A Novel Mutation in ATRX Causes Alpha-Thalassemia X-Linked Intellectual Disability Syndrome in a Han Chinese Family

Objective: To analyze genetic mutations in a Chinese pedigree affected with Alpha-thalassemia X-linked intellectual disability syndrome, providing a precise diagnosis and genetic counseling.Methods: Clinical data was collected. A novel alternative splicing variant detected by whole-exome sequencing was validated by Sanger sequencing. The functional effect of the mutation was predicted with Mutation Tasting. The analysis of 5 & PRIME; splice site score was estimated with MaxEntScan. Changes in amino acid sequencing were predicted with Mutalyzer. The tertiary structures of the wild type and mutation-carrying protein were predicted by I-TASSER. RNA was extracted from peripheral blood lymphocytes from the proband, his mother and a healthy control. Quantitative Real-Time PCR was used to detect mRNA expression.Results: The proband presented with severe intellectual disability, developmental delay, characteristic facies, seizures and cryptorchidism. A novel hemizygous duplication mutation in the ATRX gene in a splice site between exons 3 and 4, NM_000489: c.189+1dupG, was identified with WES in the proband. Sanger sequencing confirmed that the mutation was inherited from his mother, who carried a heterozygous mutation, while his father was not affected. Bioinformatics analysis indicated that the splicing region where the mutation was located is highly conserved and the variant was damaging, producing a truncated protein due to the premature translation of a stop codon. Sanger sequencing with the Quantitative Real-Time PCR product containing a G base inserted between bases 189 and 190. The level of mRNA expression showed that ATRX gene transcription decreased due to the mutation (P < 0.05).Conclusions: A novel mutation in ATRX was found in this pedigree and was confirmed to be pathogenic through functional studies. Our research expanded the spectrum of ATRX gene mutations, providing a precise diagnosis and a basis for genetic counseling.