorraine, Nancy, France.
authors.forename: P
authors.initials: P
authors.lastname: Jonveaux
authors.affiliation: Laboratoire de génétique médicale, CHU de Nancy - Hôpital de Brabois, Nancy, France.|Inserm U954 Nutrition-Genetics-Environmental Risk Exposure, Medical Faculty, Université de Lorraine, Nancy, France.
authors.forename: C
authors.initials: C
authors.lastname: Philippe
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D018389:Codon, Nonsense; D059472:Exome / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D051663:Kv1.2 Potassium Channel / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics* / Q000503:physiopathology
chemical_list: D018389:Codon, Nonsense; D020662:Guanine Nucleotide Exchange Factors; C550083:IQSEC2 protein, human; C496969:KCNA2 protein, human; D051663:Kv1.2 Potassium Channel; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human
keywords: CDKL5; IQSEC2; KCNA2; Rett syndrome; genetic heterogeneity; high-throughput sequencing