Intellectual disability - microarray and sequencing
Gene: SYNCRIPThe rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 14 Mar 2022, 2:22 p.m. | Last Modified: 14 Mar 2022, 2:22 p.m.
Panel Version: 3.1519
Comment on list classification: Upgraded from Red to Amber but there are sufficient unrelated cases to rate as Green at the next GMS review. All individuals reported to date have presented with ID of various severity as the predominant feature.Created: 20 Sep 2021, 3:27 p.m. | Last Modified: 20 Sep 2021, 3:27 p.m.
Panel Version: 3.1285
Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.
Features included DD, ID (7/7 for whom this information was available), ASD or autistic features (4/7). MRI abnormalities were observed in 3 (widening of CSF spaces, periventricular nodular heterotopia, prominent lat. ventricles). Epilepsy (myoclonic-astatic epilepsy / Doose syndrome) was reported for 2(/8) individuals.
The 3 patients here reported were identified following trio/singleton exome with Sanger confirmation of the variants and their de novo occurrence.
Variants are in almost all cases de novo (7/7 for whom this was known) and in 5/8 cases were pLoF, in 2/8 missense SNVs while a case from DECIPHER had a 77.92 kb whole gene deletion not involving other genes with unknown inheritance.
Overall the variants reported to date include [NM_006372.5]:
1 - c.858_859del p.(Gly287Leufs*5)
2 - c.854dupA p.(Asn285Lysfs*8)
3 - c.734T>C p.(Leu245Pro)
4 - chr6:85605276-85683190 deletion (GRCh38)
5 - c.629T>C p.(Phe210Ser)
6 - c.1573_1574delinsTT p.(Gln525Leu)
7 - c.1247_1250del p.(Arg416Lysfs*145)
8 - c.1518_1519insC p.(Ala507Argfs*14)
[P1-3: this report, P4: DECIPHER 254774, P5-6: Guo et al 2019 - PMID: 30504930, P7: Lelieveld et al 2016 - PMID: 27479843, P8: Rauch et al 2012 - PMID: 23020937 / all other Refs not here reviewed, clinical details summarized by Semino et al in table 1]
SYNCRIP (also known as HNRNPQ) encodes synaptotagmin‐binding cytoplasmic RNA‐interacting protein. As the authors note, this RNA-binding protein is involved in multiple pathways associated with neuronal/muscular developmental disorders. Several references are provided for its involvement in regulation of RNA metabolism, among others sequence recognition, pre-mRNA splicing, translation, transport and degradation.
Mutations in other RNA-interacting proteins and hnRNP members (e.g. HNRNPU, HNRNPD) are associated with NDD.
The missense variant (p.Leu245Pro) is within RRM2 one of the 3 RNA recognition motif (RRM) domains of the protein. These 3 domains, corresponding to the central part of the protein (aa 150-400), are relatively intolerant to variation (based on in silico predictions and/or variation in gnomAD). Leu245 localizes within an RNA binding pocket and in silico modeling suggests alteration of the tertiary structure and RNA-binding capacity of RRM2.
There are no additional studies performed.
Overall haploinsufficiency appears to be the underlying disease mechanism based on the truncating variants and the gene deletion. [pLI in gnomAD : 1, %HI : 2.48%]
Animal models are not discussed.
There is no associated phenotype in OMIM or PanelApp AUS.
This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes.Created: 26 Jul 2021, 11:18 p.m. | Last Modified: 26 Jul 2021, 11:18 p.m.
Panel Version: 3.1201
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Publications
Currently insufficient evidence to include in ID panel. Evidence comes from PMID:27479843 (2016) who perform statistical enrichment analysis on 2,637 de novo mutations identified from the exomes of 2,104 patient-parent trios, and identify SYNCRIP as a candidate ID gene.Created: 31 Oct 2017, 9:24 a.m.
Publications
Tag gene-checked tag was added to gene: SYNCRIP.
Tag Q3_21_rating was removed from gene: SYNCRIP.
Source Expert Review Green was added to SYNCRIP. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Phenotypes for gene: SYNCRIP were changed from to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Publications for gene: SYNCRIP were set to 27479843; 26350204
Tag watchlist was removed from gene: SYNCRIP. Tag Q3_21_rating tag was added to gene: SYNCRIP.
Gene: syncrip has been classified as Amber List (Moderate Evidence).
Mode of inheritance for gene: SYNCRIP was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Publications for gene SYNCRIP was set to ['27479843', ' 26350204']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
SYNCRIP was added to Intellectual disabilitypanel. Sources: Expert Review Red
SYNCRIP was created by ellenmcdonagh