Intellectual disability - microarray and sequencing
Gene: SRRM2
Strong statistical enrichment particularly for severe consequence variants in the Kaplanis et al study and then a clinical cohort of 22 cases from Cuinat et al.
We have also described 6 cases from the 100K Genomes Project which helps further confirm this condition: see www.hindawi.com/journals/humu/2023/6633248/ [PMID is still awaited] We also showed that reference genome has a complex palindrome nearby where distal breakpoints for 3 complex de novo SVs map to within - so likely a hotspot for formation of complex rearrangements.Created: 3 May 2023, 7:01 p.m. | Last Modified: 3 May 2023, 7:01 p.m.
Panel Version: 5.98
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Intellectual disability
Publications
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Comment on publications: www.hindawi.com/journals/humu/2023/6633248Created: 13 Jun 2023, 10:19 a.m. | Last Modified: 13 Jun 2023, 10:19 a.m.
Panel Version: 5.186
Not associated with a phenotype in OMIM and as definitive Gen2Phen gene for SRRM2-related developmental disorder (monoallelic). At least 22 loss of function SRRM2 variants have been reported in PMID: 35567594 in unrelated cases of which 16/20 exhibit variable mild intellectual disability.Created: 24 May 2022, 2:33 p.m. | Last Modified: 24 May 2022, 2:33 p.m.
Panel Version: 3.1590
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.Created: 24 May 2022, 2:25 p.m. | Last Modified: 24 May 2022, 2:25 p.m.
Panel Version: 3.1590
Comment on phenotypes: SRRM2-related developmental disorder (monoallelic) is the phenotype listed by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4427) to have a definitive association with SRRM2 variants.Created: 24 May 2022, 2:02 p.m. | Last Modified: 24 May 2022, 2:03 p.m.
Panel Version: 3.1589
Recent report of 22 unrelated individuals with nonsense / frameshift variants or microdeletions of SRRM2. DD was a universal feature, with ID present in some affected individuals (16/20 - in all cases mild). Note possible 'overlap' with the study by Kaplanis et al / DDD study cited in the previous review by Prof. Z. Stark.
The gene is not intolerant to missense variation (z-score of -6.28) and eventual contribution of missense variants is not known. While SRRM2 is known to encode a splicing factor promoting interaction between mRNA and the spliceosome catalytic machinery (discussed below) molecular and functional studies are required to characterize the pathogenesis of the disorder.
There is currently no SRRM2-related phenotype in OMIM. SRRM2 is included in the DD panel of G2P [confidence : definitive, SRRM2-related developmental disorder (monoallelic), cited : Kaplanis et al / DDD]. In PanelApp Australia SRRM2 has amber rating in the ID panel (based on the study by Kaplanis et al / DDD).
Consider inclusion with green rating (several individuals/families/variants - rather consistent phenotype) or amber rating (as for pathogenesis / also DD universal feature, ID observed in most but not all affected individuals, when present always mild).
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Cuinat et al. (2022 - PMID: 35567594) report on 22 individuals with LoF variants in SRRM2.
All subjects had DD (22/22) predominantly affecting language acquisition (16/19) while motor delay was less common. ID was present in 16/20 (in all cases mild) of the individuals with available neurocognitive evaluation. Some individuals displayed autistic features (9/22) although others had a friendly - in some cases excessively - sociable personality (8/22). Other features included hypotonia in some, growth abnormalities (12/22 overweight, 7/22 with obesity, 4/22 tall stature). Morphological features incl. facial (20/22 - e.g. deep-set eyes, bulbous nasal tip or smooth philtrum) or small hands and feet (6/22) were also reported. Visceral / skeletal abnormalities were uncommon.
SRRM2 encodes serine/arginine repetitive matrix protein 2 (or SRm300), a nuclear ubiquitous protein forming a complex with the protein encoded by SRRM1 (SRm160). As the authors summarize this complex is one of the main catalytic components of the spliceosome having a role in pre-mRNA maturation.
12 subjects harbored frameshift variants, 8 nonsense while 2 further ones had microdeletions (66-270kb) spanning - but not limited to - SRRM2 (other genes not predicted to be haploinsufficient). The gene has a pLI in gnomAD of 1 (o/e = 0.06) while it appears to be tolerant to missense variation (z-score of -6.28 / o/e = 1.43). With the exception of the 2 subjects harboring a microdeletion, all were investigated with singleton/trio ES with no other candidate variants.
Variants occurred de novo in 19/22. Mosaicism (in an asymptomatic parent) was suspected based on the reads in one case. One individual had inherited the variant (parent with DD). Segregation analyses was not possible in one case.
While one variant lied in ex2 (of 15) all others were in the large ex11 (encoding ~2000 of the 2752 total residues based on the schema provided / NM_016333.4), all predicted to lead to NMD.
There are no studies for pathogenesis of the disorder or the underlying effect of variants. Animal models not discussed.
The authors do a comparison with other 'spliceosomopathies', e.g. due to variants in SF3B4 or EFTUD2, where DD/ID can be a feature although these disorders have also prominent skeletal features.
Previously, as the authors note, the study by Kaplanis et al (2020 - PMID: 33057194) integrating exome sequence data from ~31,000 parent-offspring trios of individuals with developmental disorders had identified SRRM2 among 28 genes significantly enriched in LoF variants. [ The present study possibly includes individuals from the aforementioned cohort, e.g. from Radboudumc ].Created: 23 May 2022, 8:57 a.m. | Last Modified: 23 May 2022, 8:58 a.m.
Panel Version: 3.1580
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of the head or neck; Small hand; Short foot
Publications
Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.Created: 4 Dec 2020, 3:10 p.m. | Last Modified: 4 Dec 2020, 3:10 p.m.
Panel Version: 3.595
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 28 de novo variants (11 frameshift, 7 missense, 1 splice acceptor, 5 stopgain, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: LiteratureCreated: 4 Nov 2020, 5:28 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Developmental disorders
Publications
Phenotypes for gene: SRRM2 were changed from SRRM2-related developmental disorder (monoallelic) to Intellectual developmental disorder, autosomal dominant 72, OMIM:620439
Tag gene-checked was removed from gene: SRRM2.
Publications for gene: SRRM2 were set to 35567594; 33057194
Tag gene-checked tag was added to gene: SRRM2.
Tag Q2_22_rating was removed from gene: SRRM2.
Source NHS GMS was added to SRRM2. Source Expert Review Green was added to SRRM2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q2_22_rating tag was added to gene: SRRM2.
Gene: srrm2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: SRRM2 were changed from Developmental disorders to SRRM2-related developmental disorder (monoallelic)
Publications for gene: SRRM2 were set to 33057194
Gene: srrm2 has been classified as Amber List (Moderate Evidence).
gene: SRRM2 was added gene: SRRM2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SRRM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SRRM2 were set to 33057194 Phenotypes for gene: SRRM2 were set to Developmental disorders Review for gene: SRRM2 was set to AMBER