Adenosine (A)-to-inosine (I) RNA editing is a post-transcriptional RNA process capable of generating RNA and protein diversity1. Inosine at wobble position 34 of tRNA anticodons can translate codons ending in uracil, cytosine, or adenine2. The modification, which creates an I from an A at position 34 (wobble position) of tRNA, is catalyzed by the heterodimeric enzyme, adenosine deaminase, tRNA-specific 3 (ADAT3)/ADAT22.

Alazami et al. described a homozygous ADAT3 mutation (c.382 G > A, p.Val128Met) in 24 affected individuals with autosomal-recessive mental retardation 36 (MRT36; MIM*615286) from eight consanguineous Arab families3. Very recently, El-Hattab et al. reported an additional 15 patients with an identical homozygous ADAT3 mutation in 15 affected individuals from 11 Arab families. In the previous reports, strabismus, microcephaly, failure to thrive, and abnormal brain structure were frequently seen in such patients.

We encountered a 6-year-old female presenting with intellectual disability, mild cognitive impairment, attention deficit, hyperactivity disorder, neurodevelopmental delay, speech delay, and microcephaly. The patient’s face was asymmetric, and her nasal bridge was depressed. She was born to healthy Iranian consanguineous parents (Fig. 1a). The proband visited our genetic center seeking a genetic testing service. Considering the clinical findings, the targeted sequencing of 12 genes associated with microcephaly (SLC25A19, STIL, ASPM, CEP135, MCPH1, CDK5RAP2, CENPJ, CEP152, WDR62, ZNF335, ADAT3, and EFTUD2) was provided. After obtaining informed consent, genomic DNA of peripheral blood leukocytes was extracted and used for the genome partitioning. Targeted capture was performed using the GeneRead DNAseq Custom Panel V2 (QIAGEN, Hilden, Germany), and the libraries were sequenced to mean >80–100 × coverage on a HiSeq2000 sequencing platform (Illumina, San Diego, CA, USA). For read mapping and variant analysis, sample sequences were aligned to the human reference genome (GRCh37/hg19) using Burrows-Wheeler Aligner4. To identify variants relevant to the disease, the obtained data were manipulated using picard and processed with the Genome Analysis Toolkit (GATK refv1.2905)5.

Fig. 1: Segregation status of the mutation and Sanger confirmation of c.99_106dupGAGCCCGG mutation in the proband
figure 1

a Pedigree information and segregation status of the ADAT3 8-bp duplication. b Chromatogram of the c.99_106dupGAGCCCGG, p.(Glu36Glyfs*44) mutation

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Through our targeted sequencing, we identified a homozygous 8-bp duplication in ADAT3 (c.99_106dupGAGCCCGG, p.(Glu36Glyfs*44); Fig. 1b). This variant was not previously registered in the 1000 genomes database (http://browser.1000genomes.org/index.html), ExAC browser (http://exac.broadinstitute.org/), or EVS (http://evs.gs.washington.edu/EVS/). Since this gene has one coding exon, the frameshift mutation might produce a truncated protein. We confirmed both parents as heterozygous carriers (Fig. 1b), agreeing with the autosomal-recessive mode of inheritance.

The proband we present here shared many clinical features with the patients reported by El-Hattab and Alazami3, including hyperactivity, developmental delay, microcephaly, depressed nasal bridge, and asymmetric face, which were commonly seen in the current patient. In contrast, our patient showed speech delay, while El-Hattab reported speech incapability (no words) in patients with the c.382 G > A mutation. Most patients with the c.382 G > A mutation in ADAT3 have been characterized with moderate to severe cognitive impairment3,6, while the present patient was a sufferer from mild intellectual disability. Moreover, previous reports on ADAT3 mutation noted strabismus as an accompanying sign of cognitive impairment in patients with the c.382 G > A mutation3,6; however, this patient did not show strabismus. Other clinical findings were consistent with previous reports3,6 (Table 1); therefore, the difference in clinical features might be due to the different mutational effects of respective mutations.

Table 1 Clinical features of the patient compared to previous report of ADAT3-related cognitive impairment
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In conclusion, we report a novel and second ADAT3 mutation in a patient with intellectual disability and propose that ADAT3 sequencing should be considered for intellectual disability in the Middle East.