[Clinical and genetic analysis of four Chinese pedigrees affected with NAA15-related intellectual developmental...

To elucidate the clinical phenotype and molecular genetic characteristics of intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities (MRD50) due to variants of NAA15 gene.

A retrospective analysis was carried out on the clinical data of four MRT50 pedigrees (7 patients in total) diagnosed at the Children's Hospital of Nanjing Medical University between February 2022 and August 2024. Pathogenic variants carried by the patients were screened through whole exome sequencing and validated by Sanger sequencing in the respective pedigrees. Bioinformatics tools including MaxEntScan, dbscSNV, RDDC, and SpliceAI were employed to predicted the pathogenicity of splice-site variants. The functional impact of the c.692-5A>G splice-site variant was assessed by reverse transcription-PCR (RT-PCR) combined with agarose gel electrophoresis. PyMOL software was used to predict three-dimensional conformational changes of the variant proteins. Additionally, quantitative real-time PCR (qPCR) was applied to determine the mRNA expression of the NAA15 gene in the peripheral blood sample from the patients. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 202402022-1).

The patients (3 males and 4 females), with a last follow-up age ranging from 5-year-and-1-month-old to 35 year old, exhibited varying degrees of intellectual disability, language delay, and learning difficulties. Among them, 3 cases were accompanied by motor developmental delay, 1 case by seizure onset, 1 case by attention-deficit/hyperactivity disorder, 1 case by autism spectrum symptoms, and 1 case by ventricular septal defect. Genetic testing has identified four heterozygous variants in the NAA15 gene, including one case with c.822_823insTA (p.E275*) nonsense variant, two cases with c.376_379delCAAAinsTCCTTACTACAGGT (p.Q126Sfs*9) frameshift variant caused by a complex indel, three cases with c.1029_1038delAGAGTTAGTA (p.E344*) nonsense variant, and one case with a c.692-5A>G splice-site variant. Functional analysis demonstrated that all variants has led to protein truncation. The c.692-5A>G variant may cause aberrant splicing. And the expression level of NAA15 mRNA in patients with the c.692-5A>G variant was significantly lower than the healthy controls.

Variants of the NAA15 gene, including c.822_823insTA (p.E275*), c.376_379delCAAAinsTCCTTACTACAGGT (p.Q126Sfs*9), c.1029_1038delAGAGTTAGTA (p.E344*), and c.692-5A>G, may lead to MRD50. The core clinical manifestations are intellectual disability and language developmental delay, frequently accompanied by behavioral abnormalities and motor dysfunction.