Fetal anomalies
Gene: ROBO1 Green List (high evidence)Comment on mode of inheritance: Should be updated from 'monoallelic' to 'both mono- and biallelic' at the next GMS panel update.
Biallelic variants in the ROBO1 gene are associated with neurooculorenal syndrome (OMIM:620305). Clinical manifestations are generally highly variable and involve several organ systems. However, some cases do present in utero with renal agenesis and structural brain abnormalities (PMID: 29194579; 35227688) indicating that the phenotype is relevant to this panel.Created: 20 Mar 2024, 12:25 p.m. | Last Modified: 20 Mar 2024, 12:25 p.m.
Panel Version: 3.142
Green List (high evidence)
Comment on list classification: Updated rating from Amber to Green based on 3 probands reported in PMID:28592524 with ROBO loss of function variants and ventral septal heart defects.Created: 24 Apr 2019, 12:38 p.m.
Evidence for inclusion on the PAGE Additional gene list comes from a single study in Kruszka et al. (2017, PMID:28592524) but 3 families of different ethnicities; each proband had a ventricular septal defect, and one proband had tetralogy of Fallot. Plus proband 1 had craniofacial findings, consistent with the mouse model. VSD can be detected prenatally (e.g. see PMID:24456562) so is relevant for the panel.Created: 24 Apr 2019, 12:36 p.m.
ROBO1 was added to the Fetal anomalies panel as Amber based on a 'probable' rating in the PAGE original Additional gene list. In the PAGE paper (Lord et al., 2019, PMID:30712880), ROBO1 is listed as an Additional gene (Supplementary Table 2) based on association with a prenatal phenotype reported in the literature. At the time of curation (April 2019), ROBO1 is not currently associated with a disorder in DD-Gene2Phenotype or in OMIM.Created: 24 Apr 2019, 12:06 p.m.
Additional evidence from PAGE study: Potentially clinically useful variant identified in this gene from fetal exome sequencing in Lord et al., 2019 (PMID:30712880).Created: 18 Apr 2019, 3:01 p.m.
Rating in original PAGE list (Additional gene list) for 'tetralogy of Fallot and septal defects': probable. Mode of inheritance: monoallelic. Mode of pathogenicity: loss of function.Created: 11 Dec 2018, 9:05 a.m.
Publications for gene: ROBO1 were set to 28592524; 28485101; 30712880; 29194579; 35227688
Publications for gene: ROBO1 were set to 28592524; 28485101; 30712880
Mode of inheritance for gene: ROBO1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ROBO1 were changed from tetralogy of Fallot and septal defects to Tetralogy of Fallot and septal defects; Neurooculorenal syndrome, OMIM:620305
Tag Q1_24_MOI tag was added to gene: ROBO1.
Tag gene-checked was removed from gene: ROBO1.
Tag gene-checked tag was added to gene: ROBO1.
Gene: robo1 has been classified as Green List (High Evidence).
Publications for gene: ROBO1 were set to 28592524; 28485101
gene: ROBO1 was added gene: ROBO1 was added to Fetal anomalies. Sources: PAGE Additional Gene List,Expert Review Amber Mode of inheritance for gene: ROBO1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ROBO1 were set to 28592524; 28485101 Phenotypes for gene: ROBO1 were set to tetralogy of Fallot and septal defects
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.