Developmental Delay With Variable Intellectual Impairment And Behavioral Abnormalities

A number sign (#) is used with this entry because of evidence that developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA) is caused by heterozygous mutation in the TCF20 gene (603107) on chromosome 22q13.

Description

Developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA) is an autosomal dominant neurodevelopmental disorder. Most patients have impaired intellectual development with speech difficulties, and many have behavioral abnormalities, most commonly autism spectrum disorder (ASD), defects in attention, and/or hyperactivity. Many patients have dysmorphic features, although there is not a consistent gestalt. Additional more variable features may include hypotonia, somatic overgrowth with macrocephaly, mild distal skeletal anomalies, sleep disturbances, movement disorders, and gastrointestinal issues, such as constipation. The phenotype is highly variable (summary by Vetrini et al., 2019 and Torti et al., 2019).

Clinical Features

Babbs et al. (2014) reported a 25-year-old woman (family 6) with moderate intellectual disability (IQ of 45) and ASD who carried a de novo frameshift mutation in the TCF20 gene (603107.0001). She also had craniosynostosis, but this feature was also present in her mother, who did not carry the TCF20 mutation, suggesting it was a coincidental finding.

Schafgen et al. (2016) reported 2 unrelated boys, both 14 years of age, with global developmental delay with mildly delayed walking, speech delay, and impaired intellectual development (IQ of 54 and 62). Only patient 2 had features consistent with autism, although patient 1 had stereotypic movements. Both also had features of somatic overgrowth, including macrocephaly, obesity, and tall stature, as well as mild movement abnormalities, including hypotonia, ataxic movements, and problems with writing and coordination. Both had inverted nipples. Patient 1 had mild dysmorphic features, including prominent forehead, downturned corners of the mouth, and prominent lower lip, as well as scoliosis. Patient 2 had sleep disturbances and onset of seizures at age 10 years.

Vetrini et al. (2019) reported 31 unrelated families, including a family with a set of affected monozygotic twins, with an overlapping neurodevelopmental disorder. The patients were ascertained through research protocols involving several centers. Five individuals (patients 2, 8, 10, 19, and 26) had previously been reported in the Deciphering Developmental Disorders Study (2017). Common core features among all patients included developmental delay/impaired intellectual development, variable additional neurologic abnormalities, and dysmorphic features. Most had motor and language delay, as well as hypotonia (66%) and ASD (66%). Other features included movement disorder (44%), such as ataxia or spasticity, sleep disturbances (38%), seizures (25%), structural brain abnormalities (22%), growth delay (13%), macrocephaly (25%), digital anomalies (34%), somatic overgrowth (28%), and inverted nipples (13%). Dysmorphic facial features were common, although variable, and included tented upper lip, brachycephaly, midface hypoplasia, and low-set ears; there was no recognizable gestalt. In addition to the monozygotic twins (patients 27 and 28), there were 3 families in which a less severely affected parent carried the same heterozygous mutation as the proband (patients 1, 5, and 7).

Torti et al. (2019) reported 27 patients from 24 unrelated families with DDVIBA. Common features included global developmental delay with intellectual disability (mean IQ of 69), autistic features (69%), attention disorders or hyperactivity (67%) or other behavioral abnormalities (85%), and hypotonia (63%). Patient had mild motor delay, with an average age at walking around 20 months and spoken words around 23 months, although most had speech difficulties. Most were able to attend special schools, and some young adults needed help with self-care. More variable features included ataxia, gait disturbance, balance issues, and spasticity. Only 3 patients had seizures. Brain imaging was normal in most patients, although a few had nonspecific abnormalities, such as thick corpus callosum. Less common features included gastrointestinal problems (mainly constipation), skeletal problems such as scoliosis and foot deformities, and ocular abnormalities including strabismus and myopia. Many had dysmorphic facial features, but there was not a specific gestalt. There were 2 families (sibs 10a/b and sibs 17a/b/c) with evidence of germline mosaicism.

Inheritance

Although the vast majority of TCF20 mutations occur de novo, Vetrini et al. (2019) observed 4 unrelated families with DDVIBA who showed autosomal dominant inheritance.

Molecular Genetics

In a 25-year-old woman (family 6) with DDVIBA, Babbs et al. (2014) identified a de novo heterozygous frameshift mutation in the TCF20 gene (603107.0001). Analysis of patient cells showed that the mutation escaped nonsense-mediated mRNA decay and would likely produce a truncated protein. Five patients from 4 additional families with ASD were found to carry heterozygous missense variants affecting conserved residues in the TCF20 gene (K512E and P1557L); the P1557L variant was present in unaffected parents, and functional studies of these missense variants were not performed.

In 2 unrelated boys with DDVIBA, Schafgen et al. (2016) identified de novo heterozygous mutations in the TCF20 gene (603107.0002 and 603107.0003). One was a nonsense mutation and the other was a frameshift; functional studies of the variants and studies of patient cells were not performed. The mutations were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. The patients were ascertained from a cohort of 313 individuals with intellectual disability who underwent trio-based whole-exome sequencing.

In 28 patients from 27 unrelated families, including a set of monozygotic twins (patients 27 and 28), with DDVIBA, Vetrini et al. (2019) identified 25 heterozygous mutations in the TCF20 gene (see, e.g., 603107.0004-603107.0006). The mutations were found by exome sequencing and confirmed by Sanger sequencing; none were found in the ExAC or gnomAD databases. Most of the mutations were predicted to result in a loss of function: there were 18 frameshifts, 5 nonsense, 1 splice site, and 1 missense (K1710R). Most of the mutations occurred de novo, although there were 4 families in which the pathogenic mutation was inherited from an affected parent; the parents tended to have a milder phenotype. Four additional patients carried heterozygous deletions ranging from 128 kb to 2.64 Mb that disrupted the TCF20 gene. A few patients carried additional variants in other genes, which may have contributed to the phenotype. Functional studies of the variants and studies of most patient cells were not performed. However, RNA studies of 3 of the variants that were predicted to cause premature termination showed that they escaped nonsense-mediated mRNA decay. No genotype/phenotype correlations were observed.

In 27 patients from 24 families with DDVIBA, Torti et al. (2019) identified heterozygous mutations in the TCF20 gene (see, e.g., 603107.0007-603107.0009). The patients were ascertained from several clinical and research centers, and the mutations were found by exome sequencing with Sanger confirmation. Almost all mutations occurred de novo; germline mosaicism was demonstrated or predicted in 2 familial cases. There were 23 frameshift or nonsense mutations, all predicted to result in a loss of function, and 1 missense mutation. Functional studies of the variants and studies of patient cells were not performed, but none of the variants were present in large population cohorts. Several patients carried possible pathogenic variants in other genes, which may have contributed to the phenotype.