Intellectual disabilityGene: SMG9 Amber List (moderate evidence)
Green List (high evidence)
Biallelic pathogenic SMG9 variants cause Heart and brain malformation syndrome (MIM 616920). In total 4 individuals from 3 unrelated families have been identified:
- PMID: 27018474 (Shaheen et al. - 2016) : 3 individuals from 2 consanguineous Arab families
- PMID: 31390136 (Lecoquierre et al. - 2019) : 1 individual born to consanguineous parents
The phenotype consisted of profound GDD (3/3 - from 2 families - 1 individual from a 3rd family died at the age of few weeks following sepsis), failure to thrive and microcephaly (3/3), brain MRI abnormalities (4/4) including Dandy-Walker malformation, VSD (4/4) with additional cardiovascular anomalies in some cases, variable ophthalmologic findings and dysmorphic facial features.
SMG9 encodes a protein - component of the SURF complex - which plays a critical role in nonsense-mediated mRNA decay.
All affected subjects were homozygous for truncating variants, private to each family (NM_019108.3) : c.520_521delCC (p.Pro174Argfs*12 - Shaheen Fam1), c.701+4A>G (Shaheen Fam2), c.1177C>T (p.Gln393* - Lecoquierre).
In silico predictions for c.701+4A>G suggested (small?) reduction of the score for the consensus donor site but RT-PCR in lymphoblasts from the patient revealed presence of only one transcript with complete skipping of exon 6, predicting premature truncation (p.Tyr197Aspfs*10). (Very low abundance of this abnormal transcript was also observed in controls). SMG9 transcript levels were significantly reduced compared to controls (50% upon qRT-PCR), with absence of the truncated protein upon Western Blot suggesting that both NMD and reduced protein stability apply.
Transcriptional profile of this subject did not show significant differences compared to profiles of control individuals as for transcripts containing premature termination codons, failing to prove defect of the NMD.
Global transciptional dysregulation was however observed.
Smg9 knockout mice generated via CRISPR/Cas9 mutagenesis, have reduced viability. Embryos were smaller and presented major brain, eye and cardiovascular malformations (similar to the human phenotype).
In G2P, SMG9 is associated with 'SMG9 Multiple Congenital Anomaly Syndrome' (disease confidence: probable). In SysID it is listed among the Current primary ID genes.
SMG9 is included in gene panels for ID offered by some diagnostic laboratories (eg. Radboudumc / GeneDx).
Overall, amber (details on 2 families, underlying disease mechanism not clear) or possibly green rating (consistent phenotype, Dandy-Walker with additional brain MRI abnormalities and seizures also in the deceased individual, biallelic LoF variants, mouse model, global transcriptional dysregulation) can be considered.
Created: 29 Sep 2019, 4:43 p.m. | Last Modified: 29 Sep 2019, 4:43 p.m.
Panel Version: 2.1047
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Variants in this GENE are reported as part of current diagnostic practice
Maintaining Amber rating as although another individual with a variant has been identified in PMID: 31390136 there are still only full details of serve developmental delays for 2 unrelated families due to the young age of death of one reported individual in 27018474
Created: 24 Oct 2019, 3:53 p.m. | Last Modified: 24 Oct 2019, 3:53 p.m.
Panel Version: 2.1083
Comment on list classification: Gene identified in literature PMID:30914295 as missing in PanelApp compared to other curated gene list for ID genes.
Only one publication (PMID: 27018474) to date reporting biallelic variants in three individuals from two families in SMG9 as causative of a Multiple Congenital Anomaly Syndrome. Global Development Delay was reported in one family, however in the other family the individual died at 7 weeks, therefore impossible to classify either a DD/ID phenotype.
As insufficient cases and evidence SMG9 will be classified as Amber and added to the watchlist.
Created: 29 May 2019, 4:08 p.m.
Publications for gene: SMG9 were set to 27018474; 30914295
Tag watchlist tag was added to gene: SMG9.
Mode of inheritance for gene SMG9 was changed from to BIALLELIC, autosomal or pseudoautosomal
gene: SMG9 was added gene: SMG9 was added to Intellectual disability. Sources: Literature,Expert Review Amber Mode of inheritance for gene: SMG9 was set to Publications for gene: SMG9 were set to 27018474; 30914295 Phenotypes for gene: SMG9 were set to Heart and brain malformation syndrome, 616920
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).
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).
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.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
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.