Intellectual disabilityGene: KDM3B Amber List (moderate evidence)
Comment on publications: PMID: 30929739. 8/16 patients had short stature (< -2.5 SD) and 9/15 had neonatal feeding difficulties. 5/16 had joint hypermobility, 4/17 had hearing loss.
Created: 28 Jun 2021, 1:10 p.m. | Last Modified: 28 Jun 2021, 1:10 p.m.
Panel Version: 3.1146
After consulting with the Genomics England Clinical Team it was decided that this gene should be promoted to Green status at the next review.
Created: 28 Jun 2021, 1:08 p.m. | Last Modified: 28 Jun 2021, 1:08 p.m.
Panel Version: 3.1145
As the majority of patients have mild to moderate ID, this gene will be kept as Amber.
Created: 19 Oct 2020, 3:19 p.m. | Last Modified: 19 Oct 2020, 3:19 p.m.
Panel Version: 3.462
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
Intellectual disability; short stature
Variants in this GENE are reported as part of current diagnostic practice
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.
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
Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures
Publications for gene: KDM3B were set to 30929739
Tag Q2_21_rating tag was added to gene: KDM3B.
Gene: kdm3b has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: KDM3B were changed from to Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures
Mode of inheritance for gene: KDM3B was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KDM3B were set to
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
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.