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Intellectual disability

Gene: KDM5B

Green List (high evidence)

KDM5B (lysine demethylase 5B)
EnsemblGeneIds (GRCh38): ENSG00000117139
EnsemblGeneIds (GRCh37): ENSG00000117139
OMIM: 605393, Gene2Phenotype
KDM5B is in 3 panels

7 reviews

Ivone Leong (Genomics England Curator)

Comment on mode of inheritance: Changed mode of inheritance from Monoallelic to Both monoallelic and biallelic based on evidence provided by expert review.
Created: 27 Feb 2019, 2:38 p.m.
Comment on publications: PMID: 30217758 reports on 2 de novo splice variants found in 3 patients from 2 unrelated families who have ID and ASD. One variant was found in a boy with mild ID and autism traits. In vitro studies found that this variant reduced KDM5B mRNA production. The sister of this affected patient did not have carry this splice variant but she also presented with mild ID and epilepsy. The authors suggest that a variant in another gene may be linked to these phenotypes and that KDM5B haploinsufficiency cannot explain the ID/ASD phenotype.

The other variant was found in a pair of monozygotic twins who both presented with global developmental delay, poor language and ASD. In vitro studies of this second variant showed that it causes the production of an abnormal transcript which is degraded by nonsense-mediated decay.
Created: 27 Feb 2019, 2:28 p.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Initially reported in a publication with participation of DDD study (PMID: 29276005) it is further demonstrated in a recent DDD article (PMID: 30409806) that BOTH biallelic as well as monoallelic variants are associated with intellectual disability.

In the latter publication 4 individuals with ID and biallelic mutations in KDM5B are reported. 3 of these patients had biallelic loss-of-function (LoF) variants while a fourth one was compound heterozygous for a splice variant and a large deletion disrupting KDM5B.

KDM5B seems to be tolerant to LoF variants (pLI of 5x10-5 - in gnomAD o/e ratio for LoF variants : 0.45) while some LoF variants were transmitted by - most commonly - unaffected parents.

The authors found no evidence for :
- A parent-of-origin bias suggestive of imprinting.
- Possibility of de novo variants occuring as second hits and/or missed second variants in the dominant cases (as they comment this may have been the case for only 2 individuals).
- Certain LoF variants escaping nonsense mediated decay.
- Modifying variants in other genes.

Overall incomplete penetrance for heterozygous LoF variants and complete for biallelic LoF variants is favored as a plausible mechanism.

In the article it is not clear whether the individuals with biallelic variants present with more severe intellectual disability. Based on the initial article (PMID: 29276005) reporting on 3 of the (4 total) DDD participants published in the latter study, this seems to be unlikely (1 with severe and 2 with moderate ID).

As a result the mode of inheritance should probably be modified.
Created: 18 Nov 2018, 11:44 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf . Main mutation mechanism : NA
Created: 27 Jul 2017, 7:03 p.m.

Mode of inheritance
Unknown

Publications

Caroline Wright (Genomics England Curator)

Comment when marking as ready: New DDD gene
Created: 15 Feb 2016, 1:25 p.m.

Richard Scott (Genomics England Curator)

Green List (high evidence)

Comment when marking as ready: New gene on G2P list
Created: 29 Jan 2016, 1:29 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Ellen McDonagh (Genomics England Curator)

Supporting functional evidence...
- PMID: 26077434; a review "Disrupted intricacy of histone H3K4 methylation in neurodevelopmental disorders"
- PMID: 21369698; The Histone Demethylase Jarid1b Ensures Faithful Mouse Development by Protecting Developmental Genes from Aberrant H3K4me3. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly.
Created: 26 Nov 2015, 10:48 a.m.
Family members KDM5A (rated red) and KDM5C (rated green) are on the current ID gene panel.
Created: 26 Nov 2015, 10:25 a.m.

Maria Bitner-Glindzicz (UCL)

Green List (high evidence)

2 papers in literature; >4 patients with truncating mutations and similar phenotypes
Created: 25 Nov 2015, 10:44 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Neurodevelopmental delay and autistic spectrum disorder

Publications

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Victorian Clinical Genetics Services
  • Expert Review Green
Phenotypes
  • neurodevelopment delay and autism spectrum disorder
  • Mental retardation, autosomal recessive 65, 618109
OMIM
605393
Clinvar variants
Variants in KDM5B
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

27 Feb 2019, Gel status: 4

Set mode of inheritance

Ivone Leong (Genomics England Curator)

Mode of inheritance for gene: KDM5B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

27 Feb 2019, Gel status: 4

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: KDM5B were set to 25363768; 24307393; 29276005; 30409806; 25529582

22 Feb 2019, Gel status: 4

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: KDM5B were changed from neurodevelopment delay and autism spectrum disorder to neurodevelopment delay and autism spectrum disorder; Mental retardation, autosomal recessive 65, 618109

22 Feb 2019, Gel status: 4

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: KDM5B were set to http://www.nature.com/nature/journal/v515/n7526/pdf/nature13908.pdf; 24307393

28 Sep 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to KDM5B.

12 Mar 2018, Gel status: 3

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

15 Feb 2016, Gel status: 4

Gene classified by Genomics England curator

Caroline Wright (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

15 Feb 2016, Gel status: 4

Gene classified by Genomics England curator

Caroline Wright (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

15 Feb 2016, Gel status: 0

Approved Gene

Caroline Wright (Genomics England Curator)

This proposed gene was validated and added to this panel

15 Feb 2016, Gel status: 0

Approved Gene

Caroline Wright (Genomics England Curator)

This proposed gene was validated and added to this panel

29 Jan 2016, Gel status: 0

Gene classified by Genomics England curator

Richard Scott (Genomics England Curator)

This gene has been removed from the panel.

29 Jan 2016, Gel status: 0

Set publications

Richard Scott (Genomics England Curator)

Publications for KDM5B were set to http://www.nature.com/nature/journal/v515/n7526/pdf/nature13908.pdf; 24307393

29 Jan 2016, Gel status: 0

Set publications

Richard Scott (Genomics England Curator)

Publications for KDM5B were set to http://www.nature.com/nature/journal/v515/n7526/pdf/nature13908.pdf PMID; 24307393

29 Jan 2016, Gel status: 0

Set Mode of Inheritance

Richard Scott (Genomics England Curator)

Mode of inheritance for KDM5B was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

25 Nov 2015, Gel status: 0

Created

Maria Bitner-Glindzicz (UCL)

KDM5B was created by mbitnerg

25 Nov 2015, Gel status: 0

Added New Source

Maria Bitner-Glindzicz (UCL)

KDM5B was added to Intellectual disabilitypanel. Sources: Literature