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Intellectual disability

Gene: KDM3B

Amber List (moderate evidence)

KDM3B (lysine demethylase 3B)
EnsemblGeneIds (GRCh38): ENSG00000120733
EnsemblGeneIds (GRCh37): ENSG00000120733
OMIM: 609373, Gene2Phenotype
KDM3B is in 2 panels

3 reviews

Zornitza Stark (Australian Genomics)

Green List (high evidence)

14 unrelated individuals and 3 affected parents with varying degrees of ID, DD, short stature, dysmorphism, and de novo or inherited pathogenic variants in KDM3B (inherited variants segregated with phenotype).
Created: 8 Feb 2020, 9:45 a.m. | Last Modified: 8 Feb 2020, 9:45 a.m.
Panel Version: 3.0

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual disability; short stature

Publications

Variants in this GENE are reported as part of current diagnostic practice

Louise Daugherty (Genomics England Curator)

Comment on list classification: Rated gene as Amber based on current information in the literature and external expert review there is not enough evidence to support gene-disease association rating of this gene to Green.
Created: 2 Apr 2019, 10:14 a.m.

Konstantinos Varvagiannis (Other)

I don't know

Diets et al. (2019 - https://doi.org/10.1016/j.ajhg.2019.02.023) report on 17 individuals with de novo or inherited KDM3B variants.

Overlapping features consisted of DD/ID (almost universal feature although 1 subject did not have appropriate age for evaluation), short stature, feeding difficulties in infancy, etc. ID was specifically reported for 12 individuals (mild in most, mild-moderate or moderate in others). Some facial features appeared to be more frequent among affected individuals (as further supported by facial recognition models). Seizures were reported for 3 subjects.

KDM3B encodes lysine-specific demethylase 3B, involved in H3K9 demethylation which -in turn - is important for transcriptional regulation.

5 individuals harbored nonsense variants whereas 12 carried missense variants. In 10 individuals the variants had occurred as de novo events while in 3 individuals the variant was inherited from a similarly affected parent. For one subject, paternal sample was unavailable for testing. All variants were absent from gnomAD and had in silico predictions (CADD/SIFT/PolyPhen2 scores) supportive of a deleterious effect.

Most variants occurred in regions intolerant to missense variation. 2 missense variants were classified by the authors as VUS requiring further study based on their localization in regions neutral/tolerant to missense variation but also their occurrence in individuals with suggestive features and gestalt.

Haploinsufficiency is suggested to be the underlying mechanism given the type of variants observed (nonsense/missense), the pLI and Z-scores of 1 and 4.99 respectively in ExAC as well as the effect of mutations in other histone lysine methylases (KMTs) or histone lysine demethylases (KDMs) resulting in neurodevelopmental disorders.

Functional studies: The authors comment that the impact of missense variants has to be clarified as studies of mono- and tri- methylation status of H3K9 in HEK293 cells overexpressing either the wt or mutant KDM3B were inconclusive.

Animal model: Kdm3b-knockout mice display growth restriction possibly due to decreased IGF1 levels. It is commented that 50% of individuals had short stature while one (who had relevant work-up) had isolated GH deficiency. Subfertility is a further feature in ko mice while this was a feature reported for one subject.

KDM3B is not commonly included in gene panels for ID offered by diagnostic laboratories.
It is not associated with any phenotype in G2P, nor in OMIM.

As a result this gene can be considered for upgrade to amber or green (depending on whether the degree of ID is relevant for the current panel and/or whether additional evidence is required).
Created: 31 Mar 2019, 9:44 p.m.

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

Phenotypes
Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures

Publications

  • doi.org/10.1016/j.ajhg.2019.02.023

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Short stature
  • Behavioral abnormality
  • Seizures
OMIM
609373
Clinvar variants
Variants in KDM3B
Penetrance
None
Publications
Panels with this gene

History Filter Activity

2 Apr 2019, Gel status: 2

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: kdm3b has been classified as Amber List (Moderate Evidence).

2 Apr 2019, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: KDM3B were changed from to Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures

2 Apr 2019, Gel status: 1

Set mode of inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for gene: KDM3B was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

2 Apr 2019, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: KDM3B were set to

28 Sep 2018, Gel status: 1

Created, Added New Source, Set mode of inheritance

Louise Daugherty (Genomics England Curator)

gene: KDM3B was added gene: KDM3B was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: KDM3B was set to