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.
INTERPRETATION: 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.