Intellectual Developmental Disorder With Autism And Speech Delay

A number sign (#) is used with this entry because of evidence that an intellectual developmental disorder with autism and speech delay (IDDAS) is caused by heterozygous mutation in the TBR1 gene (604616) on chromosome 2q.

Description

IDDAS is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, autism spectrum disorder, and language deficits (Deriziotis et al., 2014; den Hoed et al., 2018).

Clinical Features

Deriziotis et al. (2014) reported 4 unrelated patients with sporadic occurrence of autism and mutation in TBR1. Clinical details were somewhat limited, but 3 were noted to have delayed intellectual development and language delay. One was nonverbal at age 7 years, another had phrase speech at age 8, and the third was verbally fluent at age 7. Deriziotis et al. (2014) also reported 4 patients with autism with mutation in TBR1 inherited from an unaffected parent. Cognitive functioning in these patients ranged from average to intellectually disabled; 3 patients were verbally fluent and 1 was nonverbal. Language delay was reported in all of these patients.

Den Hoed et al. (2018) reported 2 unrelated patients diagnosed with autism spectrum disorder, both of whom also had delayed intellectual development. One of the patients was nonverbal and unable to understand simple commands. The parents were unaffected.

McDermott et al. (2018) reported a patient, born of unrelated Caucasian parents, with IDDAS. In the first months of life, she was noted to have global developmental delay, which was followed by delayed walking (age 23 months) and delayed speech. In childhood, she had joint hypermobility, poor expressive language, stereotypic behaviors, and impaired social interaction. Her parents were unaffected. A second unrelated child had a similar phenotype.

Vegas et al. (2018) reported 2 unrelated boys with IDDAS and evidence of cortical migration defects on brain imaging. The patients presented in the first year of life with global developmental delay and hypotonia. At age 7 years, 1 of the patients could walk with help, but was nonverbal and showed stereotypic movements. At age 5 years, the other patient was unable to walk or speak. Brain imaging of both patients showed irregularity of the cortical gray-white matter junction, evidence of pachygyria, and a thick cortex; 1 patient also had a thin corpus callosum. The findings expanded the phenotype associated with IDDAS.

Mapping

Buxbaum et al. (2001) reported linkage evidence for a susceptibility gene for autism on chromosome 2. They found a maximum multipoint heterogeneity lod score (hlod) of 1.96 and a maximum multipoint nonparametric linkage (NPL) score of 2.39 on 2q in an analysis of 95 affected-relative-pair families.

By genomewide linkage analysis of 152 autistic sib pairs, the International Molecular Genetic Study of Autism Consortium (2001) (IMGSAC) identified a locus on chromosome 2q (maximum multipoint lod score of 3.74 at marker D2S2188). The lod score increased to 4.80 when stricter diagnostic criteria for autism were used.

Autism-Related Phrase Speech Delay

In an attempt to increase the power for identifying susceptibility genes by decreasing sample heterogeneity, Buxbaum et al. (2001) studied autism-affected relative pairs with delayed onset (at age greater than 36 months) of phrase speech (PSD, for phrase speech delay). In an analysis of 49 families with 2 or more individuals having a narrow diagnosis of autism and PSD, they found a maximal multipoint heterogeneity lod score of 2.99 and a nonparametric linkage score of 3.32 for linkage to 2q.

Like Buxbaum et al. (2001), Shao et al. (2002) classified their data set of 82 sib pairs with autism, identifying 45 families with autism and phrase speech delay. Analysis of the latter subset increased support for linkage to 2q (MLS = 2.86 and hlod = 2.12 for marker D2S116).

Cytogenetics

Newbury et al. (2009) reported 2 unrelated girls with developmental delay and language impairment who had 2 different but overlapping deletions of chromosome 2q. The first girl, who had mild developmental delay particularly affecting her speech and language but not fulfilling the criteria for autism spectrum disorder, had a 3.6-Mb deletion spanning chromosome 2q23.3-q24.1 and containing 6 genes. The second girl, who had pervasive developmental disorder, attention deficit difficulties, obsessive traits, and bipolar disorder, had a 4.5-Mb deletion spanning 2q24.1-q24.2 and containing 14 genes. Both had interruption of the KCNJ3 gene (601534); however, a mutation screen of the gene in 47 autistic probands indicated that coding variants are unlikely to underlie the linkage between autism and chromosome 2q.

Molecular Genetics

In 4 unrelated patients with impaired intellectual development with autism and speech delay, Deriziotis et al. (2014) identified 4 different de novo heterozygous mutations in the TBR1 gene (604616.0001-604616.0004). There were 2 frameshift mutations, resulting in premature termination, and 2 missense mutations at highly conserved residues in the T-box domain. In vitro functional expression studies using cellular transfection models (HEK293 cells and SHSY5Y neuroblastoma cells) showed that the frameshift mutations resulted in nonfunctional proteins that lost nuclear localization, lost interaction with CASK (300172) and FOXP2 (605317), and had deficient transcriptional repression activity compared to wildtype. Furthermore, these mutations may have resulted in nonsense-mediated mRNA decay, but patient tissue was not available for study. The findings related to these mutations were consistent with haploinsufficiency. Similar in vitro studies of the missense variants showed that they retained some transcriptional repression activity, suggesting that DNA-binding activity was not completely abolished, although they were unable to interact with FOXP2. These variants were able to interact with CASK and homodimerize with wildtype TBR1 to form abnormal aggregates in the nucleus. The findings related to these mutations suggested a dominant-negative effect. The patients carrying loss-of-function mutations had more severe cognitive impairment than those with missense mutations. Several additional missense variants were found in patients that had been inherited from unaffected parents. Functional studies of the inherited variants showed that they had little or no impact on TBR1 function, suggesting that inherited TBR1 mutations do not have a role in autism, although minor contributions in conjunction with additional unidentified variants in other genes could not be excluded. The study also suggested that disruption of TBR1-FOXP2 interactions, caused by mutations in either gene, result in speech and language deficits, thus providing a mechanistic bridge between neurodevelopmental disorders.

In 2 unrelated patients with IDDAS, den Hoed et al. (2018) identified de novo heterozygous mutations in the TBR1 gene that affected conserved residues in the T-box domain (604616.0005 and 604616.0006). In vitro functional expression studies in HEK293 cells showed that these mutant proteins retained the ability to repress luciferase activity, self-associate and interact with wildtype TBR1, and colocalize with CASK, but formed abnormal aggregates in the nucleus, suggesting a dominant-negative effect. The mutations abolished the TBR1-FOXP2 interaction.

In 2 unrelated patients with IDDAS, McDermott et al. (2018) identified de novo heterozygous mutations in the TBR1 gene (G316X and L311P). Functional studies of the variants were not performed.

In 2 unrelated boys with IDDAS, Vegas et al. (2018) identified the same de novo heterozygous frameshift mutation in the TBR1 gene (604616.0007). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors suggested that the mutation may lead to disruption of the downstream reelin pathway (see RELN, 600514). Both patients had malformations of cortical development, including pachygyria, on brain imaging, thus expanding the phenotype associated with TBR1 mutations.

Animal Model

Hevner et al. (2001) developed mice with targeted disruption of the Tbr1 gene. Mutant mice died shortly after birth in the absence of hand feeding. The cortex of neonatal mutants was approximately normal size, but early-born neurons, which guide early neuronal migrations and axonal projections, showed molecular and functional defects. Early-born cells formed a preplate but did not express markers of Cajal-Retzius, subplate, or layer 6 neurons. Cajal-Retzius cells expressed decreased levels of reelin (600514), resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. Markers of later-born cortical layers were relatively normal, and other properties of cortical neurons, such as neurotransmitter expression, cell death, and neuronal morphology, were mostly unaffected.

Huang et al. (2014) showed that haploinsufficiency of Tbr1 in mice resulted in features of autism, including impaired social interaction, impaired vocalization, and impaired cognition and memory. Examination of brains from Tbr1 +/- mice showed defective axonal projection of neurons in the amygdala. Tbr-null mice had severely impaired neuronal migration in the cerebral cortex.