Fetal anomalies
Gene: NONO Amber List (moderate evidence)I don't know
This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.
Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).
Outcome of review: May be fetally relevant but still limited evidence, support keeping as Amber gene for now.
Currently rated Green on the following other PanelApp panel(s): ID and cardiomyopathies
Details of review:
Further fetal case reported by Guo et al 2020 (PMID: 31680349) with 'abnormal heart morphology' (specific details not published) and a likely pathogenic variant in NONO designated as 'probably diagnostic'.Created: 11 Aug 2022, 9:23 a.m. | Last Modified: 11 Aug 2022, 9:23 a.m.
Panel Version: 1.900
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications
I don't know
Comment on list classification: Currently there is not enough evidence to promote this gene to Green. Additional cases with a fetally-relevant phenotype are required prior to inclusion at diagnostic-grade. Maintaining Amber rating on this panel.Created: 21 Jan 2021, 1:02 p.m. | Last Modified: 21 Jan 2021, 1:02 p.m.
Panel Version: 1.170
Sun et al. 2020 (PMID: 32397791) report on 5 male fetuses from two unrelated families with a consistent cardiac phenotype including LVNC, VSD, and pulmonary stenosis/atresia. No significant extracardiac malformations were identified. Two different frameshift NONO variants were detected in each family.
NONO variants have also been reported in 7 other unrelated males with a syndromic neurodevelopmental disorder (MIM# 300967); however, prenatal course mostly unremarkable with the exception of IUGR in two cases (patient in PMID: 30773818, DDD patient in PMID: 26571461)Created: 21 Jan 2021, 1 p.m. | Last Modified: 21 Jan 2021, 1 p.m.
Panel Version: 1.169
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications
PMID: 32397791 describes cardiac anomalies of fetuses with X-linked recessive NONO variants, including left ventricular non-compaction cardiomyopathy and ventricular septal defect.Created: 16 Jul 2020, 12:04 p.m. | Last Modified: 16 Jul 2020, 12:04 p.m.
Panel Version: 1.74
Publications
I don't know
DDG2P rating in original PAGE list: Probable for SYNDROMIC INTELLECTUAL DISABILITYCreated: 11 Dec 2018, 9:05 a.m.
Tag watchlist tag was added to gene: NONO.
Publications for gene: NONO were set to 32397791
Phenotypes for gene: NONO were changed from SYNDROMIC INTELLECTUAL DISABILITY to Left ventricular non-compaction cardiomyopathy (LVNC); Ventricular septal defect (VSD); Pulmonary stenosis; Atresia; Ebstein’s anomaly
Gene: nono has been classified as Amber List (Moderate Evidence).
Publications for gene: NONO were set to
gene: NONO was added gene: NONO was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber Mode of inheritance for gene: NONO was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: NONO were set to SYNDROMIC INTELLECTUAL DISABILITY
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.