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

Fig. 1

Facial features and pedigree of Subjects 1 and 2. ( A , B ) Subject 1 when she was 12 years, 1 month old. She had a myopathic face, high forehead, bulbous nasal tip, right-sided epicanthal fold, hypertelorism, long, smooth philtrum, and a hemangioma on her left cheek. ( C , D ) Subject 2 when he was 7 years, 10 months old. He had a myopathic face, high forehead, bulbous nasal tip, hypertelorism, down-slanting palpebral fissures, and a long smooth philtrum. ( E ) Pedigree showing subjects 1 and 2 along with the ADAT3 variants they inherited from their unrelated mother and father. ADAT3, adenosine deaminase, tRNA specific 3 gene.

Fig. 2

Photographs of Subject 1 (S1) over time. Photos taken at 6 months (m), 1, 2, 3, 4, 5, 7, and 8 years (y) of age.

Fig. 3

Photographs of Subject 2 (S2) over time. Photos taken at 6 months (m), 1, 2, 3, 4, and 6 years (y) of age.

Fig. 4

ADAT3 variants associated with ADAT3 deficiency. ( A ) The locations of the ADAT3 variants reported in individuals with ADAT3 deficiency are shown in relation to the protein domains of ADAT3. Variants found in Subjects 1 and 2 are shown in gray. Previously described pathogenic variants are shown in black. ( B ) The variants seen in Subjects 1 and 2 affect a conserved residue located in the CMP/dCMP-type deaminase domain of ADAT3 (small outline). The large outline indicates residues around these changes that are part of the ADAT3's CMP/dCMP-type deaminase domain. ADAT3, adenosine deaminase, tRNA specific 3; CMP/dCMP, cytidine monophosphate/deoxycytidine monophosphate.