Mendeliome
Gene: NDUFS4 Green List (high evidence)Green List (high evidence)
Multiple families reported, generally associated with a fulminant course.
PMID 11181577: report one patient with homozygous variant and supportive patient-derived fibroblast functional studies.
Proband presented with tonic-clonic seizures, vomiting and FTT age 2 weeks. Other features -hyperechoic basal ganglia signals, hypertrophic cardiomyopathy, lactic acidosis and hypotonia. Death age 7 months.
PMID 11165261: Homozygous 5bp dup NDUFS4 gene. Hospitalized at the age of 8 months with a Leigh-like neurological syndrome and died at the age of 16 months from cardiorespiratory failure.
PMID 10944442: Report 2 unrelated patients. P1 - FTT, dev delay, progressive microcephaly, respiratory insufficiency. P2 - hypospadias, hypotonia, hepatosplenomegaly, MRI-B: hyperintense signals in T2 weighted images in the basal ganglia pedunculi cerebri and the pariaquaductal region. Cardiac left ventricular hypertrophy.
PMID 24295889: Report a patient with homozygous deletion on 5q11.2 involving NDUFS4. Presented shortly after birth psychomotor retardation, poor coordination of ocular movements, recurrent vomiting, feeding problems and severe lactic acidosis became apparent.
PMID 14765537: report one additional unrelated patients with similar features to previously described cases.
PMID 22326555: report 5 new unrelated patients. Reviewed characteristics of 13 patients from 10 families. Shared features included early onset of symptoms and hypotonia in all patients, vision impairment, failure to thrive, feeding problems (7/7) and pyramidal syndrome. Frequent signs included apnoeic episodes, bradypnea or cyanosis (10/12, 83%), psychomotor retardation or regression (9/12, 75%), abnormal EEG (6/9, 67%) with epilepsy or seizures (4/7, 57%), depressed tendon reflexes (3/5, 60%), hepatomegaly (4/7, 57%), post-natal growth retardation (6/12, 50%) and hypertrophic cardiomyopathy
(5/11, 45%). Intra-uterine growth retardation (IUGR) was occasionally observed (6/14, 43%) with birth of 4 premature babies. Vomiting was occasionally observed (2/7, 29%). [one family with 2/3 with IUGR in the context of triplet conception, limited phenotypic information provided about the 5 unrelated patients, describe shared North African haplotype]
PMID 19107570: 3 affected siblings with Leigh Syndrome phenotype.
PMID 27079373: Summarise 22 patients from 18 families with symptom onset between 5 days and 4 months of life, with poor prognosis. Most frequent symptoms were hypotonia, abnormal ocular movements and visual impairment (nystagmus, strabismus, ophthalmoplegia, ptosis, absence of visual fixating), psychomotor arrest or regression and episodes of respiratory failure, abnormal MRI-B with involvement of the brainstem, basal ganglia, and less frequently, the cerebral cortex.Created: 21 Mar 2022, 5:23 a.m. | Last Modified: 21 Mar 2022, 5:23 a.m.
Panel Version: 0.11665
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Mitochondrial complex I deficiency, nuclear type 1 - MIM#252010
Publications
Gene: ndufs4 has been classified as Green List (High Evidence).
Phenotypes for gene: NDUFS4 were changed from to Mitochondrial complex I deficiency, nuclear type 1 - MIM#252010
Publications for gene: NDUFS4 were set to
Mode of inheritance for gene: NDUFS4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
gene: NDUFS4 was added gene: NDUFS4 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: NDUFS4 was set to Unknown
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.