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Intellectual disability

Gene: SMG9

Amber List (moderate evidence)

SMG9 (SMG9, nonsense mediated mRNA decay factor)
EnsemblGeneIds (GRCh38): ENSG00000105771
EnsemblGeneIds (GRCh37): ENSG00000105771
OMIM: 613176, Gene2Phenotype
SMG9 is in 5 panels

2 reviews

Konstantinos Varvagiannis (Other)

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

Catherine Snow (Genomics England)

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.



Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
  • Expert Review Amber
  • Literature
  • Expert Review Amber
  • Literature
  • Heart and brain malformation syndrome, 616920
Clinvar variants
Variants in SMG9
Panels with this gene

History Filter Activity

24 Oct 2019, Gel status: 2

Set publications

Catherine Snow (Genomics England)

Publications for gene: SMG9 were set to 27018474; 30914295

25 Jul 2019, Gel status: 2

Added Tag

Catherine Snow (Genomics England)

Tag watchlist tag was added to gene: SMG9.

25 Jul 2019, Gel status: 2

Set mode of inheritance

Catherine Snow (Genomics England)

Mode of inheritance for gene SMG9 was changed from to BIALLELIC, autosomal or pseudoautosomal

25 Jul 2019, Gel status: 2

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Catherine Snow (Genomics England)

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