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Intellectual disability

Gene: SIN3B

Amber List (moderate evidence)

SIN3B (SIN3 transcription regulator family member B)
EnsemblGeneIds (GRCh38): ENSG00000127511
EnsemblGeneIds (GRCh37): ENSG00000127511
OMIM: 607777, Gene2Phenotype
SIN3B is in 1 panel

3 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: New gene added and reviewed by Zornitza Stark (Green) and Konstantinos Varvagiannis (Green/Amber). Overall there are sufficient unrelated cases (>3) of ID associated with SNVs in this gene to warrant a Green rating on this panel at the next GMS review. Deletions of the region containing SIN3B have also been linked to ID, lending further support to this gene-disease association.
Created: 11 Jun 2021, 12:07 p.m. | Last Modified: 11 Jun 2021, 12:07 p.m.
Panel Version: 3.1125

Konstantinos Varvagiannis (Other)

I don't know

Latypova et al (2021 - PMID: 33811806) describe the phenotype of 9 individuals with heterozygous deletions or SNVs disrupting SIN3B.

Among individuals referred for ID or ASD, the authors identified 5 subjects with overlapping 19q13.11 deletions of variable sizes (0.43 - 1.5 Mb) spanning SIN3B as well as additional genes. Given also a neurodevelopmental phenotype described in two previous reports by Aten et al (0.99 Mb dn deletion of 28 genes - PMID cited : 19353584) and Bens et al (1.12 Mb microdeletion - PMID cited : 21700002) the authors delineated a 230 kb region of overlap containing 4 genes.

Based on the pLI scores of these 4 genes (SIN3B pLI of 1 in gnomAD, pLI for the others was 0) the former was considered to be the most likely candidate for the observed phenotypes.

As a de novo frameshift SIN3B variant had previously been reported by Martinez et al (2017 - PMID: 27620904 / this corresponds to individual 6 in the present study) within a cohort of 92 individuals investigated for ID, the authors used data-sharing platforms to identify 3 further individuals with SIN3B SNVs.

Variants identified included : Individuals 1-5 de novo 427 kb - 1.52 Mb deletions (one had an additional 1.6 Mb de novo chr18 microdeletion), individuals 6,8 (de novo SNVs, fs and missense), 7 and 9 (fs and missense SNV with parental sample(s) unavailable, ind.9 had an additional CNOT1 VUS).

DD and ID where among the most frequent features (8/9 overall, one individual with microdeletion without ID but with ASD diagnosis - among SNVs 3/4 had mild ID - 1/4 moderate). Other features included behavioral abnormalities (6/9 overall, incl. ADHD or ASD the latter in 3/9 or 2/4 with SNV), MRI abnormalities (3/6 overall - 2 with deletions), cardiac defects (in 3, although all had deletions), cleft/bifid uvula (in 3, although all had deletions) and some non-specific facial features (broad nasal root, arched/full eyebrows, synophrys or epicanthus).

SIN3B as well as SIN3A - disruption of which causes Witteveen-Kolk syndrome with ID among the features - encode factors of the Sin3 complex. Sin3/HDAC complexes play a role in histone deacetylation and further to transcriptional repression.

Genome editing experiments in zebrafish demonstrated abnormal craniofacial patterning (ceratohyal angle - CH), shorter body length and depletion of commisural axons (as proxy for neuroanatomical/CC defects observed in few individuals). Morpholino (MO) knockdown of the gene reproduced the abnormal CH and body length. Coinjection of MO and wt mRNA was shown to rescue these phenotypes, which was not the case for 2 missense variants identified in the patient cohort.

In a previous study by Moravec et al (2017 - PMID cited : 28850761) zebrafish with truncating sin3b variants displayed locomotion defects, delayed ossification and shortened body length.

Embryonic development defects, increased mortality and growth retardation were reported for Sin3b-/- mouse mutants (David et al 2008 - PMID cited : 18332431).

Using isolated peripheral blood mononuclear cells from one individual with SIN3B microdeletion, another with SIN3A microdeletion and controls, the authors carried out CHIP-seq H3K27ac analysis, showing hyperacetylation in affected individuals. Gene ontology analysis revealed enrichment for genes in relevant pathways e.g. nucleosome assembly.

SIN3B is included in the SysID database among the current primary ID genes. There is currently no associated phenotype in OMIM or G2P.

Overall this gene can be considered for inclusion in the current panel with amber/green rating.
Created: 22 May 2021, 8:51 p.m. | Last Modified: 22 May 2021, 8:51 p.m.
Panel Version: 3.1092

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Behavioral abnormality

Publications

Zornitza Stark (Australian Genomics)

Green List (high evidence)

PMID: 33811806
- 9 affected individuals, variants all de novo (2 PTCs, 2 missense, multigenic CNVs)
- syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant ASD, congenital malformations, corpus callosum defects, and impaired growth.
Sources: Literature
Created: 10 May 2021, 10:17 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Syndromic intellectual disability

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • Syndromic intellectual disability
Tags
Q2_21_rating
OMIM
607777
Clinvar variants
Variants in SIN3B
Penetrance
None
Publications
Panels with this gene

History Filter Activity

11 Jun 2021, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_21_rating tag was added to gene: SIN3B.

11 Jun 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: sin3b has been classified as Amber List (Moderate Evidence).

10 May 2021, Gel status: 0

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

Zornitza Stark (Australian Genomics)

gene: SIN3B was added gene: SIN3B was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SIN3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SIN3B were set to 33811806 Phenotypes for gene: SIN3B were set to Syndromic intellectual disability Review for gene: SIN3B was set to GREEN gene: SIN3B was marked as current diagnostic