Intellectual disability - microarray and sequencing
Gene: RUBCN Red List (low evidence)Seidahmed et al. 2020 (PMID: 32450808) identified a second consanguineous Saudi family with 2 sibs harbouring the same c.2624delC variant, as previously described in another family by Asoum et al. 2010. Autozygosity mapping confirmed this to be a founder variant in the Arab population. Similarities in the clinical phenotype in both families included early-onset cerebellar ataxia and developmental delay. Both brothers had cognitive impairment (IQ = 67 and 72, respectively).
*Note a third publication (PMID:30237576) refers to the same sib pair as in PMID:32450808. The variants appear distinct as the two papers refer to different reference sequences (NM_014687 vs NM_001145642.2) but the variant/case are in fact the same.
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Overall as there is only a single variant in a single population with only limited in vitro functional support, maintaining Red rating on this panel until further evidence on the gene/variants emerges.Created: 16 Jun 2021, 4:24 p.m. | Last Modified: 16 Jun 2021, 4:24 p.m.
Panel Version: 3.1136
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Publications
Red List (low evidence)
Little evidence currently available to suggest a link between variants in this gene and intellectual disability. One paper describes three sisters from a consanguineous family with spinocerebellar ataxia (autosomal recessive), two of whom went onto develop moderate mental retardation after developing epilepsy at 7 months old (epileptic seizures from 7 months - 3 years of age). Unsure as to the origin of the intellectual disability - from the variant or from the epilepsy.Created: 12 Mar 2018, 9:47 a.m.
New gene symbol: RUBCN. Only one paper describing a possible link between variants in this gene and intellectual disability in 3 siblings of the same consanguineous family.Created: 13 Dec 2017, 10:16 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Red List (low evidence)
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
SYNDROMIC MR WITH ATAXIA, DYSARTHRIA AND EPILEPSY
Publications
added new-gene-name tag. New HGNC approved gene symbol RUBCNCreated: 13 Jun 2017, 11:28 a.m.
Red List (low evidence)
Tag founder-effect tag was added to gene: RUBCN.
Publications for gene: RUBCN were set to 20826435
Phenotypes for gene: RUBCN were changed from SYNDROMIC MR WITH ATAXIA, DYSARTHRIA AND EPILEPSY to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
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.
Publications for gene RUBCN was set to ['20826435']
KIAA0226 was changed to RUBCN
Other was added to KIAA0226. Panel: Intellectual disability new-gene-name was removed from KIAA0226. Panel: Intellectual disability
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
KIAA0226 was created by ellenmcdonagh
KIAA0226 was added to Intellectual disabilitypanel. Sources: Expert Review Red
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).
OR
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).
OR
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.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
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.