title: Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.
abstract: OBJECTIVE
  Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS.
  
  
  METHODS
  Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized.
  
  
  RESULTS
  The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold.
  
  
  CONCLUSIONS
  This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression.
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry and Laboratory for Molecular Medicine, Institute for Brain Science, Brown University, Providence, RI; Developmental Disorders Genetics Research Program, Emma Pendleton Bradley Hospital and Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, East Providence, RI.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Pescosolido
authors.forename: David M
authors.initials: DM
authors.lastname: Stein
authors.forename: Michael
authors.initials: M
authors.lastname: Schmidt
authors.forename: Christelle Moufawad
authors.initials: CM
authors.lastname: El Achkar
authors.forename: Mark
authors.initials: M
authors.lastname: Sabbagh
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Rogg
authors.forename: Umadevi
authors.initials: U
authors.lastname: Tantravahi
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: McLean
authors.forename: Judy S
authors.initials: JS
authors.lastname: Liu
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
authors.forename: Eric M
authors.initials: EM
authors.lastname: Morrow
mesh_terms: D000293:Adolescent; D001259:Ataxia / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D001321:Autistic Disorder / Q000209:etiology / Q000235:genetics; D001921:Brain / Q000254:growth & development / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D004569:Electroencephalography; D004827:Epilepsy / Q000150:complications* / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D015835:Ocular Motility Disorders / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D012044:Regression Analysis; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*; D055815:Young Adult
chemical_list: C445316:SLC9A6 protein, human; D017923:Sodium-Hydrogen Exchangers