De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females

Abstract

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive–compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4’s function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

Novel mutations and phenotypes of epilepsy‐associated genes in epileptic encephalopathies

“…In the present study, the patient with a de novo KCNQ2 missense mutation displayed a very early‐onset age (2 days), similar to that of BFNS; but the patient also presented features of EIMFS, such as intellectual disability and multiple focal discharges on EEG. Similarly, mutations in CLCN4 have been reported to cause X‐linked intellectual disability and epilepsies, in which focal seizures were prominent in some cases . We identified a de novo CLCN4 mutation in a boy with EIMFS featuring frequent complex partial seizures and multiple focal discharges.…”

“…In contrast, KCNQ2 mutations were mainly associated with benign familial neonatal epilepsy (BFNS) and severe neonatal onset epileptic encephalopathies, such as Ohtahara syndrome . CLCN4 mutations were mainly identified in patients with intellectual disabilities with only a few associated with epileptic encephalopathies . Three of the 4 mutations in EIMFS were novel findings.…”

“…25 CLCN4 mutations were mainly identified in patients with intellectual disabilities with only a few associated with epileptic encephalopathies. 26,27 Three of the 4 mutations in EIMFS were novel findings.…”

“…Similarly, mutations in CLCN4 have been reported to cause X-linked intellectual disability and epilepsies, in which focal seizures were prominent in some cases. 26,27 We identified a de novo CLCN4 mutation in a boy with EIMFS featuring frequent complex partial seizures and multiple focal discharges. Until now, distinct association between gene and phenotype of epileptic encephalopathy has been found in only a few genes, such as SLC6A1 mutations in EMAS 37 and SLC35A2 mutations in infantile spasms with hypsarrhythmia on EEGs.…”

Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration

“…The physiological importance of vesicular CLCs is highlighted by mouse models and patients carrying CLCN mutations. Their pathologies range from impaired renal endocytosis and kidney stones (ClC‐5) (Lloyd et al , ; Piwon et al , ; Wang et al , ) to severe neurodegeneration (ClC‐3) (Stobrawa et al , ), intellectual disability and epilepsy (ClC‐4) (Veeramah et al , ; Hu et al , ; Palmer et al , ), to lysosomal storage disease (ClC‐6) (Poët et al , ) or osteopetrosis associated with lysosomal storage and neurodegeneration (ClC‐7) (Kornak et al , ; Kasper et al , ). A gain‐of‐function mutation in CLCN7 causes lysosomal storage disease and hypopigmentation without osteopetrosis (Nicoli et al , ).…”