Intellectual disabilityGene: SIN3B Amber List (moderate evidence)
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
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
Global developmental delay; Intellectual disability; Behavioral abnormality
Green List (high evidence)
- 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.
Created: 10 May 2021, 10:17 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Syndromic intellectual disability
Variants in this GENE are reported as part of current diagnostic practice
Tag Q2_21_rating tag was added to gene: SIN3B.
Gene: sin3b has been classified as Amber List (Moderate Evidence).
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
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.