CNKSR2 deletions: A novel cause of X‐linked intellectual disability and seizures

X-linked intellectual disability (XLID) accounts for approximately 10% of intellectual disability in males and contributes to the excess of males in the intellectually disabled population (male to female ratio 1.3–1.4 to 1) [Ropers andHamel, 2005]. Underlying causes of XLID have been extensively studied in recent years, and as a result mutations causing XLID have been described in about 106 genes [Piton et al., 2013]. Recently, Houge et al. [2012] described a maternally inherited 234 kilobase deletion on the X chromosome, which removed themajority of theCNKSR2 gene (OMIM#300724; 21,375,312 – 21,609,484, genomebuild hg19; Fig. 1E) in amalewith developmental delay, epilepsy, and microcephaly. Since CNKSR2 gene is highly expressed only in the brain [Nagase et al., 1998], Houge et al. [2012] suggested that the phenotypic effects of loss of function mutations in the CNKSR2 gene may be restricted to the brain. They concluded that the CNKSR2 gene is a novel candidate gene for nonsyndromic X-linked intellectual disability. A recent report byPiton et al. [2013]onXLID-causingmutations reassessed the implications of 106 genes in their involvement in XLID and classified them into five groups: genes with known mutations, genes with questionable involvement, those that never been replicated, those awaiting replication, and some with likely involvement. The CNKSR2 gene was included in the awaiting replication category since its association with intellectual disability has not been replicated. We report on a deletion in the CNKSR2 gene in a boy with intellectual disability and seizures, therefore replicating the findings of Houge et al. [2012]. The proband was a 7-year-old boy who presented to the Neurology Department for a second opinion regarding his medically intractable focal seizures and developmental delay. He was the first child born to a 24-year-old mother. Aside from occasional alcoholic beverages (one to two drinks at a time at most twice aweek) and smokinguntil approximately fivemonths of gestation, the pregnancy was not complicated by maternal illnesses or exposure to other teratogens. The mother did not take any medications during gestation. Birth was at term and via spontaneous vaginal delivery without complications. Birth weight was 6 pounds, 14 ounces (3118 g, 25th centile), and no postnatal complications were reported. Concerns regarding the patient’s psychomotor development arose within the first year of life, particularly regarding his speech. The patient was slow in achievingmilestones but had no regression.