Christianson Type X-Linked Mental Retardation via the SLC9A6 Gene

Variants in the SLC9A6 gene (OMIM 300231) cause syndromic X-linked mental retardation of the Christianson type (OMIM 300243), a syndrome with remarkable clinical overlap with Angelman syndrome (AS; OMIM 105830). Christianson type XLMR is characterized by affected males with profound mental retardation, seizures, absent speech, and microcephaly (Christianson et al. Med Genet 36:759-766, 1999). Other features include frequent smiling and episodes of unprovoked laughter (Gilfillan et al. Am J Hum Genet 82:1003-1010, 2008). Cerebellar atrophy has been demonstrated in affected males (Christianson et al. 1999; Gilfillan et al. 2008), and a reduced life expectancy has also been observed. Impaired ocular movements, including esotropia, are a frequent finding (Schroer et al. Am J Med Genet Part A 152A:2775-2783, 2010). Carrier females have been reported with mild mental retardation or learning problems (Christianson et al., 1999) and severe dyslexia (Gilfillan et al. 2008). As a consequence of the significant overlap of features between Christianson type XLMR and Angelman syndrome, it has been suggested that males with symptoms consistent with Angelman syndrome, but who test normal for UBE3A defects, are candidates for SLC9A6 testing (Gilfillan et al. 2008). Neuropathological and radiological findings include generalized cerebral atrophy with atrophy of the white matter and neuronal loss (Garbern et al. Brain 133:1391-1402, 2010; Schroer et al. 2010). The former authors also reported finding Tau-positive intracellular inclusions in the glial cells throughout the white matter of patients.

Christianson type X-linked mental retardation is inherited in an X-linked recessive manner. The SLC9A6 gene encodes isoform A6 of the solute carrier family 9 proteins which localizes to mitochondria and functions as a sodium/hydrogen exchanger (Numata et al. J Biol Chem 273:6951-6959, 1998). A small number of SLC9A6 variants have been described. Types of variant thus far reported include nonsense variants and frame-shifting small deletions (Gilfillan et al. 2008; Garbern et al. 2010) and an intragenic deletion (Whibley et al. Am J Hum Genet 87:173-188, 2010). At PreventionGenetics, patients with splicing and small duplication variants have been found.

The etiology of this disorder has only recently been described (Gilfillan et al. 2008). Thus, it is not possible to reliably predict clinical sensitivity of SLC9A6 testing. This gene is likely one of multiple causes of the 10%-15% of Angelman syndrome cases that are unrelated to UBE3A. Sequence analysis of all exons of the X chromosome in 208 XLMR families resulted in the identification of two cases with SLC9A6 variants (Tarpey et al. Nat Genet 41:535-543, 2009).

This test provides full coverage of all coding exons of the SLC9A6 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.