CDKL5

protein-coding

cyclin dependent kinase like 5, the group of Cyclin dependent kinases|Cilia and flagella associated

Gene summary

This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

Previous symbols:

STK9

MANE transcript

NM_001323289.2

Inheritance

XL, AD

ClinVar variants

P:584U:454B:276

Top phenotype

Developmental and epileptic encephalopathy 2

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chrX:18,425,583-18,653,629

External References & Databases

Ensembl (ENSG00000008086)

Transcript & Mutation Effects

hg38 • Region Span ~228.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

CDKL5 disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100039

Submitter: ClinGen

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.

developmental and epileptic encephalopathy, 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010396

Submitter: Labcorp Genetics (formerly Invitae)

precocious pubertyLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0000088

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 2DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010396

Submitter: Ambry Genetics

atypical Rett syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017746

Submitter: Orphanet

genetic developmental and epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Orphanet

developmental and epileptic encephalopathy, 2DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010396

Submitter: G2P

developmental and epileptic encephalopathy, 2SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010396

Submitter: Orphanet

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 2XL

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 15499549; 15492925; 15689447; 18266744; 18809835; 18063413; 17993579; 19793311; 19241098; 19396824; 20602487; 21765152; 21770923; 21802232; 22264704; 22430159; 22521361; 22670135; 22678952; 22867051; 23064044

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDKL5 variants in ClinVar

33 Conditions Cataloged

Developmental and epileptic encephalopathy, 2Total: 990

Angelman syndrome-likeTotal: 763

not providedTotal: 425

CDKL5 disorderTotal: 325

not specifiedTotal: 135

Inborn genetic diseasesTotal: 95

CDKL5-related disorderTotal: 60

Atypical Rett syndromeTotal: 43

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001323289.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	2 clinvar	1 clinvar	30 clinvar	173 clinvar	10 clinvar	216
missense	42 clinvar	95 clinvar	398 clinvar	68 clinvar	25 clinvar	628
nonsense	79 clinvar	22 clinvar	7 clinvar			108
start loss			1 clinvar			1
frameshift	190 clinvar	78 clinvar				268
splice donor/acceptor (+/-2bp)	44 clinvar	31 clinvar	18 clinvar			93
Total	357	227	454	241	35	1314

Highest pathogenic variant AF is 0.000003642178

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001323289.2	RefSeq	NP_001310218.1	17	MANE Select
ENST00000623535.2	Ensembl	ENSP00000485244.1	17	MANE Select
NM_001037343.2	RefSeq	NP_001032420.1	20	Standard
NM_003159.3	RefSeq	NP_003150.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Brain-Derived Neurotrophic Factor (BDNF) signaling pathway

Biological Process

neuron migration
protein phosphorylation
positive regulation of GTPase activity
positive regulation of axon extension
protein autophosphorylation

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
cyclin-dependent protein serine/threonine kinase activity
ATP binding
kinase activity

Cellular Component

nucleus
nucleoplasm
centrosome
cytosol
ruffle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379989
Coding exons: 20
Length: 228047
Individuals with no LoFs: 125721
Homozygous LoFs: 1
Heterozygous LoFs: 1
Defined: 125723
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.74	246	400	0.615	0.0000323	6774
Missense (PolyPhen)		14	44.31	0.31596		662
Synonymous	-0.498	157	149	1.05	0.0000121	1987
Loss of Function	4.95	3	34.3	0.0875	0.00000261	613

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000024	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mediates phosphorylation of MECP2 (PubMed:15917271, PubMed:16935860). May regulate ciliogenesis (PubMed:29420175). {ECO:0000269|PubMed:15917271, ECO:0000269|PubMed:16935860, ECO:0000269|PubMed:29420175}.;
Disease: DISEASE: Note=Chromosomal aberrations involving CDKL5 are found in patients manifesting early-onset seizures and spams and psychomotor impairment. Translocation t(X;6)(p22.3;q14); translocation t(X;7)(p22.3;p15).; DISEASE: Epileptic encephalopathy, early infantile, 2 (EIEE2) [MIM:300672]: A severe form of epilepsy characterized by seizures or spasms beginning in infancy. Patients with epileptic encephalopathy early infantile type 2 manifest features resembling Rett syndrome such as microcephaly, lack of speech development, stereotypic hand movements. However, EIEE2 and Rett syndrome are considered two distinct entities. {ECO:0000269|PubMed:12736870, ECO:0000269|PubMed:15492925, ECO:0000269|PubMed:15499549, ECO:0000269|PubMed:15689447, ECO:0000269|PubMed:15917271, ECO:0000269|PubMed:16015284, ECO:0000269|PubMed:16611748, ECO:0000269|PubMed:16935860, ECO:0000269|PubMed:17993579, ECO:0000269|PubMed:18790821, ECO:0000269|PubMed:18809835, ECO:0000269|PubMed:19241098, ECO:0000269|PubMed:19253388, ECO:0000269|PubMed:23662938, ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:24564546, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.128
RVIS EVS: -0.67
RVIS percentile EVS: 15.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.924

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium