A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with autistic features and language delay, with or without seizures (IDDALDS), is caused by heterozygous mutation in the TANC2 gene (615047) on chromosome 17q23.

Intellectual developmental disorder with autistic features and language delay, with or without seizures (IDDALDS), is a neurodevelopmental disorder characterized by global developmental delay, variable intellectual disability, impaired speech development, and behavioral abnormalities, most commonly on the autism spectrum. About half of patients develop seizures; brain imaging is typically normal. Additional features are highly variable, but may include chronic constipation, walking difficulties, and dysmorphic facial features (summary by Guo et al., 2019).

Guo et al. (2019) reported 20 unrelated probands with a similar neurodevelopmental disorder. Two families (families NN2 and CF) contained 2 or 3 affected sibs, but most of the patients were singleton cases. The patients were ascertained through genetic analysis from several international collaborators; many were identified in large cohorts of patients with autism spectrum disorder. The patients, who ranged in age from childhood to adult, had global developmental delay with variably impaired intellectual development and poor speech and language acquisition; a few were nonverbal. IQ, formally measured in some patients, ranged from about 40 to 90, and a few patients were noted to attend special schools. Many had mildly delayed early motor development, but they were able to walk independently, sometimes with a wide-based or unsteady gait. Almost all patients had behavioral abnormalities, most commonly autism or features of autism, such as stereotypic/repetitive movements and poor social skills. Aggression was rarely observed. About half of patients had seizures, with variable onset, type, and severity. Significant poor growth and/or feeding problems were not reported, but many had chronic constipation. Less common findings included hypotonia, ataxia, spasticity, sleep disturbances, foot deformities, scoliosis/kyphosis, and joint hypermobility. Dysmorphic features were sometimes observed, particularly in the more severely affected individuals. These included large ears with thick helices, thick eyebrows with synophrys, deep-set eyes, strabismus, large nose with high nasal bridge, short and flat philtrum, large mouth with thin upper lip and thick everted lower lip, widely spaced teeth, tongue protrusion, and low hairline. Brain imaging was essentially normal. In 4 families (SS2, GU, NN2, and CF), an affected parent with neuropsychiatric and/or behavioral abnormalities was found to carry a heterozygous TANC2 mutation. Features in these individuals included learning difficulties, ADHD, PTSD, and bipolar disorder.

Most of the heterozygous mutations in the TANC2 gene that were identified in patients with IDDALDS by Guo et al. (2019) occurred de novo. However, there were rare instances of autosomal dominant inheritance with variable expressivity.

In 20 unrelated probands with IDDALDS, Guo et al. (2019) identified heterozygous nonsense, frameshift, or splice site mutations, or intragenic deletions in the TANC2 gene (see, e.g., 615047.0001-615047.0006). The mutations, which were found by whole-exome sequencing, targeted sequencing, and array-based CGH, were confirmed by Sanger sequencing; none were present in the ExAC database. The patients were ascertained through a network of international collaborators and the GeneMatcher database. Eleven of the patients had de novo point mutations, and 5 probands inherited point mutations (from a mildly affected parent in 4 of those cases); the inheritance pattern could not be determined in 1 patient. Two affected sibs had an intragenic deletion inherited from their mosaic father, and 2 unrelated patients had de novo intragenic deletions. Functional studies of the variants and studies of patient cells were not performed, but the authors postulated a loss-of-function effect. Guo et al. (2019) also identified 5 unrelated individuals with overlapping phenotypes who were found to carry de novo heterozygous missense variants in the TANC2 gene. Three variants (R755H, R961Q, and H1689R) were found in 3 patients with a primary diagnosis of autism spectrum disorder. Another variant (R760C) was found in a patient with impaired intellect and speech delay (de Ligt et al., 2012), and the last (A794V) was found in a patient with schizophrenia (Fromer et al., 2014). The R755H, R760C, and A794V variants occurred in the ATPase regulatory domain, and R961Q was in 1 of the ANK domains. H1689R, R760C, and A794V and were not found in the ExAC nonpsychiatric samples, whereas R755H and R961Q were both reported 4 times in ExAC. Functional studies of these missense variants were not performed. All mutations occurred throughout the gene and there were no apparent genotype/phenotype correlations, although all the disruptive mutations occurred before the PDZ interacting motif.