Sotos Syndrome 3

A number sign (#) is used with this entry because of evidence that Sotos syndrome-3 (SOTOS3) is caused by homozygous mutation in the APC2 gene (612034) on chromosome 19p13. One such family has been reported.

For a discussion of genetic heterogeneity of Sotos syndrome, see SOTOS1 (117550).

Clinical Features

Almuriekhi et al. (2015) reported 2 sibs, born of consanguineous Egyptian parents, with intellectual disability (IQs of 60 and 56), a severe receptive and expressive language disorder, learning disabilities, and hyperactive behavior associated with relative macrocephaly, long face, and prominent chin and nose. Brain imaging in 1 patient showed dilated lateral ventricles. Neither patient had advanced bone age, hypotonia, seizures, or autism. The findings were reminiscent of Sotos syndrome, but genetic analysis excluded mutations in the NSD1 gene (606681). The patients were diagnosed with a Sotos-like syndrome.

Inheritance

The transmission pattern of SOTOS3 in the family reported by Almuriekhi et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous Egyptian parents, with SOTOS3, Almuriekhi et al. (2015) identified a homozygous truncating mutation in the APC2 gene (612034.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Expression of the mutation in neuronal cells showed that the mutant protein had abnormal punctate localization, was not distributed along microtubules, did not colocalize with F-actin, and had lost microtubule stabilization activity, all consistent with a loss of function. Almuriekhi et al. (2015) suggested that subtle neuronal migration defects in the patients, although not apparent on imaging, may underlie the intellectual disability in this disorder.

Animal Model

Almuriekhi et al. (2015) found that Apc2-null mice had impaired learning and memory associated with an abnormal head shape, dilated ventricles, and thin corpus callosum. Knockdown of Nsd1 significantly reduced the expression of Apc2, indicating that Apc2 is a downstream effector of Nsd1. Nsd1 knockdown also caused impaired cerebral neuronal migration and layering defects similar to that observed in Apc2-null mice, and expression of Apc2 in Nsd1-null cells rescued the defect. The findings indicated that expression of NSD1 controlled neuronal migration through the induction of APC2.