ADAT3-related neurodevelopmental disorder in 24 new patients with a high frequency of the p.Val144Met and a new founder variant

TL;DR

This study reports 24 Egyptian patients with a rare neurodevelopmental disorder caused by mutations in the ADAT3 gene, highlighting a common genetic variant and a new one.

Contribution

The study identifies a new founder variant in the ADAT3 gene and confirms a high frequency of an existing variant in the Egyptian population.

Findings

24 patients from 16 Egyptian families were found to have ADAT3-related neurodevelopmental disorder.

The p.Val144Met variant was detected in 70% of patients, suggesting a founder effect in the region.

A new founder variant, p.Glu107Lys, was identified in 25% of patients with a shared haplotype.

Abstract

Biallelic variants in the adenosine deaminase tRNA specific 3 (ADAT3) gene are associated with a distinct neurodevelopmental disorder characterized by dysmorphic facies, poor growth, cognitive impairment, and variable brain anomalies. We describe 24 patients from 16 unrelated Egyptian families with ADAT3-related neurodevelopmental disorder. All patients presented with developmental delay, growth retardation, cognitive impairment, and the characteristic facial features of the disorder, which appears to be more recognizable in older patients. Seizures were noted in 20% of patients and showed favorable responses to treatment. Brain imaging showed corpus callosum abnormalities in most patients (91.6%), followed by delayed myelination and cortical atrophy. Exome sequencing identified three ADAT3 variants, including the Saudi founder variant c.430G > A (p.Val144Met), which was detected in 17 patients (70%). In addition, two novel variants were identified, c.319G > A (p.Glu107Lys) and c.1013_1018dup (p.Arg338_Ile339dup). The c.319G > A (p.Glu107Lys) was recurrent in 6 patients (25%) who shared a similar haplotype, suggesting a likely founder effect in our population. On the other hand, the c.1013_1018dup (p.Arg338_Ile339dup) was identified in a single patient. Our study reports a large cohort of patients with ADAT3-related neurodevelopmental disorder from Egypt and reinforces the clinical and brain imaging characteristics of the disorder. The high prevalence of the c.430G > A (p.Val144Met) in our population strongly suggests the existence of a founder effect of this variant in the Middle East and Arab region. In addition, we report a new founder variant expanding the mutational spectrum of this rare disorder.

The online version contains supplementary material available at 10.1038/s41598-025-06857-2.

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