Submission Details

ADAT3 encodes the non-catalytic subunit of the heterodimeric ADAT2/ADAT3 tRNA deaminase complex, which catalyzes adenosine-to-inosine modification at position 34 of transfer RNAs, essential for accurate protein translation and decoding of C-ending codons. Biallelic loss-of-function variants in ADAT3 cause autosomal recessive intellectual disability through deficient wobble inosine modification, leading to impaired protein synthesis that particularly affects neurodevelopment.

Five different genetic variants identified so far include the highly recurrent p.Val144Met founder mutation found in over 90% of total reported patients, with 55 patients from 29 consanguineous families, predominantly from Middle Eastern countries (Alazami et al, PMID: 23620220; Del-Pozo-Rodriguez et al, PMID: 40120092), along with two missense variants (p.Ala196Val, p.Ala196Leu) (Ramos et al. PMID: 32763916; Thomas et al. PMID: 31687266), one frameshift variant (8-bp duplication causing p.Glu36Glyfs44) (Chaleshtori, et al. PMID: 29796286), and one nonsense variant (p.Gln274*) (PMID: 32763916), found in homozygous and compound heterozygous states. Strong segregation evidence with maximum points awarded demonstrates co-segregation of variants with disease phenotype across multiple affected families. Clinical features consistently include intellectual disability (100%) and absent or severely delayed speech, with variable features such as microcephaly, seizures, muscle tone defects, and other features such as failure to thrive, strabismus, and dysmorphic facial features. Functional studies demonstrate that ADAT3 variants reduce enzymatic activity, protein stability, and tRNA modification in patient cells, with rescue experiments confirming that catalytic function is essential for proper neuronal migration and cortical development.

In summary, there is moderate evidence supporting the relationship between ADAT3 and autosomal recessive intellectual disability-strabismus syndrome. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panels on August 5, 2025 (SOP Version 11). Gene Clinical Validity Standard Operating Procedures (SOP) - SOP11

ADAT3 encodes the non-catalytic subunit of the heterodimeric ADAT2/ADAT3 tRNA deaminase complex, which catalyzes adenosine-to-inosine modification at position 34 of transfer RNAs, essential for accurate protein translation and decoding of C-ending codons. Biallelic loss-of-function variants in ADAT3 cause autosomal recessive intellectual disability through deficient wobble inosine modification, leading to impaired protein synthesis that particularly affects neurodevelopment.

Five different genetic variants identified so far include the highly recurrent p.Val144Met founder mutation found in over 90% of total reported patients, with 55 patients from 29 consanguineous families, predominantly from Middle Eastern countries (Alazami et al., PMID: 23620220; Del-Pozo-Rodriguez et al., PMID: 40120092), along with two missense variants (p.Ala196Val, p.Ala196Leu) (Ramos et al., PMID: 32763916; Thomas et al., PMID: 31687266), one frameshift variant (8-bp duplication causing p.Glu36Glyfs44) (Chaleshtori et al., PMID: 29796286), and one nonsense variant (p.Gln274*) (PMID: 32763916), found in homozygous and compound heterozygous states. Strong segregation evidence with maximum points awarded demonstrates co-segregation of variants with disease phenotype across multiple affected families. Clinical features consistently include intellectual disability (100%) and absent or severely delayed speech, with variable features such as microcephaly, seizures, muscle tone defects, and other features such as failure to thrive, strabismus, and dysmorphic facial features.

Functional studies demonstrate that ADAT3 variants reduce enzymatic activity, protein stability, and tRNA modification in patient cells, with rescue experiments confirming that catalytic function is essential for proper neuronal migration and cortical development.

In summary, there is moderate evidence supporting the relationship between ADAT3 and autosomal recessive intellectual disability-strabismus syndrome. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 16, 2025 (SOP Version 11).