Human Gene Module / Chromosome 15 / BBS4

BBS4Bardet-Biedl syndrome 4

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
8 / 0
Aliases
-
Associated Syndromes
Bardet-Biedl syndrome 4, Tourette syndrome
Chromosome Band
15q24.1
Associated Disorders
ID, EPS
Relevance to Autism

Inherited exon-disruptive deletions in the BBS4 gene was identified in two unrelated ASD cases (Girirajan et al., 2013).

Molecular Function

This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse. The similar phenotypes exhibited by mutations in BBS gene family members are likely due to the protein's shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene has sequence similarity to O-linked N-acetylglucosamine (O-GlcNAc) transferases in plants and archaebacteria and in human forms a multi-protein "BBSome" complex with seven other BBS proteins.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to BBS4 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder Girirajan S , et al. (2013) Yes -
2 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No ID, epilepsy/seizures, microcephaly
3 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder Willsey AJ , et al. (2017) No -
4 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes Macrocephaly
6 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Paternal Multiplex 23375656 Girirajan S , et al. (2013)
c.623T>A p.Leu208Ter stop_gained Familial Paternal Simplex 31674007 Wu H , et al. (2019)
c.154A>G p.Lys52Glu missense_variant De novo - Simplex 28472652 Willsey AJ , et al. (2017)
c.157-2A>G - splice_site_variant Familial Both parents - 27848944 Trujillano D , et al. (2016)
c.-190+2dup - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.670_671del p.Gln224GlyfsTer13 frameshift_variant Familial Maternal Simplex 31674007 Wu H , et al. (2019)
c.1548_1549del p.Ile516MetfsTer8 frameshift_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Inherited exon-disruptive deletions in the BBS4 gene was identified in two unrelated ASD cases but not in 580 controls (Girirajan et al., 2013). Homozygous mutations in the BBS4 gene are responsible for a form of Bardet-Biedl syndrome (Bardet-Biedl syndrome-4; OMIM 615982), a multisystem disorder in which some affected individuals present with developmental delay/intellectual disability.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Inherited exon-disruptive deletions in the BBS4 gene was identified in two unrelated ASD cases but not in 580 controls (Girirajan et al., 2013). Homozygous mutations in the BBS4 gene are responsible for a form of Bardet-Biedl syndrome (Bardet-Biedl syndrome-4; OMIM 615982), a multisystem disorder in which some affected individuals present with developmental delay/intellectual disability.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Inherited exon-disruptive deletions in the BBS4 gene was identified in two unrelated ASD cases but not in 580 controls (Girirajan et al., 2013). Homozygous mutations in the BBS4 gene are responsible for a form of Bardet-Biedl syndrome (Bardet-Biedl syndrome-4; OMIM 615982), a multisystem disorder in which some affected individuals present with developmental delay/intellectual disability.

Reports Added
[Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.2019] [New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Inherited exon-disruptive deletions in the BBS4 gene was identified in two unrelated ASD cases but not in 580 controls (Girirajan et al., 2013). Homozygous mutations in the BBS4 gene are responsible for a form of Bardet-Biedl syndrome (Bardet-Biedl syndrome-4; OMIM 615982), a multisystem disorder in which some affected individuals present with developmental delay/intellectual disability.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2018
icon
4

Increased from to 4

Description

Inherited exon-disruptive deletions in the BBS4 gene was identified in two unrelated ASD cases but not in 580 controls (Girirajan et al., 2013). Homozygous mutations in the BBS4 gene are responsible for a form of Bardet-Biedl syndrome (Bardet-Biedl syndrome-4; OMIM 615982), a multisystem disorder in which some affected individuals present with developmental delay/intellectual disability.

Krishnan Probability Score

Score 0.45127671897281

Ranking 10693/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.0001410173680722

Ranking 12905/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.9443678630762

Ranking 16048/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.31688425667051

Ranking 2489/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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