Short-term memory deficits in carrier females with KDM5C mutations.

Summary: Short-term memory deficits in carrier females with KDM5C mutations: We present the cognitive abilities of females from five families who carry a mutation in a gene (KDM5C, formerly JARIDIC or SMCO m XpI 1 .2 that encodes a transcriptional regulator with histone demethylase activity that is specific for dimethylated and trimethy lated H3K4. In this report, the cognitive abilities of females who carry KDM5C mutations are compared to females who carry mutations in other genes known to cause X-linked intellectual and developmental disability (XLIDD) conditions. The KDM5C mutation carriers had higher mean scores on the abstract/visual and quantitative sections of the StanfordBinet Intelligence Scale: Fourth Edition and lower mean short term memory scores. Implications for counseling are presented. Key-words: X-linked intellectual and developmental disability - Immediate recall - Visuo spatial dysfunction - Verbal dysfunction. INTRODUCTION An intellectual and developmental disability (IDD) is defined as a cognitive ability quotient of less than 70 and impairment in adaptive behavior. The estimated prevalence of IDD in the population is two to three percent (2, 1 0). A specific etiology can be found in less than 50% of cases after clinical and laboratory evaluations (3, 17). The excess of males in the IDD population has been attributed, in part, to genes located on the X chromosome (9, 18). The male-female ratio of IDD indicates that almost half of all mild IDD in males is due to X-linked genes (14). Over 90 genes associated with XLIDD have now been identified (4, 5, 13). In addition to FMRl and ARX, KDM5C (also known as JARIDlC and SAO") may be one of the more common genes mutated in families with XLIDD (1, 8, 21). The KDM5C gene encodes a highly conserved ARID protein which is strongly expressed in muscle and brain tissue (21). The protein has 94% homology with the mouse homolog and contains several DNA-binding domains indicating a role in gene regulation (6(. METHOD SUBJECTS As one component of a study to identify causative genes for XLIDD we assessed cognitive abilities of affected males, carrier females and unaffected family members in families with XLIDD. We present the cognitive abilities of 10 females (mean CA 44.2 years; range 17.0-66.1 years) and 3 affected males (mean CA 30.4 years; range 16-7-38-11 who carry a KDM5C mutation. Their cognitive abilities as measured by Stanford-Binet Intelligence Scale: Fourth Edition (SBFE) (19) were compared to six carrier females (mean CA 23.34 years; range 7.0-36.6 years) from two families that have the same missense mutation in ribosomal S6 kinase-2 (RSK-2) that was previously shown to have a negative effect on generalized cognitive functioning (16). They were also compared to seven carrier females from four families with glutamate receptor, ionotrophic, AMPA3 (GR1A3) (mean CA 44.67 years; range 29-3-58.2 years) or interleukinl receptor accessory protein-like 1 (ILlRAPLl) (mean CA 52. 17 years; range 33 -64-10 years) gene mutations that have no reported effect on cognitive function (Simensen, unpublished data). Three affected males and 10 carrier females with KDM5C mutations were administered the SBFE. Eight other affected males with KDM5C mutations were evaluated but could not attain the base-line for administration of the SBFE. MATERIALS Utilization of a standardized measure (SBFE) yields a comparison to a large normal population. Two untimed tasks from the SBFE were utilized to assess short term memory (STM). In the Bead Memory (visuo-spatial memory) task the patient is required to reconstruct patterns utilizing red, white, and blue beads, ellipsoids, cones and saucers following a five second presentation of the stimulus. To test Memory for Sentences (verbal memory), the examiner reads a sentence to the patient and the task is to repeat it word for word with no additions or deletions. These data from the SBFE were then compared to the other cohorts using an unpaired unequal variance two-tailed Student's t-test. …