Supplementary Material for: Complex Neurological Phenotype in Female Carriers of <b><i>NHE6</i></b> Mutations

Mutations in <i>NHE6</i> (also termed <i>SLC9A6</i>) cause the X-linked neurological disorder Christianson syndrome (CS) in males. The purpose of this study was to examine the phenotypic spectrum of female carriers of <i>NHE6</i> mutations. Twenty female carriers from 9 pedigrees were enrolled, ranging from approximately age 2 to 65. A subset of female carriers was assessed using standardized neuropsychological measures. Also, the association of <i>NHE6</i> expression with markers of brain age was evaluated using 740 participants in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). A majority, but not all, female carriers demonstrated a deficit in at least one neurocognitive domain (85%). A recognizable neuropsychological profile emerged, revealing impairments in visuospatial function, attention, and executive function. Common neuropsychiatric diagnoses included: intellectual disability/developmental delay (20%), learning difficulties (31%), speech/language delays (30%), and attention-deficit/hyperactivity disorder (20%). Notable neurological diagnoses in aging CS female carriers include corticobasal degeneration and atypical parkinsonism. In postmortem brains from the ROS/MAP dataset of normal and pathological aging, decreased <i>NHE6</i> expression was correlated with greater tau deposition. Our study provides an examination of the phenotypic range in female carriers of <i>NHE6</i> mutations. The findings indicate that NHE6-related disease in females represents a new neurogenetic condition.