SLC12A2 mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia

OBJECTIVE: To describe the phenotype in 2 sisters with a rare constellation of neurologic symptoms and secretory impairments and to identify the etiology by the use of whole-genome sequencing (WGS). METHODS: After an extensive workup failed to reveal the cause of disease, in a girl with a previously not reported phenotype, WGS of the proband, her diseased older sister, an older healthy brother, and their parents was performed, and potentially pathogenic variants were analyzed. RESULTS: The proband and her older sister both presented with neonatal Staphylococcus aureus parotitis, apneas, disappearance of the Moro reflex, and hypotonia. The proband survived. Her brain MRI showed white matter and basal ganglia abnormalities, and CSF damage biomarkers were increased. At age 8 years, she exhibits a constellation of symptoms including severe neurodevelopmental disorder, hearing impairment, gastrointestinal problems, and a striking lack of tear fluid, saliva, and sweat. Her respiratory mucosa is dry with potentially life-threatening mucus plugging. Through WGS, 2 loss-of-function variants in SLC12A2 were identified that follow an autosomal recessive inheritance pattern. CONCLUSIONS: Taken together with a single previously reported case and the close resemblance to the phenotypes of corresponding mouse models, our study firmly establishes biallelic variants in SLC12A2 as causing human disease and adds data regarding the neurologic phenotype.