Mendeliome
Gene: ROBO4 Amber List (moderate evidence)I don't know
Jaouadi 2023 (PMID: 36855159): cohort of 71 patients with clinical diagnosis of bicuspid aortic valve (40 adult and 20 paediatric patients), tetralogy of Fallot (10 paediatric cases) and one paediatric case with coarctation of the aorta (CoA). Via WES, identified 4x missense and 1x canonical splice site variant in 5x paediatric bicuspid aortic valve and 2x tetralogy of Fallot cases.
However, some of these variants, as well as those reported in Gould 2019, have very high allele counts in gnomAD v4 ranging from absent to >16,000 hets and >100 homs.Created: 8 May 2025, 3:32 a.m. | Last Modified: 8 May 2025, 3:32 a.m.
Panel Version: 1.2564
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Aortic valve disease 8 MIM#618496
Publications
I don't know
Gould (2019) animal models show:
- zebrafish larvae with transfected fs had no gross defects, only 25% adults had valve regurgitation even when homozygous
- mice with het ex1-3 deletion had no structural/functional issues, ~15% hom mice with no detectable mRNA had heart phenotype
ROBO4 mutations disrupt endothelial cellular performance and barrier function, contributing to pathological remodelling of the aortic media. Both variant lacking exon 13 (inframe, canonical splice) and p.R64C were shown to compromise endothelial identity and performance.
NMD PTCs in gnomAD with 25 heterozygotes, and a canonical splice with a predicted out-of-frame outcome has >100 hets.
4 NMD PTCs reported (Gould 2019, Musfee 2020) with BAV, aortic valve disease, thoracic aortic aneurysm. Now unlikely to be solid associations with disease.Created: 28 Jul 2022, 6:30 a.m. | Last Modified: 28 Jul 2022, 6:30 a.m.
Panel Version: 1.179
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Aortic valve disease 8 MIM#618496
Publications
Green List (high evidence)
Two families, functional data, incomplete penetrance.
Sources: LiteratureCreated: 5 Jan 2020, 2:58 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
bicuspid aortic valve; ascending aortic aneurysm; ascending aorta dilatation
Publications
Publications for gene: ROBO4 were set to 30455415; 32748548
Phenotypes for gene: ROBO4 were changed from bicuspid aortic valve; ascending aortic aneurysm; ascending aorta dilatation to Aortic valve disease 8, MIM#618496; bicuspid aortic valve; ascending aortic aneurysm; ascending aorta dilatation
Publications for gene: ROBO4 were set to 30455415
Gene: robo4 has been classified as Amber List (Moderate Evidence).
Gene: robo4 has been classified as Green List (High Evidence).
Gene: robo4 has been classified as Green List (High Evidence).
gene: ROBO4 was added gene: ROBO4 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: ROBO4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ROBO4 were set to 30455415 Phenotypes for gene: ROBO4 were set to bicuspid aortic valve; ascending aortic aneurysm; ascending aorta dilatation Review for gene: ROBO4 was set to GREEN
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 panelapp@genomicsengland.co.uk
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.