ADAT3‐related intellectual disability: Further delineation of the phenotype

Abstract

ADAT3-related intellectual disability has been recently described in 24 individuals from eight Saudi families who had cognitive impairment and strabismus. Other common features included growth failure, microcephaly, tone abnormalities, epilepsy, and nonspecific brain abnormalities. A single homozygous founder mutation (c.382G>A:p.(V128M)) in the ADAT3 gene, which encodes a protein that functions in tRNA editing, was identified in all affected individuals. In this report, we present additional 15 individuals from 11 families (10 Saudis and 1 Emirati) who are homozygous for the same founder mutation. In addition to the universal findings of intellectual disability and strabismus, the majority exhibited microcephaly and growth failure. Additional features not reported in the original cohort include dysmorphic facial features (prominent forehead, up-slanted palpebral fissures, epicanthus, and depressed nasal bridge), behavioral problems (hyperactivity and aggressiveness), recurrent otitis media, and growth hormone deficiency. ADAT3-related intellectual disability is an important recognizable cause of intellectual disability in Arabia.

A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition

“…This would be consistent with the finding by us and others that mutations in other genes involved in tRNA modification result in phenotypes with predilection to the brain e.g. ADAT3 , WDR4 , TRM10 , NSUN2 , and FTSJ1 (Abbasi-Moheb et al 2012; Alazami et al 2013; El-Hattab et al 2016; Fahiminiya et al 2014; Freude et al 2004; Gillis et al 2014; Guy et al 2015; Igoillo-Esteve et al 2013; Khan et al 2012; Martinez et al 2012; Ramser et al 2004; Shaheen et al 2015). Similarly, many disease-causing mutations in tRNA synthetases and in the ribosome manifest their effects in functional disturbance of the nervous system (Antonellis et al 2003; Antonellis and Green 2008; Brooks et al 2014; Yao and Fox 2013).…”

“…One such process that emerged from the discovery of Mendelian forms of ID is tRNA modification. For example, the most common form of autosomal recessive ID in Arabia was found to be due to mutation of ADAT3 , which edits adenosine to inosine at the wobble position 34 of mature tRNA (Alazami et al 2013; El-Hattab et al 2016; Gerber and Keller 1999). More recently, we have identified a form of severe microcephalic primordial dwarfism with global developmental delay that is caused by mutation of WDR4 , a subunit of the methyltransferase that catalyzes 7-methylguanosine modification of residue G 46 of tRNA (Shaheen et al 2015).…”

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

“…Notably, defects in tRNA modification have emerged as the cause of diverse neurological and neurodevelopmental disorders, thereby highlighting the critical role of tRNA modification in human health and physiology (Angelova et al, 2018; Ramos & Fu, 2019). In particular, the brain appears to be sensitive to any perturbation in translation efficiency and fidelity brought about by defects in tRNA modifications, as evidenced from the numerous cognitive disorders linked to tRNA modification enzymes such as: the Elongator complex (Hawer et al, 2018; Kojic & Wainwright, 2016); ADAT3 (Alazami et al, 2013; El‐Hattab et al, 2016; Ramos, Han, et al, 2019); NSUN2 (Abbasi‐Moheb et al, 2012; Khan et al, 2012; Martinez et al, 2012); FTSJ1 (Dai et al, 2008; Freude et al, 2004; Froyen et al, 2007; Gong et al, 2008; Guy et al, 2015; Ramser et al, 2004; Takano et al, 2008); WDR4 (Chen et al, 2018; Shaheen et al, 2015; Trimouille et al, 2018); KEOPS complex (Braun et al, 2017); PUS3 (Abdelrahman, Al‐Shamsi, Ali, & Al‐Gazali, 2018; Shaheen, Han, et al, 2016); CTU2 (Shaheen, Al‐Salam, El‐Hattab, & Alkuraya, 2016; Shaheen, Mark, et al, 2019); TRMT10A (Gillis et al, 2014; Igoillo‐Esteve et al, 2013; Narayanan et al, 2015; Yew, McCreight, Colclough, Ellard, & Pearson, 2016; Zung et al, 2015); PUS7 (de Brouwer et al, 2018; Shaheen, Tasak, et al, 2019); and ALKBH8 (Monies, Vagbo, Al‐Owain, Alhomaidi, & Alkuraya, 2019).…”

A missense variant impairing TRMT1 function in tRNA modification is linked to intellectual disability

“…Notably, defects in tRNA modification have emerged as the cause of diverse neurological and neurodevelopmental disorders, thereby highlighting the critical role of tRNA modification in human health and physiology (Angelova et al 2018;Ramos and Fu 2018). In particular, the brain appears to be exquisitely sensitive to any perturbation in translation efficiency and fidelity brought about by defects in tRNA modifications, as evidenced from the numerous cognitive disorders linked to tRNA modification (Abbasi-Moheb et al 2012;Alazami et al 2013;Blanco et al 2014;de Brouwer et al 2018;El-Hattab et al 2016;Khan et al 2012;Komara et al 2015;Martinez et al 2012;Monies et al 2019;Ramos et al 2019;Shaheen et al 2015;Shaheen et al 2016a;Shaheen et al 2016b;Shaheen et al 2019a;Shaheen et al 2019b).…”