CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature

Rouxel, Flavien; Relator, Raissa; Kerkhof, Jennifer; McConkey, Haley; Levy, Michael A.; Dias, Patrícia; Barat‐Houari, Mouna; Bednarek, Nathalie; Boute, Odile; Chatron, Nicolas; Cherik, Florian; Delahaye‐Duriez, Andrée; Doco‐Fenzy, Martine; Faivre, Laurence; Gauthier, Lucas Willy; Héron, Delphine; Hildebrand, Michael S.; Lesca, Gaëtan; Lespinasse, James; Mazel, Benoît; Menke, Leonie A.; Morgan, Angela; Pinson, Lucile; Quēlin, Chloé; Rossi, Massimiliano; Ruiz-Pallares, Nathalie; Mau-Them, Frédéric Tran; Kessel, Imke N. van; Vincent, Marie; Wéber, Mathys; Willems, Marjolaine; Leguyader, Gwenael; Sadiković, Bekim; Geneviève, David

doi:10.1016/j.gim.2021.12.016

Cited by 16 publications

(21 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DNAm signatures have also been identified in CHARGE syndrome (MIM: 214800 ) ( CHD7 [MIM: 608892 ]), 10 Nicolaides-Baraitser syndrome (MIM: 601358 ) ( SMARCA2 [MIM: 600014 ] ) , 13 and Floating Harbor syndrome (MIM: 136140 ) ( SRCAP [MIM: 611421 ]), 14 which implicate chromatin remodelers. Initially, DNAm signatures were reported for genes with primary roles in epigenetic regulation; however, more recently, evidence has emerged that genes with pleiotropic functions that include various interactions with DNA can also demonstrate DNAm signatures, such as DYRK1A (MIM: 600855 ), 15 CDK13 (MIM: 603309 ), 16 and ADNP (MIM: 611386 ). 17 There are now >40 disorder/gene-specific DNAm signatures currently available that can be used as a second-tier test to functionally classify VUSs.…”

Section: Introductionmentioning

confidence: 99%

An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome

Choufani¹,

McNiven²,

Cytrynbaum³

et al. 2022

The American Journal of Human Genetics

Self Cite

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome

Choufani¹,

McNiven²,

Cytrynbaum³

et al. 2022

The American Journal of Human Genetics

Self Cite

View full text Add to dashboard Cite

“…Pathogenic CDK13 variants cause CDK13-related disorder (4). The literature reports over 60 individuals with this condition, with most published CDK13 variants being missense and occurring de novo (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Physical features of CDK13-related disorder include recognisable upslanting palpebral ssures, epicanthal folds, a broad nasal bridge, thin upper lip, small mouth, posteriorly rotated ears, peg-shaped teeth, and curly hair (4)(5)(6)(7)(8)14).…”

Section: Introductionmentioning

confidence: 99%

“…The literature reports over 60 individuals with this condition, with most published CDK13 variants being missense and occurring de novo (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Physical features of CDK13-related disorder include recognisable upslanting palpebral ssures, epicanthal folds, a broad nasal bridge, thin upper lip, small mouth, posteriorly rotated ears, peg-shaped teeth, and curly hair (4)(5)(6)(7)(8)14). Other physical phenotypes include congenital cardiac, renal and skeletal abnormalities, hypotonia, feeding di culties and a high-arched palate (5)(6)(7)(8)13).…”

Section: Introductionmentioning

confidence: 99%

“…Recognition of CAS, a rare speech disorder, is required to ensure appropriately targeted therapy. The high prevalence of speech and language impairment underscores the importance of tailored speech therapy, particularly early access to AAC supports.commonly impacted areas of neurodevelopment in CDK13-related disorder (5, 6, 8,10,13,14). Yet whilst communication di culties are ubiquitously reported, there has been no speci city to the clinical diagnoses, with very general terms such as 'speech and language delay' being used.…”

mentioning

confidence: 99%

“…commonly impacted areas of neurodevelopment in CDK13-related disorder (5, 6, 8,10,13,14). Yet whilst communication di culties are ubiquitously reported, there has been no speci city to the clinical diagnoses, with very general terms such as 'speech and language delay' being used.…”

mentioning

confidence: 99%

See 2 more Smart Citations

CDK13-related disorder: a deep characterization of speech and language abilities and addition of 33 novel cases

et al. 2023

Self Cite

View full text Add to dashboard Cite

Speech and language impairments are central features of CDK13-related disorder. While pathogenic CDK13 variants have been associated with childhood apraxia of speech (CAS), a systematic characterisation of communication has not been conducted. Here we examined speech, language, non-verbal communication skills, social behaviour and health and development in 41 individuals with CDK-13 related disorder (male = 22, median-age 7 years 1 month, range 1-25 years; 33 novel). Most participants used augmentative and alternative communication (AAC) in early childhood (24/41). CAS was common (14/22). Performance varied widely across intellectual ability, social behaviour and expressive language skills, with participants ranging from within average through to the severely impaired range. Receptive language was signi cantly stronger than expressive language ability. Social motivation was a relative strength. In terms of broader phenotype, a quarter had one or more of: renal, urogenital, musculoskeletal and cardiac malformations, vision impairment, ear infections and/or sleep disturbance. All had gross and ne motor impairments (41/41). Other conditions included mild-moderate intellectual disability (16/22) and autism (7/41). No genotype-phenotype correlations were found. Recognition of CAS, a rare speech disorder, is required to ensure appropriately targeted therapy. The high prevalence of speech and language impairment underscores the importance of tailored speech therapy, particularly early access to AAC supports.commonly impacted areas of neurodevelopment in CDK13-related disorder (5, 6, 8,10,13,14). Yet whilst communication di culties are ubiquitously reported, there has been no speci city to the clinical diagnoses, with very general terms such as 'speech and language delay' being used. Nor have studies used standardised measures/assessment protocols. A variant in CDK13 was recently associated with a rare and severe speech disorder, childhood apraxia of speech (CAS), in a gene discovery cohort of children ascertained for CAS (13). However, there has been no systematic reverse phenotyping evaluation of speech or language de cits in a cohort of individuals with pathogenic CDK13 variants to date to con rm this association with CAS. Further, the absence of a comprehensive speech and language evaluation in this population limits prognostic counselling and the provision of targeted intervention. Here, we systematically characterise speech and language abilities in children with CDK13-related disorder using standardised outcome measures. Methods ParticipantsInclusion criteria were a molecularly con rmed pathogenic diagnosis of CDK13-related disorder. Exclusion criteria were the existence of other pathogenic variants in other neurodevelopmental genes. Participants were recruited via an online CDK13 support group or via their treating clinical geneticist. The Royal Children's Hospital Human Research Ethics Committee provided ethical approval (HREC 37353A). Caregivers provided written and informed consent for their children to partic...

show abstract

CCNK Gene Deficiency Influences Neural Progenitor Cells Via Wnt5a Signaling in CCNK‐Related Syndrome

Dai,

Wang,

Zhan

et al. 2023

Annals of Neurology

View full text Add to dashboard Cite

ObjectiveRare variants of CCNK (cyclin K) give rise to a syndrome with intellectual disability. The purpose of this study was to describe the genotype–phenotype spectrum of CCNK‐related syndrome and the underlying molecular mechanisms of pathogenesis.MethodsWe identified a number of de novo CCNK variants in unrelated patients. We generated patient‐induced pluripotent stem cells (iPSCs) and neural progenitor cells (NPCs) as disease models. In addition, we constructed NPC‐specific Ccnk knockout (KO) mice and performed molecular and morphological analyses.ResultsWe identified 2 new patients harboring CCNK missense variants and followed‐up 3 previous reported patients, which constitute the largest patient population analysis of the disease. We demonstrate that both the patient‐derived NPC models and the Ccnk KO mouse displayed deficient NPC proliferation and enhanced apoptotic cell death. RNA sequencing analyses of these NPC models uncovered transcriptomic signatures unique to CCNK‐related syndrome, revealing significant changes in genes, including WNT5A, critical for progenitor proliferation and cell death. Further, to confirm WNT5A's role, we conducted rescue experiments using NPC and mouse models. We found that a Wnt5a inhibitor significantly increased proliferation and reduced apoptosis in NPCs derived from patients with CCNK‐related syndrome and NPCs in the developing cortex of Ccnk KO mice.InterpretationWe discussed the genotype–phenotype relationship of CCNK‐related syndrome. Importantly, we demonstrated that CCNK plays critical roles in NPC proliferation and NPC apoptosis in vivo and in vitro. Together, our study highlights that Wnt5a may serve as a promising therapeutic target for the disease intervention. ANN NEUROL 2023

show abstract

CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature

Cited by 16 publications

References 22 publications

An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome

An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome

CDK13-related disorder: a deep characterization of speech and language abilities and addition of 33 novel cases

CCNK Gene Deficiency Influences Neural Progenitor Cells Via Wnt5a Signaling in CCNK‐Related Syndrome

Contact Info

Product

Resources

About