Novel Missense Variants in ADAT3 as a Cause of Syndromic Intellectual Disability

Abstract

Autosomal recessive variants in the adenosine deaminase, tRNA specific 3 (ADAT3) gene cause a syndromic form of intellectual disability due to a loss of ADAT3 function. This disorder is characterized by developmental delay, intellectual disability, speech delay, abnormal brain structure, strabismus, microcephaly, and failure to thrive. A small subset of individuals with ADAT3 deficiency have other structural birth defects including atrial septal defect, patent ductus arteriosus, hypospadias, cryptorchidism, and micropenis. Here, we report a sibling pair with novel compound heterozygous missense variants that affect a conserved amino acid in the deaminase domain of ADAT3. These siblings have many of the features characteristic of this syndrome, including, intellectual disability, hypotonia, esotropia, failure to thrive, and microcephaly. Both had gastroesophageal reflux disease (GERD), feeding problems, and aspiration requiring thickening of feeds. Although they have no words, their communication abilities progressed rapidly when they began to use augmentative and alternative communication (AAC) devices. One of these siblings was born with an anterior congenital diaphragmatic hernia, which has not been reported previously in association with ADAT3 deficiency. We conclude that individuals with ADAT3 deficiency should be monitored for GERD, feeding problems, and aspiration in infancy. They may also benefit from the use of AAC devices and individualized educational programs that take into account their capacity for nonverbal language development. Additional studies in humans or animal models will be needed to determine if ADAT3 deficiency predisposes to the development of structural birth defects.

Keywords

ADAT3 - mental retardation autosomal recessive 36 - syndromic intellectual disability - congenital diaphragmatic hernia - augmentative and alternative communication devices

• References

• 1 Torres AG, Piñeyro D, Filonava L, Stracker TH, Batlle E, Ribas de Pouplana L. A-to-I editing on tRNAs: biochemical, biological and evolutionary implications. FEBS Lett 2014; 588 (23) 4279-4286
• 2 Gerber AP, Keller W. An adenosine deaminase that generates inosine at the wobble position of tRNAs. Science 1999; 286 (5442): 1146-1149
• 3 Crick FH. Codon–anticodon pairing: the wobble hypothesis. J Mol Biol 1966; 19 (02) 548-555
• 4 Alazami AM, Hijazi H, Al-Dosari MS. , et al. Mutation in ADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus. J Med Genet 2013; 50 (07) 425-430
• 5 El-Hattab AW, Saleh MA, Hashem A. , et al. ADAT3-related intellectual disability: further delineation of the phenotype. Am J Med Genet A 2016; 170A [phone]
• 6 Sharkia R, Zalan A, Jabareen-Masri A, Zahalka H, Mahajnah M. A new case confirming and expanding the phenotype spectrum of ADAT3-related intellectual disability syndrome. Eur J Med Genet 2018; S1769-7212(18)30574-3
• 7 Salehi Chaleshtori AR, Miyake N, Ahmadvand M, Bashti O, Matsumoto N, Noruzinia M. A novel 8-bp duplication in ADAT3 causes mild intellectual disability. Hum Genome Var 2018; 5: 7
• 8 van den Engel-Hoek L, de Groot IJM, de Swart BJM, Erasmus CE. Feeding and swallowing disorders in pediatrci neuromuscular diseases: an overview. J Neuromuscul Dis 2015; 2 (04) 357-369
• 9 Seddon PC, Khan Y. Respiratory problems in children with neurological impairment. Arch Dis Child 2003; 88 (01) 75-78
• 10 Duncan DR, Larson K, Davidson K, May K, Rahbar R, Rosen RL. Feeding interventions are associated with improved outcomes in children with laryngeal penetration. J Pediatr Gastroenterol Nutr 2019; 68 (02) 218-224
• 11 Wilkinson KM, Hennig S. The state of research and practice in augmentative and alternative communication for children with developmental/intellectual disabilities. Ment Retard Dev Disabil Res Rev 2007; 13 (01) 58-69
• 12 Light J, McNaughton D, Caron J. New and emerging AAC technology supports for children with complex communication needs and their communication partners: state of the science and future research directions. Augment Altern Commun 2019; 35 (01) 26-41
• 13 Kardon G, Ackerman KG, McCulley DJ. , et al. Congenital diaphragmatic hernias: from genes to mechanisms to therapies. Dis Model Mech 2017; 10 (08) 955-970