Neurodevelopmental phenotypes in individuals with pathogenic variants in CHAMP1

Discapacitat intel·lectual; Retard greu del desenvolupament global; Microcefàlia severaDiscapacidad intelectual; Retraso severo en el desarrollo global; Microcefalia severaIntellectual disability; Severe global developmental delay; Severe microcephalyBackground: De novo pathogenic variants in CHAMP1 (chromosome alignment maintaining phosphoprotein 1) that encodes kinetochore-microtubule associated protein on 13q34 cause a rare neurodevelopmental disorder. Methods: We enrolled 14 individuals with pathogenic variants in CHAMP1 that were documented by exome sequencing or gene panel sequencing. Medical history interviews, seizure surveys, Vineland Adapted Behavior Scales Second Edition, and other behavioral surveys were completed by primary care givers of available participants in Simons Searchlight. Clinicians extracted clinical data from the medical record for two participants. Results: We report on clinical features of fourteen individuals (ages 2-26) with de novo predicted loss of function variants in CHAMP1 and compare them with previously reported cases (total n=32). At least two individuals have the same de novo variant: p.(Ser181Cysfs*5), p.(Trp348*), p.(Arg398*), p.(Arg497*), or p.(Tyr709*). Common phenotypes include intellectual disability/developmental delay, language impairment, congenital and acquired microcephaly, behavioral problems including autism spectrum disorder, seizures, hypotonia, gastrointestinal issues of reflux and constipation, and ophthalmologic issues. Other rarely observed phenotypes include leukemia, failure to thrive and high pain tolerance. Conclusion: Pathogenic variants in CHAMP1 are associated with a variable clinical phenotype of developmental delay/intellectual disability and seizures.This work is supported by the Columbia University College of Dental Medicine Research Committee who awarded Madison Garrity Summer Fellowship Honors and grants from SFARI and the JPB Foundation

Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders

Background Variants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined. Methods Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder. Results We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain. Conclusion We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.Peer reviewe

Neurodevelopmental phenotypes in individuals with pathogenic variants in <i>CHAMP1</i>

International audienceDe novo pathogenic variants in CHAMP1 (chromosome alignment maintaining phosphoprotein 1), which encodes kinetochore-microtubule associated protein on 13q34, cause a rare neurodevelopmental disorder. We enrolled 14 individuals with pathogenic variants in CHAMP1 that were documented by exome sequencing or gene panel sequencing. Medical history interviews, seizure surveys, Vineland Adapted Behavior Scales Second Edition, and other behavioral surveys were completed by primary caregivers of available participants in Simons Searchlight. Clinicians extracted clinical data from the medical record for two participants. We report on clinical features of 14 individuals (ages 2-26) with de novo predicted loss-of-function variants in CHAMP1 and compare them with previously reported cases (total n = 32). At least two individuals have the same de novo variant: p.(Ser181Cysfs*5), p.(Trp348*), p.(Arg398*), p.(Arg497*), or p.(Tyr709*). Common phenotypes include intellectual disability/developmental delay, language impairment, congenital and acquired microcephaly, behavioral problems including autism spectrum disorder, seizures, hypotonia, gastrointestinal issues of reflux and constipation, and ophthalmologic issues. Other rarely observed phenotypes include leukemia, failure to thrive, and high pain tolerance. Pathogenic variants in CHAMP1 are associated with a variable clinical phenotype of developmental delay/intellectual disability and seizures