De novo pathogenic variants in <i>CHAMP1</i> are associated with global developmental delay, intellectual disability, and dysmorphic facial features

Tanaka, Akemi; Cho, Megan T.; Retterer, Kyle; Jones, Julie R.; Nowak, C.; Douglas, Jessica; Jiang, Yong‐Hui; McConkie‐Rosell, Allyn; Schaefer, Gerald; Kaylor, Julie; Rahman, Omar Abdul; Telegrafi, Aida; Friedman, Bethany; Douglas, Ganka; Monaghan, Kristin G.; Chung, Wendy K.

doi:10.1101/mcs.a000661

Cited by 33 publications

(39 citation statements)

References 22 publications

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“…The study of Tanaka et al 4 included five females with CHAMP1 mutations, all significantly intellectually disabled, three had congenital microcephaly, and one had postnatal microcephaly. The patients were either nonverbal or minimally so.…”

Section: Discussionmentioning

confidence: 99%

CHAMP1 Mutations cause Refractory Infantile Myoclonic Epilepsy

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

CHAMP1 Mutations cause Refractory Infantile Myoclonic Epilepsy

et al. 2019

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“…In addition to the above family, eight unrelated affected individuals with variants in EBF3 were identified through WES 10–14 by groups that independently submitted to GeneMatcher. In addition to c.625C>T (p.Arg209Trp), we found missense variants c.196A>G (p.Asn66Asp) in subject 4, c.422A>G (p.Tyr141Cys) in subject 7, c.512G>A (p.Gly171Asp) in subject 8, and c.530C>T (p.Pro177Leu) in subject 6; 9-bp duplication c.469_477dup (p.His157_ Ile159dup) in subject 10; nonsense variants c.907C>T (p.Arg303*) in subject 9 and c.913C>T (p.Gln305*) in subject 3; and splice-site mutation c.1101 + 1G>T in subject 5 (Figures 1A and 1B and Table S3).…”

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confidence: 99%

Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism

Harms

Girisha

Hardigan

et al. 2017

The American Journal of Human Genetics

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From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in ~0.1% of individuals with unexplained neurodevelopmental disorders.

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“…) (Tanaka et al. ), the biological evidence for linking between the patient mutations in CHAMP1 and ID is insufficient.…”

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confidence: 99%

Disturbed chromosome segregation and multipolar spindle formation in a patient with CHAMP 1 mutation

Okamoto

Tsuchiya

Kuki

et al. 2017

Mol Genet Genomic Med

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BackgroundPatients with intellectual disability (ID) typically exhibit significant defects in both intelligence and adaptive behavior. Aberration of several genes involved in proper progression of mitosis has been reported to underlie ID. Here, we report a new patient with a novel mutation of CHAMP1.MethodsWhole exome sequencing (WES) analysis was performed. We isolated lymphoblast cells from the CHAMP1 patient and observed chromosome segregation.ResultsWe identified a de novo frameshift mutation in CHAMP1. We find that these cells exhibit an increase in centrosome number and resulting multipolar spindle formation. The phenotypes observed in the patient's lymphoblastoid cells were presumably because of cytokinesis failure. We also confirm the identical phenotypes in human culture cells depleted of CHAMP1.Conclusion CHAMP1 encodes a protein regulating kinetochore–microtubule attachment and chromosome segregation. These data strongly support that CHAMP1 mutations cause ID, and suggest that CHAMP1 is critical for progression of cytokinesis and maintenance of centrosome number.

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De novo pathogenic variants in CHAMP1 are associated with global developmental delay, intellectual disability, and dysmorphic facial features

Cited by 33 publications

References 22 publications

CHAMP1 Mutations cause Refractory Infantile Myoclonic Epilepsy

CHAMP1 Mutations cause Refractory Infantile Myoclonic Epilepsy

Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism

Disturbed chromosome segregation and multipolar spindle formation in a patient with CHAMP 1 mutation

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