title: Expanding the clinical phenotype of patients with a ZDHHC9 mutation.
abstract: In 2007, 250 families with X-linked intellectual disability (XLID) were screened for mutations in genes on the X-chromosome, and in 4 of these families, mutations in the ZDHHC9 gene were identified. The ID was either isolated or associated with a marfanoid habitus. ZDHHC9 encodes a palmitoyl transferase that catalyzes the posttranslational modification of NRAS and HRAS. Since this first description, no additional patient with a ZDHHC9 mutation has been reported in the literature. Here, we describe a large family in which we identified a novel pathogenic ZDHHC9 nonsense mutation (p.Arg298*) by parallel sequencing of all X-chromosome exons. The mutation cosegregated with the clinical phenotype in this family. An 18-year-old patient and his 40-year-old maternal uncle were evaluated. Clinical examination showed normal growth parameters, lingual fasciculation, limited extension of the elbows and metacarpophalangeal joints, and acrocyanosis. There was neither facial dysmorphism nor marfanoid habitus. Brain MRI detected a dysplastic corpus callosum. Neuropsychological testing showed mild intellectual disability. They both displayed generalized anxiety disorder, and the younger patient also suffered from significant behavior impairment that required attention or treatment. Speech evaluation detected satisfactory spoken language since both were able to provide information and to understand conversations of everyday life. Occupational therapy examination showed impaired visual-spatial and visual-motor performance with poor drawing/graphic skills. These manifestations are not specific enough to guide ZDHHC9 screening in patients with ID, and emphasize the value of next generation sequencing for making a molecular diagnosis and genetic counseling in families with XLID.
authors.affiliation: Centre de Génétique et Centre de Référence Anomalies du développement et Syndromes Malformatifs, Hôpital d'Enfants, CHU, Dijon, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Masurel-Paulet
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebrun
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Fabienne
authors.initials: F
authors.lastname: Levy
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.forename: Véronique
authors.initials: V
authors.lastname: Darmency-Stamboul
authors.forename: Salima
authors.initials: S
authors.lastname: El Chehadeh
authors.forename: Julien
authors.initials: J
authors.lastname: Thevenon
authors.forename: Sophie
authors.initials: S
authors.lastname: Chancenotte
authors.forename: Marie
authors.initials: M
authors.lastname: Ruffier-Bourdet
authors.forename: Marlène
authors.initials: M
authors.lastname: Bonnet
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pinoit
authors.forename: Frédéric
authors.initials: F
authors.lastname: Huet
authors.forename: Vincent
authors.initials: V
authors.lastname: Desportes
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
mesh_terms: D000217:Acyltransferases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology; D002648:Child; D019066:Facies; D017809:Fatal Outcome; D050172:Genes, X-Linked; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009483:Neuropsychological Tests; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D000217:Acyltransferases; C504825:ZDHHC9 protein, human
keywords: X-linked intellectual disability; ZDHHC9 gene; dysplastic corpus callosum