A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44) is caused by heterozygous mutation in the TRIO gene (601893) on chromosome 5p15.

Heterozygous mutation in the TRIO gene can also cause the related disorder MRD63 (618825).

Autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44) is characterized by mildly delayed global development resulting in variable intellectual deficits or learning difficulties, distinctive facial features, and abnormalities of the fingers, particularly brachydactyly, tapering fingers, and broad interphalangeal joints. Additional features are highly variable (summary by Ba et al., 2016).

Mercer et al. (2008) reported 2 brothers, their mother, and a maternal cousin who had a distinctive facial phenotype involving a straight pointed nose, micrognathia, and variable slanting of the palpebral fissures, mild brachydactyly with tapering fingers and distal phalangeal hypoplasia, and prominence of the interphalangeal joints. Microcephaly was present in 2, and there was evidence of hypodontia in 3 of the 4 affected individuals. One brother and the mother had multiple ventricular extrasystoles, but no syncope. Both brothers had mild learning disabilities and attended special schools; the mother had normal intelligence, but reported academic difficulties. Six other relatives over 4 generations were probably affected on the basis of history and family photographs. Pengelly et al. (2016) reported follow-up of this family. One of the affected brothers had a similarly affected daughter, who was the index case. She had mild global developmental delay with delayed speech. Dysmorphic features included microcephaly (-5 SD), short nose, long philtrum, thin upper lip, and epicanthal folds. Skeletal anomalies included right radial aplasia, rudimentary thumb, and absent first metacarpal. She also had several congenital cardiac septal defects that were clinically insignificant. Her father and his brother (the 2 brothers in the original report) had microcephaly (-3 and -5 SD, respectively) and the previously noted dysmorphic features, with the addition of low anterior hairline.

Ba et al. (2016) reported 5 patients with a similar disorder. The patients included 7- and 10-year-old boys, a 35-year-old woman with no family history, and a 20-year-old man whose father was similarly affected. All patients had borderline to mild intellectual disability with delayed motor development or delay of fine motor skills and variable speech delay. The patients also had behavioral problems, including autistic-like features or attention deficit-hyperactivity disorder. Other common features in the index cases included small head circumference (range -1 to -2.5 SD), broad forehead, micrognathia with dental crowding, and minor hand anomalies, such as brachydactyly, tapering fingers, and broad interphalangeal joints. Additional features were highly variable: increased reflexes, hyperacusis, swallowing difficulties, facial asymmetry, full lips, high palate, kyphosis, pes planus, and pectus excavatum, among others. Three were noted to have recurrent infections. The 7-year-old boy, who had an intragenic deletion of the TRIO gene, had previously been reported by Vulto-van Silfhout et al. (2013) in a large study of 5,531 patients who underwent screening for copy number variations.

Pengelly et al. (2016) reported 2 additional unrelated children with MRD44. Both had microcephaly, global developmental delay, and behavioral abnormalities, such as autistic features and obsessive-compulsive traits. Dysmorphic features and distal hand anomalies were more variable, but consistent with previous descriptions.

Barbosa et al. (2020) reported 12 unrelated patients (patients 10-16, 18-22), including the 2 unrelated patients reported by Pengelly et al. (2016), as well as a family (patients 17a, 17b, and 17c) previously reported by Pengelly et al. (2016), with MRD44. Most of the patients ranged in age from 20 months to 19 years; the previously reported mother was 36. All had global developmental delay with normal or mildly delayed walking, variably impaired intellectual development, often with speech and language delay, and behavioral abnormalities, such as aggression, poor attention, and stereotypies. Overall growth was poor, and most had microcephaly (down to -5 SD). Additional abnormalities, seen in about half or less of patients, included feeding difficulties or constipation, short tapering fingers, and scoliosis. Seizures were confirmed in only 1 patient. Dysmorphic facial features were highly variable, but included ptosis, upslanting palpebral fissures, flat nasal bridge, large nose, large ears, synophrys, retrognathia, midface hypoplasia, and dental anomalies.

The transmission pattern of MRD44 in the family reported by Mercer et al. (2008) and Pengelly et al. (2016) was consistent with autosomal dominant inheritance.

The heterozygous mutations in the TRIO gene that were identified in most patients with MRD44 by Barbosa et al. (2020) occurred de novo.

In 4 patients from 3 unrelated families with MRD44, Ba et al. (2016) identified 3 different heterozygous truncating mutations in the TRIO gene (601893.0001-601893.0003). Two of the mutations occurred de novo. Studies of patient cells were not performed, but knockdown of the Trio gene in rat hippocampal cells resulted in an increase in dendrites and alterations in synaptic transmission, resulting in increased excitatory transmission during development (see ANIMAL MODEL). Ba et al. (2016) noted that premature maturation of excitatory synapses has been observed in several models of autism spectrum disorder, which was observed in these patients.

By exome sequencing in 3 members of a family originally reported by Mercer et al. (2008), Pengelly et al. (2016) identified a heterozygous truncating mutation in the TRIO gene (601893.0004). One of the patients also had a pathogenic variant in the KCNJ2 gene (600681), which may have been responsible for the ectopic ventricular beats seen in this patient. Exome sequencing subsequently identified de novo heterozygous missense mutations in the TRIO gene in 3 additional unrelated patients with MRD44 (601893.0005-601893.0007). All mutations were confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the truncating mutation and 2 of the missense mutations affecting the GEFD1 domain resulted in decreased RAC1 (602048) activation. The last mutation (N1080I; 601893.0007), in a spectrin repeat domain, did not affect RAC1 activation; this patient had slightly different features with absence of microcephaly and presence of seizures.

In 5 unrelated patients (patients 10, 12, 14, 15, and 16) with MRD44, Barbosa et al. (2020) identified de novo heterozygous missense mutations at highly conserved residues in the GEFD1 domain of the TRIO gene (see, e.g., 601893.0005 and 601893.0011). The mutations, which were found by exome sequencing, were not present in the gnomAD database. Immunoblot analysis of HEK293 cells transfected with the mutations showed that they impaired TRIO binding to RAC1 compared to wildtype. Transfection of the mutations into neuroblastoma cells caused decreased neurite outgrowth and decreased lamellipodia formation compared to controls. The findings were consistent with a loss-of-function effect. Barbosa et al. (2020) also identified heterozygous nonsense or frameshift mutations in 5 additional individuals with a similar disorder (see, e.g., 601893.0012 and 601893.0013). Three of the mutations were demonstrated to occur de novo. Similar in vitro functional studies performed on 1 of the mutations were consistent with a loss-of-function effect.

Ba et al. (2016) found expression of the Trio gene during rat hippocampal development. It was expressed during the early postnatal period, but rapidly decreased after postnatal day 11, suggesting a role in early neuronal development. Knockdown of Trio using shRNA in dissociated rat hippocampal neurons resulted in an increase in primary dendrites and branch points during early neuronal development, suggesting that TRIO functions normally to limit dendrite formation. Knockdown of Trio in hippocampal slices resulted in increased AMPA receptor-mediated, but not NMDA receptor-mediated, transmission compared to controls, which was shown to result from a decrease in AMPA receptor endocytosis. These changes were associated with an increase in excitatory currents. These data suggested that Trio negatively regulates hippocampal synaptic strength during development.

Barbosa et al. (2020) found that specific knockdown of the GEFD1 domain of the trio gene in X. tropicalis resulted in abnormal craniofacial development with microcephaly, as well as deformation in the forebrain structure compared to controls.