Exonic deletion of SLC9A9 in autism with epilepsy

Abstract

Genes encoding proteins critical for intracellular vesicular transport are an emerging area of importance for neurologists. In particular, proteins that create and maintain the correct compartmental pH, such as the endosomal Na(+)/H(+) exchangers (NHEs), have been implicated in a wide range of human diseases, including cardiovascular, inflammatory bowel, renal, and neurologic disorders, which demonstrates the critical cellular function of these proteins.(1-3) Two NHEs, NHE6 and NHE9, have been linked to neurologic disorders in children.(4) Pathologic variants in SLC9A6 encoding NHE6 cause an Angelman-like disorder called Christianson syndrome. Fewer variants have been described in SLC9A9 encoding NHE9, but individuals carrying these variants have been diagnosed with neurologic disorders ranging from autism to epilepsy to attention-deficit/hyperactivity disorder. The majority of described variants are missense, resulting in amino acid substitutions, making it difficult to determine their functional consequence.(4).

Figure. Clinical and molecular characterization

(A) Pedigree of the individual with SLC9A9 deletion. (B) EEG tracing revealing left frontotemporal focus of epileptiform activity. (C) T2-weighted MRI image with punctate temporal hyperintensity. (D) Array comparative genomic hybridization plot of region of chromosome 3q24 demonstrating exonic deletion of SLC9A9 and predicted protein truncation. Y-scale is log2. Solid vertical lines represent minimally deleted regions (chr3:145033431-145033895), and dotted vertical lines represent maximally deleted region (chr3:145021878-145049622) based on hg18. Red circles are probes with a log2 ratio of −1.0 representing deletion of 1 copy in our patient, black circle with log2 of approximately 0. (E) Schematic representation of subcellular localization and function of NHE9.