CHAMP1 Mutations cause Refractory Infantile Myoclonic Epilepsy

Abstract

The chromosome alignment maintaining phosphoprotein 1 (CHAMP1) gene has a key role in neurodevelopment. It is involved in kinetochore-microtubule attachment and in the regulation of chromosomes alignment during mitosis. So far, 17 cases of CHAMP1 mutations have been reported with a common clinical picture of developmental delay and intellectual disability, dysmorphic facial features, hypotonia and/or spasticity, and microcephaly. Four patients had epilepsy of whom three had focal seizures and one had generalized epilepsy. We report two new cases, which have in addition to developmental delay, refractory myoclonic epilepsy. These cases suggest that the phenotypic spectrum of CHAMP1 mutations may be broader and includes refractory myoclonic epilepsy as well.

Neurodevelopmental phenotypes in individuals with pathogenic variants in CHAMP1

“…Of these 14 individuals, 12 have not previously been described. The clinical manifestations of those in our cohort are similar to those previously described ( Hempel et al 2015 ; Isidor et al 2016 ; Tanaka et al 2016 ; Okamoto et al 2017 ; Ben-Haim et al 2020 ). All individuals have developmental delay or intellectual disability, hypotonia, and ophthalmologic issues (i.e., hyperopia, strabismus, and nystagmus).…”

“…Supplemental Table 1. The major clinical manifestations reported in the literature and our cohort (Hempel et al 2015;Isidor et al 2016;Tanaka et al 2016;Okamoto et al 2017;Ben-Haim et al 2020;Wang et al 2020). The prevalence of each phenotypic feature in each cohort was calculated as a percentage to demonstrate both the similarities and differences amongst the seven cohorts.…”

“…Twenty-four de novo pathogenic/likely pathogenic variants in CHAMP1 have been described: one missense, one microdeletion, eight frameshift, and 14 nonsense. The first reported missense variant ( Ben-Haim et al 2020 ) has multiple lines of computational evidence supporting a deleterious effect (PP3), is absent in controls (PM2), has confirmed de novo inheritance via parental DNA analysis (PS2), and is likely pathogenic by the American College of Medical Genetics and Genomics/American Molecular Pathology criteria ( Richards et al 2015 ). All other reported variants are null, pathogenic, or likely pathogenic variants and are predicted to cause loss of function leading to haploinsufficiency.…”

“…Subsequently, six additional manuscripts identified 20 additional individuals. These publications included data on individuals with 12 nonsense variants (60%), six frameshift variants (30%), one missense variant (5%), and one microdeletion including CHAMP1 (5%) ( Hempel et al 2015 ; Isidor et al 2016 ; Tanaka et al 2016 ; Okamoto et al 2017 ; Ben-Haim et al 2020 ; Wang et al 2020 ).…”

“…Common clinical manifestations of individuals with the CHAMP1 disorder include intellectual disability, speech and language impairment, motor developmental delay, microcephaly, seizures, ophthalmologic issues, hypotonia, and dysmorphic facial features ( Hempel et al 2015 ; Isidor et al 2016 ; Tanaka et al 2016 ; Okamoto et al 2017 ; Ben-Haim et al 2020 ; Wang et al 2020 ). In this study, we refine the phenotype associated with de novo pathogenic/likely pathogenic variants in CHAMP1 in 12 previously unreported individuals enrolled in Simons VIP/Searchlight by providing data on clinical features and standardized neurobehavioral measures.…”