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Bilateral congenital or childhood onset cataracts

Gene: CDK9

Green List (high evidence)

CDK9 (cyclin dependent kinase 9)
EnsemblGeneIds (GRCh38): ENSG00000136807
EnsemblGeneIds (GRCh37): ENSG00000136807
OMIM: 603251, Gene2Phenotype
CDK9 is in 2 panels

3 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 11 a.m. | Last Modified: 30 Jan 2023, 11 a.m.
Panel Version: 3.3

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least four variants have been reported in unrelated cases with a CHARGE-like syndrome:
NM_001261:c.280C>T, p.Arg94Cys (PMID: 29302074)
NM_001261.3:c.673C>T / p.Arg225Cys (PMID: 26633546, 30237576)
NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys (PMID: 33640901).
Supportive functional studies have also been reported (PMID: 33640901).
Created: 25 Aug 2022, 4:10 p.m. | Last Modified: 25 Aug 2022, 4:10 p.m.
Panel Version: 3.1694
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 25 Aug 2022, 3:18 p.m. | Last Modified: 25 Aug 2022, 3:18 p.m.
Panel Version: 3.1694

Konstantinos Varvagiannis (Other)

Green List (high evidence)

There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance due to consanguinity.

Using autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in one case). Overall, the authors used the term CHARGE-like for this phenotype.

Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with ophthalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two of them), heart defect (2/3 with VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags in 2/3, bilateral deafness 1/3, bilateral ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 | suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with several in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacting with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited : 27715402, 30100824).
Sources: Literature
Created: 23 Apr 2022, 9:21 a.m. | Last Modified: 23 Apr 2022, 4:19 p.m.
Panel Version: 3.1561

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures



Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
  • Expert Review Green
  • Literature
  • Global developmental delay
  • Intellectual disability
  • Abnormality of vision
  • Congenital cataract
  • Iris coloboma
  • Abnormal heart morphology
  • Choanal atresia
  • Abnormality of the ear
  • Preauricular skin tag
  • Hearing impairment
  • Abnormality of the genitourinary system
  • Abnormality of limbs
  • Abnormality of the vertebrae
  • Abnormality of nervous system morphology
  • Seizures
Clinvar variants
Variants in CDK9
Panels with this gene

History Filter Activity

7 Feb 2023, Gel status: 3

Added Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag gene-checked tag was added to gene: CDK9.

30 Jan 2023, Gel status: 3

Removed Tag, Removed Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q3_22_rating was removed from gene: CDK9. Tag Q3_22_MOI was removed from gene: CDK9.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Achchuthan Shanmugasundram (Genomics England Curator)

Source Expert Review Green was added to CDK9. Source NHS GMS was added to CDK9. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

15 Sep 2022, Gel status: 2

Created, Added New Source, Added Tag, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Sarah Leigh (Genomics England Curator)

gene: CDK9 was added gene: CDK9 was added to Cataracts. Sources: Literature,Expert Review Amber Q3_22_rating, Q3_22_MOI tags were added to gene: CDK9. Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK9 were set to 26633546; 30237576; 29302074; 33640901 Phenotypes for gene: CDK9 were set to Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures Penetrance for gene: CDK9 were set to Complete