ClinGen Dosage Sensitivity Curation Page

CDKL5

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
15492925 Weaving et al. (2004) describe a family consisting of a proband with atypical Rett syndrome (RTT), her identical twin sister with autism and intellectual disability (ID), and a brother with profound ID and seizures. A 1-bp deletion was identified (c.183delT) in CDKL5 resulting in a premature termination in all the affected family members, but not in unaffected members. The proband's unaffected mother tested negative for the mutation and the authors postulate germline mosaicism. Further screening of 44 patients with RTT without a MECP2 mutation revealed one individual with a splice-site mutation (IVS13-1G>A) in CDKL5.
15689447 Scala et al. (2005) observed two unrelated female patients with infantile spasms, developmental delays, and intellectual disability who fulfilled the criteria for RTT including microcephaly, hand apraxia, generalized hypotonia, and stereotypic hand movements. Sequencing and deletion/duplication analysis of MECP2 was negative. Sequencing of CDKL5 revealed a 4-bp deletion resulting in a premature stop codon in one girl and a 2-bp deletion resulting in a premature stop codon in the second girl.
19241098 Russo et al. (2008) screened a population of 92 patients with classic or atypical Rett syndrome, 17 Angelman/Angelman-like patients and six with idiopathic autism for mutation in CDKL5. Six CDKL5 mutations were identified in the Rett subset including 2 missense mutations, 2 splicing mutations, a nonsense mutation, and a two exon deletion. An additional insertion mutation was identified in a patient with features consistent with a clinical diagnosis of Angelman syndrome.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for Triplosenstive Phenotype

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.