Human Gene Module / Chromosome 5 / NIPBL

NIPBLNipped-B homolog (Drosophila)

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
7 / 20
Rare Variants / Common Variants
26 / 0
EAGLE Score
15.3
Strong Learn More
Aliases
NIPBL, CDLS,  CDLS1,  DKFZp434L1319,  FLJ11203,  FLJ12597,  FLJ13354,  FLJ13648,  FLJ44854,  IDN3,  IDN3-B,  Scc2
Associated Syndromes
Cornelia de Lange syndrome, Tourette syndrome, Cornelia de Lange syndrome 1, DD
Chromosome Band
5p13.2
Associated Disorders
DD/NDD, ID, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the NIPBL gene have been identified with Cornelia de Lange syndrome (Krantz et al., 2004).

Molecular Function

This gene encodes the homolog of the Drosophila melanogaster Nipped-B gene product and fungal Scc2-type sister chromatid cohesion proteins. It is also homologous to a family of chromosomal adherins with broad roles in sister chromatid cohesion, chromosome condensation, and DNA repair. The human protein has a bipartite nuclear targeting sequence and a putative HEAT repeat. Mutations in this gene result in Cornelia de Lange syndrome, a disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and mental retardation. Two transcript variants encoding different isoforms have been found for this gene.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NIPBL (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B Krantz ID , et al. (2004) No ASD
2 Support Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with autism spectrum disorder Koshimizu E , et al. (2013) Yes ID, epilepsy
3 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
4 Recent Recommendation Drosophila Nipped-B Mutants Model Cornelia de Lange Syndrome in Growth and Behavior Wu Y , et al. (2015) No -
5 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing Martnez F , et al. (2016) No ID
6 Recent Recommendation Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration van den Berg DL , et al. (2017) No -
7 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder Willsey AJ , et al. (2017) No -
8 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
9 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
10 Recent Recommendation Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement Kline AD , et al. (2018) No -
11 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders Jiao Q , et al. (2019) No -
12 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes Cornelia de Lange syndrome, DD, ID
13 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
14 Support - Mahjani B et al. (2021) Yes -
15 Support - Álvarez-Mora MI et al. (2022) No -
16 Support - Verberne EA et al. (2022) No -
17 Support - Chuan Z et al. (2022) No -
18 Support - Riquin K et al. (2023) No Stereotypy
19 Support - Erica Rosina et al. (2024) No -
20 Support - Karen Lob et al. () Yes DD
Rare Variants   (26)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - frameshift_variant De novo - Simplex 37495270 Riquin K et al. (2023)
c.230+2dup - splice_site_variant De novo - - 39136901 Karen Lob et al. ()
c.6892C>A p.Arg2298Ser missense_variant De novo - - 30945278 Jiao Q , et al. (2019)
c.5778_5808+2dup - inframe_insertion Unknown - - 35253369 Verberne EA et al. (2022)
G>T p.? splice_site_variant Familial - Multiplex 15146186 Krantz ID , et al. (2004)
c.8270G>A p.Arg2757His missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.923G>A p.Arg308Gln missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.8182G>A p.Val2728Met missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.8378G>A p.Arg2793Gln missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.5329-15A>G - intron_variant De novo - Simplex 35183220 Álvarez-Mora MI et al. (2022)
c.5689_5691del p.Asn1897del inframe_deletion De novo - - 27620904 Martnez F , et al. (2016)
c.7816dup p.Ile2606AsnfsTer26 frameshift_variant De novo - - 35571021 Chuan Z et al. (2022)
c.7515A>C p.Lys2505Asn missense_variant De novo - Multiplex 28714951 Lim ET , et al. (2017)
c.150del p.Asn51ThrfsTer27 frameshift_variant De novo - - 15146186 Krantz ID , et al. (2004)
c.3024_3028del p.Ser1009GlyfsTer2 frameshift_variant - - - 15146186 Krantz ID , et al. (2004)
c.1547dup p.Ala517CysfsTer5 frameshift_variant De novo - - 15146186 Krantz ID , et al. (2004)
c.2520del p.Arg841GlufsTer6 frameshift_variant De novo - - 15146186 Krantz ID , et al. (2004)
c.7957C>G p.Leu2653Val missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.5506G>A p.Gly1836Ser missense_variant De novo - Simplex 28472652 Willsey AJ , et al. (2017)
c.8242T>C p.Trp2748Arg missense_variant De novo - Simplex 28472652 Willsey AJ , et al. (2017)
c.1553C>T p.Thr518Ile missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.2T>A p.Met1? initiator_codon_variant Familial - Multiplex 15146186 Krantz ID , et al. (2004)
c.7790T>C p.Leu2597Pro missense_variant De novo - Simplex 38041506 Erica Rosina et al. (2024)
c.7637T>C p.Leu2546Pro missense_variant De novo - Simplex 31038196 Callaghan DB , et al. (2019)
c.385T>C p.Ser129Pro missense_variant De novo - Simplex 35183220 Álvarez-Mora MI et al. (2022)
c.4841G>C p.Gly1614Ala missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Mutations in NIPBL cause Cornelia de Lange syndrome (PMID 15146186), characterized by growth failure, intellectual disability, upper limb abnormalities, hirsutism, craniofacial features and often autistic and self-destructive behaviors. Investigation of NIPBL variants in non-syndromic autism has not been carried out to date. A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with NIPBL mutations presented with autism spectrum disorder.

Reports Added
[New Scoring Scheme]
7/1/2019
S
icon
S

Increased from S to S

Description

Mutations in NIPBL cause Cornelia de Lange syndrome (PMID 15146186), characterized by growth failure, intellectual disability, upper limb abnormalities, hirsutism, craniofacial features and often autistic and self-destructive behaviors. Investigation of NIPBL variants in non-syndromic autism has not been carried out to date. A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with NIPBL mutations presented with autism spectrum disorder.

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

Increased from S to S

Description

Mutations in NIPBL cause Cornelia de Lange syndrome (PMID 15146186), characterized by growth failure, intellectual disability, upper limb abnormalities, hirsutism, craniofacial features and often autistic and self-destructive behaviors. Investigation of NIPBL variants in non-syndromic autism has not been carried out to date. A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with NIPBL mutations presented with autism spectrum disorder.

Reports Added
[The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.2019] [Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
7/1/2018
S
icon
S

Increased from S to S

Description

Mutations in NIPBL cause Cornelia de Lange syndrome (PMID 15146186), characterized by growth failure, intellectual disability, upper limb abnormalities, hirsutism, craniofacial features and often autistic and self-destructive behaviors. Investigation of NIPBL variants in non-syndromic autism has not been carried out to date. A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with NIPBL mutations presented with autism spectrum disorder.

Reports Added
[Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.2018]
10/1/2017
S
icon
S

Increased from S to S

Description

Mutations in NIPBL cause Cornelia de Lange syndrome (PMID 15146186), characterized by growth failure, intellectual disability, upper limb abnormalities, hirsutism, craniofacial features and often autistic and self-destructive behaviors. Investigation of NIPBL variants in non-syndromic autism has not been carried out to date.

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
7/1/2017
S
icon
S

Increased from S to S

Description

Mutations in NIPBL cause Cornelia de Lange syndrome (PMID 15146186), characterized by growth failure, intellectual disability, upper limb abnormalities, hirsutism, craniofacial features and often autistic and self-destructive behaviors. Investigation of NIPBL variants in non-syndromic autism has not been carried out to date.

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
4/1/2017
S
icon
S

Increased from S to S

Description

Mutations in NIPBL cause Cornelia de Lange syndrome (PMID 15146186), characterized by growth failure, intellectual disability, upper limb abnormalities, hirsutism, craniofacial features and often autistic and self-destructive behaviors. Investigation of NIPBL variants in non-syndromic autism has not been carried out to date.

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B.2004] [Drosophila Nipped-B Mutants Model Cornelia de Lange Syndrome in Growth and Behavior.2015] [High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration.2017] [De Novo Coding Variants Are Strongly Associated with Tourette Disorder.2017]
1/1/2017
S
icon
S

Increased from S to S

Description

Mutations in NIPBL cause Cornelia de Lange syndrome (PMID 15146186), characterized by growth failure, intellectual disability, upper limb abnormalities, hirsutism, craniofacial features and often autistic and self-destructive behaviors. Investigation of NIPBL variants in non-syndromic autism has not been carried out to date.

Reports Added
[Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration.2017]
10/1/2016
S
icon
S

Increased from S to S

Description

Mutations in NIPBL cause Cornelia de Lange syndrome (PMID 15146186), characterized by growth failure, intellectual disability, upper limb abnormalities, hirsutism, craniofacial features and often autistic and self-destructive behaviors. Investigation of NIPBL variants in non-syndromic autism has not been carried out to date.

Reports Added
[High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016]
1/1/2016
S
icon
S

Increased from S to S

Description

Mutations in NIPBL cause Cornelia de Lange syndrome (PMID 15146186), characterized by growth failure, intellectual disability, upper limb abnormalities, hirsutism, craniofacial features and often autistic and self-destructive behaviors. Investigation of NIPBL variants in non-syndromic autism has not been carried out to date.

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B.2004] [Drosophila Nipped-B Mutants Model Cornelia de Lange Syndrome in Growth and Behavior.2015]
1/1/2015
S
icon
S

Increased from S to S

Description

Mutations in NIPBL cause Cornelia de Lange syndrome (PMID 15146186), characterized by growth failure, intellectual disability, upper limb abnormalities, hirsutism, craniofacial features and often autistic and self-destructive behaviors. Investigation of NIPBL variants in non-syndromic autism has not been carried out to date.

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
Krishnan Probability Score

Score 0.58253878358053

Ranking 561/25841 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 1

Ranking 5/18225 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 0.94895207384475

Ranking 17893/18665 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 0.45619257259595

Ranking 861/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
PRSS23 protease, serine, 23 Human Protein Binding 11098 O95084
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