Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CDKL5 : CDKL5 disorder

HGNC:11411 | MONDO_0100039
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Rett Angelman EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Tao J et al. 2004 Dec (PMID:15499549); Nemos C et al. 2009 Oct (PMID:19793311);
Proband with predicted or proven null variant 1.5 0-2 10 2 2
Weaving LS et al. 2004 Dec (PMID:15492925);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 4
Jhang CL et al. 2017 Oct 15 (PMID:29016850);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Trazzi S et al. 2018 May 1 (PMID:29474534);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 4 16 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The CDKL5 gene is associated with CDKL5 disorder, a disorder sometimes referred to as a Rett syndrome variant, but which can be considered a distinct condition. Individuals with CDKL5 disorder lack some of the distinctive clinical features of classical Rett syndrome such as the clear period of regression and the characteristic intense eye-gaze (PMID:21154482). Of note, normal development during the first 6 months of life commonly seen in Rett syndrome is rare in individuals with CDKL5 disorder. Heterozygous truncating as well as missense variants of CDKL5 cause CDKL5 disorder, almost exclusively arising de novo. Two mouse models of CDKL5 disorder have been characterized (Wang 2012, Amendola 2014), which recaputulate many of the autism-associated phenotypes of CDKL5 disorder. Notably, however, neither mouse model exhibited spontaneous seizures, challenging the usefulness of Cdkl5 KO mice in modeling the human phenotype. Most mice studied have also been hemizygous males, while CDKL5 disorder primarily affects heterozygous females. In summary, CDKL5 is definitively associated with CDKL5 disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Approved by the ClinGen Rett/Angelman Expert Panel 4/30/2018.