Recurrent mutations in the <i>CDKL5</i> gene: Genotype–phenotype relationships

Bahi‐Buisson, Nadia; Villeneuve, Nathalie; Caietta, Emilie; Jacquette, Aurélia; Maurey, Hélène; Matthijs, Gert; Esch, Hilde Van; Delahaye, Andrée; Moncla, Anne; Milh, Mathieu; Zufferey, Flore; Diebold, Bertrand; Bienvenu, Thierry

doi:10.1002/ajmg.a.35401

Cited by 54 publications

(56 citation statements)

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“…The clinical severity may be associated with the location and the type of mutations, but the genotype-phenotype correlation still remains obscure [22]. It has been reported that some recurrent mutations in N-terminal catalytic domain such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, c.145 + 2 T > C and frameshift mutations in the C-terminal region such as c.2635_2636del CT cause more severe phenotype, which is manifested by earlier onset, infantile spasms and hypsarrhythmia, refractory epileptic encephalopathy, microcephaly, and inability to walk [31]. The patients with p.Ala40Val mutation which affects ATP-binding site in catalytic domain, showed mild phenotype (walked unaided, normocephaly, better hand use ability, and less frequent refractory epilepsy), compared to those with other CDKL5 mutations [5,6,13].…”

Section: Discussionmentioning

confidence: 99%

Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients

et al. 2014

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BackgroundMutations in the cyclin-dependent kinase-like 5 (CDKL5) (NM_003159.2) gene have been associated with early-onset epileptic encephalopathies or Hanefeld variants of RTT(Rett syndrome). In order to clarify the CDKL5 genotype-phenotype correlations in Chinese patients, CDKL5 mutational screening in cases with early-onset epileptic encephalopathies and RTT without MECP2 mutation were performed.MethodsThe detailed clinical information including clinical manifestation, electroencephalogram (EEG), magnetic resonance imaging (MRI), blood, urine amino acid and organic acid screening of 102 Chinese patients with early-onset epileptic encephalopathies and RTT were collected. CDKL5 gene mutations were analyzed by PCR, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The patterns of X-chromosome inactivation (XCI) were studied in the female patients with CDKL5 gene mutation.ResultsDe novo CDKL5 gene mutations were found in ten patients including one missense mutation (c.533G > A, p.R178Q) which had been reported, two splicing mutations (ISV6 + 1A > G, ISV13 + 1A > G), three micro-deletions (c.1111delC, c.2360delA, c.234delA), two insertions (c.1791 ins G, c.891_892 ins TT in a pair of twins) and one nonsense mutation (c.1375C > T, p.Q459X). Out of ten patients, 7 of 9 females with Hanefeld variants of RTT and the remaining 2 females with early onset epileptic encephalopathy, were detected while only one male with infantile spasms was detected. The common features of all female patients with CDKL5 gene mutations included refractory seizures starting before 4 months of age, severe psychomotor retardation, Rett-like features such as hand stereotypies, deceleration of head growth after birth and poor prognosis. In contrast, the only one male patient with CDKL5 mutation showed no obvious Rett-like features as females in our cohort. The X-chromosome inactivation patterns of all the female patients were random.ConclusionsMutations in CDKL5 gene are responsible for 7 with Hanefeld variants of RTT and 2 with early-onset epileptic encephalopathy in 71 girls as well as for 1 infantile spasms in 31 males. There are some differences in the phenotypes among genders with CDKL5 gene mutations and CDKL5 gene mutation analysis should be considered in both genders.

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Section: Discussionmentioning

confidence: 99%

Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients

et al. 2014

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“…The types of mutations include translocations, deletions, insertions, nonsense and missense mutations, and the majority of CDKL5 mutations are located within the N-terminal kinase domain, suggesting that the kinase function of CDKL5 is particularly important for brain function (Bahi-Buisson et al, 2008, 2012; Fehr et al, 2016). Moreover, genotype-phenotype correlation study has found mutations in the N-terminal kinase domain are associated with more severe clinical symptoms than mutations in the C terminus (Fehr et al, 2016).…”

Section: Genetic Studiesmentioning

confidence: 99%

“…In addition, clinical phenotypes among patients with recurrent mutations are heterogeneous. For example, patients with the most common recurrent mutation, CDKL5 A40V, show a range of symptoms from severe to mild epileptic encephalopathy (Nemos et al, 2009; Bahi-Buisson et al, 2012). This is likely due to the fact that CDKL5 is an X-linked gene and the majority of patients are heterozygous females.…”

Section: Genetic Studiesmentioning

confidence: 99%

Molecular and genetic insights into an infantile epileptic encephalopathy – CDKL5 disorder

2017

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Background The discovery that mutations in cyclin-dependent kinase-like 5 (CDKL5) gene are associated with infantile epileptic encephalopathy has stimulated world-wide research effort to understand the molecular and genetic basis of CDKL5 disorder. Given the large number of literature published thus far, this review aims to summarize current genetic studies, draw a consensus on proposed molecular functions, and point to gaps of knowledge in CDKL5 research. Methods A systematic review process was conducted using the PubMed search engine focusing on CDKL5 studies in the recent ten years. We analyzed these publications and summarized the findings into four sections: genetic studies, CDKL5 expression patterns, molecular functions, and animal models. We also discussed challenges and future directions in each section. Results On the clinical side, CDKL5 disorder is characterized by early onset epileptic seizures, intellectual disability, and stereotypical behaviors. On the research side, a series of molecular and genetic studies in human patients, cell cultures and animal models have established the causality of CDKL5 to the infantile epileptic encephalopathy, and pointed to a key role for CDKL5 in regulating neuronal function in the brain. Mouse models of CDKL5 disorder have also been developed, and notably, manifest behavioral phenotypes, mimicking numerous clinical symptoms of CDKL5 disorder and advancing CDKL5 research to the preclinical stage. Conclusions Given what we have learned thus far, future identification of robust, quantitative, and sensitive outcome measures would be the key in animal model studies, particularly in heterozygous females. In the meantime, molecular and cellular studies of CDKL5 should focus on mechanism-based investigation and aim to uncover druggable targets that offer the potential to rescue or ameliorate CDKL5 disorder-related phenotypes.

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“…Genotype-phenotype correlation has been challenging in CDD due to relatively small cohorts historically and a lack of recurrent pathogenic variants. 2,16 To overcome this challenge, a system of classifying variants into four groups has been proposed: type A, absence of any functional protein; type B, missense variants in the kinase domain; type C, truncating variants between amino acids (aa) 172 and 781; and type D, truncating variants between aa 781 and 905. 9 This system was originally correlated with achievement of developmental milestones without clear statistical correlations.…”

Section: Introductionmentioning

confidence: 99%

CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development

et al. 2019

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Objective The cyclin‐dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). We sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure‐free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones. Methods This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit. Results Ninety‐two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0‐11.0). Eighty‐one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor‐tonic‐spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty‐three percent of patients experienced a seizure‐free period ranging from 1 to >12 months, but only 6% were still seizure‐free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia. Significance The most common seizure types in CDD are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. CVI is a common feature in CDD and is correlated with achieving fewer milestones.

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Recurrent mutations in the CDKL5 gene: Genotype–phenotype relationships

Cited by 54 publications

References 35 publications

Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients

Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients

Molecular and genetic insights into an infantile epileptic encephalopathy – CDKL5 disorder

CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development

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