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Intellectual disability
Gene: SYNCRIP

SYNCRIP (synaptotagmin binding cytoplasmic RNA interacting protein)
EnsemblGeneIds (GRCh38): ENSG00000135316
EnsemblGeneIds (GRCh37): ENSG00000135316
OMIM: 616686, Gene2Phenotype
SYNCRIP is in 3 panels

6 reviews

Sarah Leigh (Genomics England Curator)

The 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

Created: 14 Mar 2022, 2:22 p.m.
Last Modified: 14 Mar 2022, 2:22 p.m.
Panel version: 3.1519

Arina Puzriakova (Genomics England Curator)

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

Created: 20 Sep 2021, 3:27 p.m.
Last Modified: 20 Sep 2021, 3:27 p.m.
Panel version: 3.1285

Konstantinos Varvagiannis (Other)

I don't know

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

Created: 26 Jul 2021, 11:18 p.m.
Last Modified: 26 Jul 2021, 11:18 p.m.
Panel version: 3.1201

Caroline Wright (Sanger)

Red List (low evidence)

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

Rebecca Foulger (Genomics England curator)

Red List (low evidence)

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

Created: 31 Oct 2017, 9:24 a.m.

Panel version: Imported from Intellectual disability update Oct 2017 panel version 0.4

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:39 a.m.

Panel version: 0.306

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review Green

Phenotypes

Global developmental delay
Intellectual disability
Autism
Myoclonic atonic seizures
Abnormality of nervous system morphology

Tags

gene-checked

OMIM

616686

Clinvar variants

Variants in SYNCRIP

Penetrance

Complete

Publications

Panels with this gene

History Filter Activity

8 May 2022, Gel status: 3

Added Tag

Eleanor Williams (Genomics England Curator)

Tag gene-checked tag was added to gene: SYNCRIP.

14 Mar 2022, Gel status: 3

Removed Tag

Ivone Leong (Genomics England Curator)

Tag Q3_21_rating was removed from gene: SYNCRIP.

14 Mar 2022, Gel status: 3

Added New Source, Status Update

Ivone Leong (Genomics England Curator)

Source Expert Review Green was added to SYNCRIP. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

20 Sep 2021, Gel status: 2