The Clinical and Molecular Spectrum of Patients With X-Linked Intellectual Disability and Novel Variations in...

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. In this study, we aimed to describe the clinical and molecular spectrum of patients with XLID. We also evaluated the clinical efficacy of a targeted gene panel in patients with suspected XLID.

Eighty-four patients with suspected XLID were enrolled in the study. Array comparative genomic hybridization, fragile X fragman analysis, and targeted XLID gene panel were performed.

Genetic diagnosis was established in a total of 24 patients (22 male and two female) with XLID. Different copy number variations of the X chromosome were detected in four patients, including two duplications and two deletions. Fifteen patients had fragile X syndrome. Point mutations were detected in five unrelated patients. Variants detected in RPS6KA3 gene were previously reported by our team. A novel two-nucleotide deletion was shown in the MID1 gene. Additionally, novel missense variations were revealed in IL1RAPL1 and ATRX genes. The IL1RAPL1 variant was detected in additional five affected male patients in the same family. The patient, who had ATRX variation, had pachygyria in the cerebral cortex and hypoplasia of cerebellar vermis.

Our findings have broadened the spectrum of mutations and clinical manifestations of patients with XLID. Additionally, this represents the second reported missense variation in the IL1RAPL1 gene identified in patients with XLID. We also emphasized the importance of a stepwise diagnostic algorithm that incorporates chromosomal microarray analysis, FMR1 gene repeat analysis, and next-generation sequencing analysis for patients with XLID.