Intellectual disability
IQSEC2-related disorders are associated with intellectual disability.
All males will have intellectual disability, and some males have autism, epilepsy or epileptic encephalopathy. However, the clinical features seen in females with IQSEC2-related disorders are variable and influenced by how the variant affects the normal function of the IQSEC2 protein.
Missense mutations are often seen in families displaying a typical X-linked inheritance pattern, with affected male patients and asymptomatic or only mildly affected carrier females.
Conversely, nonsense and frameshift mutations, which can occur in both males and females, are usually sporadic with no family history of IQSEC2-related disorders. These de novo variants are more likely to be associated with moderate to severe intellectual disability and epilepsy or epileptic encephalopathy in males and females.
Seven of the 15 sporadic cases described in the literature [Zermen et al, 2016] are females.
Epilepsy
Zermen et al [2016] reported the molecular and phenotypic spectrum of IQSEC2-related epilepsy.
Review of the medical literature confirmed 48 reported patients with IQSEC2 variants, of which 18 had epilepsy in addition to intellectual disability, with a male-to-female ratio of 12:6. All patients had moderate to severe intellectual disability. Within this group of patients with both intellectual disability and epilepsy, 12/18 had de novo variants. 50% (9/18) had epileptic encephalopathy with age of onset from 8 months to 4 years. The types of seizures included spasms, atonic, myoclonic, tonic, absence, focal seizures and generalised tonic-clonic seizures. The epilepsy in the other nine patients had a variable age of onset between infancy and 18 years.
Other clinical features
Other features associated with IQSEC2-related disorders include: autistic features, hypotonia, strabismus, microcephaly and white matter changes on MRI. These features are not present in all patients.
Ewans et al [2017] reported gonadal mosaicism of a novel loss of function IQSEC2 variant in a family of four girls with moderate to severe intellectual disability and epilepsy. Two girls showed regression in adolescence, both dying of presumed sudden unexplained death in epilepsy (SUDEP) at age 16 and 22 years. This case demonstrates that IQSEC2 is one of a number of X-linked genes presenting with a female-specific phenotype. This family illustrates the importance of parents being counselled about the possibility of germline mosaicism and the option of prenatal diagnosis when planning more children.