Intellectual disability - microarray and sequencing
Gene: FARS2 Green List (high evidence)Green List (high evidence)
Although the majority of cases present with either early onset seizures or mid-childhood spasticity, in association with developmental problems, a case is reported with GDD pre-dating the seizures. In view of the evidence for the gene:disease association and a potentially relevant phenotype to an ID cohort, include as green.Created: 19 Jul 2019, 12:10 p.m. | Last Modified: 19 Jul 2019, 12:10 p.m.
Panel Version: 0.205
Comment on list classification: Expert review by Konstantinos Varvagiannis on FARS2. PMID:30869852 (Almannai et al, 2019) is a review on FARS2 deficiency. DD/ID and seizures are observed in both infantile- and later-onset forms of the disorder. The phenotype of 26 individuals (from 19 families) and 11 individuals (from 6 families) with infantile and later-onset FARS2 deficiency is summarized in table 2 of PMID:30869852.
FARS2 is in OMIM and included in the DD panel of G2P, although phenotypes are more relevant to Epilepsy panels.
There are sufficient cases of ID/DD from unrelated families to warrant a Green rating.Created: 20 May 2019, 3:35 p.m.
Green List (high evidence)
PMID: 30869852 (Almannai et al, 2019) is a review on FARS2 deficiency.
DD/ID and seizures are observed in both infantile- and later-onset forms of the disorder (FARS2-related infantile-onset epileptic mitochondrial encephalopathy and FARS2-related later-onset spastic paraplegia respectively). The phenotype of 26 individuals (from 19 families) and 11 individuals (from 6 families) with infantile and later-onset FARS2 deficiency is summarized in table 2. As commented by the authors, pathogenic variants may include missense, nonsense, splice-site variants, small indels as well as larger deletions/duplications (table 1 and footnote).
The relevant OMIM entries are the following: Combined oxidative phosphorylation deficiency 14 (MIM 614946) and Spastic paraplegia 77, autosomal recessive (MIM 617046).
FARS2 is included in the DD panel of G2P, associated with Neurometabolic disorder due to FARS2 deficiency (disease confidence: confirmed).
This gene is included in gene panels for ID offered by some diagnostic laboratories.
As a result, FARS2 can be considered for inclusion in the ID panel as green (or amber)
Sources: LiteratureCreated: 16 Mar 2019, 7:48 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Combined oxidative phosphorylation deficiency 14, 614946; Spastic paraplegia 77, autosomal recessive, 617046
Publications
Variants in this GENE are reported as part of current diagnostic practice
Source Expert Review Green was added to FARS2. Source Expert Review was added to FARS2. Added phenotypes Spastic paraplegia 77, autosomal recessive, 617046; Combined oxidative phosphorylation deficiency 14, 614946 for gene: FARS2 Rating Changed from No List (delete) to Green List (high evidence)
gene: FARS2 was added gene: FARS2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FARS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FARS2 were set to 30869852 Phenotypes for gene: FARS2 were set to Combined oxidative phosphorylation deficiency 14, 614946; Spastic paraplegia 77, autosomal recessive, 617046 Penetrance for gene: FARS2 were set to Complete Review for gene: FARS2 was set to GREEN gene: FARS2 was marked as current diagnostic
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.