RPS6KA3 duplication in a male child with severe intellectual disability

Rare inherited and de novo copy number variations (CNVs) are the cause of a variety of genetic disorders with intellectual disability (ID). Chromosomal microarray analysis (CMA) has been a rapid method to identify both large and small pathogenic genomic imbalances causing those disorders. The identification and classification of a CNV as pathogenic is not always easy to establish. If for deletions, or loss of function of specific genes, the likelihood of being causal is higher, for duplications, or overexpression for the same genes, the correlation is harder. Here we present a male child with severe ID and a family history with a female sibling presenting mild ID. Affymetrix Cytoscan HD CMA identified a gain of 530 Kb on Xp22.12 (chrX: 20016145_20546410 [GRCh37])) encompassing EIF1AX and RPS6KA3 genes. Inheritance was not yet possible to assess. Mutations in the RPS6KA3 gene causes Coffin-Lowry syndrome, a mental retardation syndrome with dysmorphic facial features and skeletal anomalies. X-linked mental retardation-19 is a nonsyndromic form of mild to moderate ID also caused by mutations in RPS6KA3. Carrier females may be mildly affected. This shows some phenotypic variability for the loss of function of this gene. Recently both familial and isolated cases have been reported with a duplication of the entire RPS6KA3 gene associated with mild to moderate ID. Those few cases suggest the increased dosage of this gene may be the cause for the ID in these patients and point to additional heterogenicity of genotype-phenotype of imbalances in this gene. The collection of more cases with duplication of RPS6KA3, as the one described herein, will help establish a better classification for those CNVs, finding the real burden on the patient’s phenotype, and delineating the subsequent genetic counseling for their families.