Intellectual disability - microarray and sequencing
Gene: RBBP8 Green List (high evidence)Green List (high evidence)
Comment on list classification: Changed from Amber to Green. New Amber gene added by external expert reviewer. On further investigation in the literature there is enough evidence to support gene-disease association and rating of this gene to Green.Created: 27 Jul 2018, 3:15 p.m.
After clinical review, it was highlighted that In OMIM there are 2 unrelated cases of Jawad syndrome (microcephaly, ID, digital anomalies) with biallelic variants in RBBP8 and there is sufficient phenotypic overlap with Seckel syndrome 2 providing sufficient evidence, at present, with three unrelated cases involving biallelic variants and evidence of ID to support a green rating.Created: 27 Jul 2018, 3:13 p.m.
Comment on list classification: New Amber gene added by expert reviewer. Past onto clinical team for further review based on additional variant listed in ClinVar, that we could use as further evidence and consider upgrading this gene to greenCreated: 26 Jul 2018, 11:12 a.m.
Comment on phenotypes: added phenotypes from papers PMID:11781686 and PMID:8434622- both disorders are caused by mutation in the RBBP8 gene.Created: 26 Jul 2018, 10:45 a.m.
Comment on publications: Seckel syndrome PMID: 24389050 and PMID: 21998596 reports two variants in two unrelated families, there is a third pathogenic variant listed in ClinVar for Seckel syndrome submitted by Genetic Services Laboratory, University of ChicagoCreated: 26 Jul 2018, 10:38 a.m.
I don't know
Individuals from 3 families reported in the literature with bi-allelic variants in this gene: clinical diagnosis was Jawad syndrome in one, and Seckel syndrome in 2. ID is a reported feature. Consider inclusion as Amber if not Green.Created: 22 Jun 2018, 2:26 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Jawad syndrome; Seckel syndrome; 24389050
Publications
Variants in this GENE are reported as part of current diagnostic practice
Source Victorian Clinical Genetics Services was added to RBBP8.
Gene: rbbp8 has been classified as Green List (High Evidence).
Gene: rbbp8 has been classified as Amber List (Moderate Evidence).
Publications for gene: RBBP8 were set to 18071751; 21998596; 24389050; 11781686
Phenotypes for gene: RBBP8 were set to Jawad syndrome, 251255; Microcephaly with mental retardation and digital anomalies; Seckel syndrome, 24389050; growth retardation, microcephaly with mental retardation, and a characteristic facial appearance
Publications for gene: RBBP8 were set to 18071751; 21998596; 24389050
Phenotypes for gene: RBBP8 were set to Jawad syndrome, 251255; Seckel syndrome, 24389050
RBBP8 was added to Intellectual disability panel. Sources: Literature
RBBP8 was created by Zornitza Stark
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.