Human Gene Module / Chromosome 17 / NR1D1

NR1D1nuclear receptor subfamily 1 group D member 1

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 3
Rare Variants / Common Variants
4 / 0
Aliases
NR1D1, EAR1,  THRA1,  THRAL,  ear-1,  hRev
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
17q21.1
Associated Disorders
-
Relevance to Autism

Screening of circadian-relevant genes in Japanese ASD patients with or without sleep disorders identified a missense variant in the NR1D1 gene (Yang et al., 2016). Additional screening of Caucasian ASD patients for NR1D1 variants identified several novel missense variants, including a de novo missense variant that failed to rescue defects in the positioning of cortical neurons in the embryonic mouse brain following RNAi-mediated knockdown of endogeneous Nr1d1 (Goto et al., 2017). However, NR1D1 variants identified in these two studies showed incomplete segregation with ASD. Nr1d1-knockout mice were shown to display hyperactivity, impaired response habituation in novel environments, deficiencies in contextual memories, and impaired nest-building activity, suggesting impaired hippocampal function (Jager et al., 2014).

Molecular Function

This gene encodes a transcription factor that is a member of the nuclear receptor subfamily 1. The encoded protein is a ligand-sensitive transcription factor that negatively regulates the expression of core clock proteins. In particular this protein represses the circadian clock transcription factor aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL). This protein may also be involved in regulating genes that function in metabolic, inflammatory and cardiovascular processes.

Reports related to NR1D1 (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Behavioral changes and dopaminergic dysregulation in mice lacking the nuclear receptor Rev-erb. Jager J , et al. (2014) No -
2 Primary Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients. Yang Z , et al. (2015) Yes -
3 Recent Recommendation Role of a circadian-relevant gene NR1D1 in brain development: possible involvement in the pathophysiology of autism spectrum disorders. Goto M , et al. (2017) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1499G>A p.Arg500His missense_variant De novo NA Multiplex 28262759 Goto M , et al. (2017)
c.58A>C p.Ser20Arg missense_variant Familial Paternal Simplex 25957987 Yang Z , et al. (2015)
c.1012C>T p.Pro338Ser missense_variant Familial Maternal Multiplex 28262759 Goto M , et al. (2017)
c.1031A>C p.Asn344Thr missense_variant Familial Maternal Multiplex 28262759 Goto M , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Screening of circadian-relevant genes in Japanese ASD patients with or without sleep disorders identified a missense variant in the NR1D1 gene (Yang et al., 2016). Additional screening of Caucasian ASD patients for NR1D1 variants identified several novel missense variants, including a de novo missense variant that failed to rescue defects in the positioning of cortical neurons in the embryonic mouse brain following RNAi-mediated knockdown of endogeneous Nr1d1 (Goto et al., 2017). However, NR1D1 variants identified in these two studies showed incomplete segregation with ASD. Nr1d1-knockout mice were shown to display hyperactivity, impaired response habituation in novel environments, deficiencies in contextual memories, and impaired nest-building activity, suggesting impaired hippocampal function (Jager et al., 2014).

Score Delta: Decreased from 4 to 3

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Screening of circadian-relevant genes in Japanese ASD patients with or without sleep disorders identified a missense variant in the NR1D1 gene (Yang et al., 2016). Additional screening of Caucasian ASD patients for NR1D1 variants identified several novel missense variants, including a de novo missense variant that failed to rescue defects in the positioning of cortical neurons in the embryonic mouse brain following RNAi-mediated knockdown of endogeneous Nr1d1 (Goto et al., 2017). However, NR1D1 variants identified in these two studies showed incomplete segregation with ASD. Nr1d1-knockout mice were shown to display hyperactivity, impaired response habituation in novel environments, deficiencies in contextual memories, and impaired nest-building activity, suggesting impaired hippocampal function (Jager et al., 2014).

Reports Added
[New Scoring Scheme]
4/1/2017
icon
4

Increased from to 4

Description

Screening of circadian-relevant genes in Japanese ASD patients with or without sleep disorders identified a missense variant in the NR1D1 gene (Yang et al., 2016). Additional screening of Caucasian ASD patients for NR1D1 variants identified several novel missense variants, including a de novo missense variant that failed to rescue defects in the positioning of cortical neurons in the embryonic mouse brain following RNAi-mediated knockdown of endogeneous Nr1d1 (Goto et al., 2017). However, NR1D1 variants identified in these two studies showed incomplete segregation with ASD. Nr1d1-knockout mice were shown to display hyperactivity, impaired response habituation in novel environments, deficiencies in contextual memories, and impaired nest-building activity, suggesting impaired hippocampal function (Jager et al., 2014).

Krishnan Probability Score

Score 0.51276314846167

Ranking 1801/25841 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.
ExAC Score

Score 0.9460854182801

Ranking 2755/18225 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
Sanders TADA Score

Score 0.93729120576235

Ranking 13476/18665 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).
Zhang D Score

Score -0.060009392658952

Ranking 10788/20870 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.
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