The CIC haploinsufficiency syndrome is associated with neurodevelopmental impairments due to genetic mutations in the capicua (CIC) gene, which encodes the CIC protein. CIC plays an essential role in brain development, especially in the maturation of brain cells. Mutations in the CIC gene impede proper brain cell development and maturation, manifesting as developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), seizures, and/or attention deficit hyperactivity disorder (ADHD).

Previous literature has reported a number of clinical cases which include patients who have a CIC mutation and exhibit a variety of neurobehavioral deficits. There are a number of different mutations that can occur, each resulting in a variant of the CIC protein which may or may not be pathogenic (causing neurobehavioral impairments). This study finds a pathogenic variant of CIC that has not been reported in previous studies. More interestingly, this paper presents three members of a two-generation family, each with the same variant in the CIC gene. However these three patients do not share the same clinical presentation.

The family members with the CIC mutation are the mother, and her daughter and son; the father is not a carrier of the mutation. The daughter presents with ASD, ADHD, DD/ID and severe seizures. The son presents with ADHD, DD/ID, and moderate seizures. Lastly, the mother, who has the same CIC mutation as her children, has mild clinical seizures but normal cognitive function.

All three patients have been treated for seizures with a variety of medications and treatment methods. Although there are some similar features among the three family members, there is a considerable variability in the severity of seizures and their response to the different medications. Overall, this study highlights the significant variability in the clinical features of individuals with CIC haploinsufficiency syndrome, even for those with the exact same mutation. This suggests that other genetic and environmental factors can influence the clinical presentation of the CIC haploinsufficiency syndrome (this is called the modifier effect). What these factors are is unknown at this point. But as more and more cases of CIC haploinsufficiency syndrome are reported in the literature, we will be able to investigate the nature of these factors and understand how they contribute to the clinical manifestation of the disease.

Reference:

Kishnani S. et al. Phenotypic Variability of an Inherited Pathogenic Variant in CIC Gene: A New Case Report in Two-Generation Family and Literature Review. Journal of Pediatric Neurology (2020). Link to the original article.