Human Gene Module / Chromosome 11 / DHCR7

DHCR77-dehydrocholesterol reductase

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
5 / 21
Rare Variants / Common Variants
34 / 0
Aliases
DHCR7, SLOS,  delta-7-dehydrocholesterol reductase, delta7-sterol reductase
Associated Syndromes
Smith-Lemli-Opitz syndrome
Chromosome Band
11q13.4
Associated Disorders
ASD
Relevance to Autism

This gene has been associated with syndromic autism, where a subpopulation of individuals with Smith-Lemli-Opitz syndrome (SLOS) develop autism (Tierney et al., 2001).

Molecular Function

This gene encodes an enzyme that removes the C(7-8) double bond in the B ring of sterols and catalyzes the conversion of 7-dehydrocholesterol to cholesterol.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DHCR7 (21 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome Tierney E , et al. (2001) No ASD
2 Support Abnormal serotonergic development in a mouse model for the Smith-Lemli-Opitz syndrome: implications for autism Waage-Baudet H , et al. (2003) No -
3 Recent Recommendation Negative regulation of Hedgehog signaling by the cholesterogenic enzyme 7-dehydrocholesterol reductase Koide T , et al. (2006) No -
4 Highly Cited The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome Sikora DM , et al. (2006) No ASD
5 Recent Recommendation Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith-Lemli-Opitz syndrome mouse Solc C , et al. (2007) No -
6 Recent Recommendation Social approach in genetically engineered mouse lines relevant to autism Moy SS , et al. (2008) No -
7 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
8 Support Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease Karaca E , et al. (2015) No Microcephaly
9 Recent Recommendation Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/?-catenin defects in neuronal cholesterol synthesis phenotypes Francis KR , et al. (2016) No -
10 Recent Recommendation Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update Thurm A , et al. (2016) No -
11 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
12 Support Expanding the genetic heterogeneity of intellectual disability Anazi S , et al. (2017) No -
13 Support Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications Kalsner L , et al. (2017) Yes -
14 Support Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders Gao C , et al. (2019) No -
15 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes Macrocephaly
16 Support - Alonso-Gonzalez A et al. (2021) Yes -
17 Support - Zhou X et al. (2022) Yes -
18 Support - Tamam Khalaf et al. (2024) No -
19 Support - Shuya Miyazaki et al. (2024) No -
20 Highly Cited Molecular cloning and expression of the human delta7-sterol reductase Moebius FF , et al. (1998) No -
21 Highly Cited Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome Fitzky BU , et al. (1998) No -
Rare Variants   (34)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.627-642del - frameshift_variant Unknown - - 9653161 Fitzky BU , et al. (1998)
IVS8-1G>C p.? splice_site_variant Unknown - - 9653161 Fitzky BU , et al. (1998)
c.964-1G>C - splice_site_variant Unknown - - 29271092 Kalsner L , et al. (2017)
c.82C>T p.Gln28Ter stop_gained Familial - Simplex 28831199 Li J , et al. (2017)
c.278C>T p.Thr93Met missense_variant Familial - - 31178897 Gao C , et al. (2019)
c.278C>T p.Thr93Met missense_variant Unknown - - 9653161 Fitzky BU , et al. (1998)
c.296T>C p.Leu99Pro missense_variant Unknown - - 9653161 Fitzky BU , et al. (1998)
c.907G>A p.Gly303Arg missense_variant Familial - - 31178897 Gao C , et al. (2019)
c.976G>T p.Val326Leu missense_variant Unknown - - 9653161 Fitzky BU , et al. (1998)
c.1054C>T p.Arg352Trp missense_variant Unknown - - 9653161 Fitzky BU , et al. (1998)
c.1228G>A p.Gly410Ser missense_variant Unknown - - 9653161 Fitzky BU , et al. (1998)
c.452G>A p.Trp151Ter stop_gained Familial Paternal - 9653161 Fitzky BU , et al. (1998)
c.452G>A p.Trp151Ter stop_gained Unknown - Multiplex 9653161 Fitzky BU , et al. (1998)
c.16C>T p.Gln6Ter stop_gained Familial Maternal Simplex 31674007 Wu H , et al. (2019)
c.940C>A p.Leu314Met missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1168C>T p.His390Tyr missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.470T>C p.Leu157Pro missense_variant Familial Maternal - 9653161 Fitzky BU , et al. (1998)
c.976G>T p.Val326Leu missense_variant Familial Paternal - 9653161 Fitzky BU , et al. (1998)
c.1054C>T p.Arg352Trp missense_variant Familial Maternal - 9653161 Fitzky BU , et al. (1998)
c.1130G>C p.Cys380Ser missense_variant Unknown - Multiplex 9653161 Fitzky BU , et al. (1998)
c.1203C>T p.Gly401%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.452G>A p.Trp151Ter stop_gained Familial Maternal Simplex 9653161 Fitzky BU , et al. (1998)
IVS8-1G>C p.? splice_site_variant Familial Maternal Simplex 9653161 Fitzky BU , et al. (1998)
c.740C>T p.Ala247Val missense_variant Familial Maternal Simplex 9653161 Fitzky BU , et al. (1998)
c.976G>T p.Val326Leu missense_variant Familial Paternal Simplex 9653161 Fitzky BU , et al. (1998)
c.1210C>T p.Arg404Cys missense_variant Familial Paternal Simplex 9653161 Fitzky BU , et al. (1998)
c.1370G>A p.Arg457Gln missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.151C>T p.Pro51Ser missense_variant Unknown Not maternal Simplex 9653161 Fitzky BU , et al. (1998)
c.1328G>A p.Arg443His missense_variant Familial Both parents - 38438125 Tamam Khalaf et al. (2024)
c.976G>T p.Val326Leu missense_variant Unknown Not maternal Simplex 9653161 Fitzky BU , et al. (1998)
c.778C>T p.Arg260Trp missense_variant Familial Both parents Simplex 28940097 Anazi S , et al. (2017)
c.278C>T p.Thr93Met missense_variant Familial Both parents Multiplex 26539891 Karaca E , et al. (2015)
c.214-1G>C p.? splice_site_variant Familial Maternal Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.269A>G p.His90Arg missense_variant Familial Paternal 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."

1/1/2021
1
icon
1

Score remained at 1

Description

Mutations in DHCR7 are responsible for Smith-Lemli-Optiz syndrome (SLOS). Evaluation of the behavioral phenotype in 56 subjects with SLOS in Tierney et al., 2001 concluded that individuals with SLOS manifested a behavioral profile of cognitive delay, sensory hyperreactivity, irritability, language impairment, sleep-cycle disturbance, self-injurious behavior, syndrome-specific motor movements, and autistic behaviors, with nine of 17 subjects (53%) meeting the diagnostic criteria for autistic disorder using ADI-R. Using 3 different diagnostic measures of autism to evaluate 14 children with SLOS ranging from 3 to 16 years, Sikora et al., 2006 found that three-fourths of the children with SLOS (71-86% depending on the evaluation method) had ASD. A recent assessment of 33 individuals with Smith-Lemli-Optiz syndrome aged 4 to 23 years using ADOS and ADI-R resulted in 18 individuals (55%) being assigned a diagnosis of ASD (Thurm et al., 2016). A mouse model of Smith-Lemli-Optiz syndrome (Dhcr7 -/- mice) displayed commissural deficiencies, hippocampal abnormalities, and hypermorphic development of serotonin (5-HT) neurons (Waage-Baudet et al., 2003). However, there is no evidence linking this gene to idiopathic autism.

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Mutations in DHCR7 are responsible for Smith-Lemli-Optiz syndrome (SLOS). Evaluation of the behavioral phenotype in 56 subjects with SLOS in Tierney et al., 2001 concluded that individuals with SLOS manifested a behavioral profile of cognitive delay, sensory hyperreactivity, irritability, language impairment, sleep-cycle disturbance, self-injurious behavior, syndrome-specific motor movements, and autistic behaviors, with nine of 17 subjects (53%) meeting the diagnostic criteria for autistic disorder using ADI-R. Using 3 different diagnostic measures of autism to evaluate 14 children with SLOS ranging from 3 to 16 years, Sikora et al., 2006 found that three-fourths of the children with SLOS (71-86% depending on the evaluation method) had ASD. A recent assessment of 33 individuals with Smith-Lemli-Optiz syndrome aged 4 to 23 years using ADOS and ADI-R resulted in 18 individuals (55%) being assigned a diagnosis of ASD (Thurm et al., 2016). A mouse model of Smith-Lemli-Optiz syndrome (Dhcr7 -/- mice) displayed commissural deficiencies, hippocampal abnormalities, and hypermorphic development of serotonin (5-HT) neurons (Waage-Baudet et al., 2003). However, there is no evidence linking this gene to idiopathic autism.

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

Increased from S to S

Description

Mutations in DHCR7 are responsible for Smith-Lemli-Optiz syndrome (SLOS). Evaluation of the behavioral phenotype in 56 subjects with SLOS in Tierney et al., 2001 concluded that individuals with SLOS manifested a behavioral profile of cognitive delay, sensory hyperreactivity, irritability, language impairment, sleep-cycle disturbance, self-injurious behavior, syndrome-specific motor movements, and autistic behaviors, with nine of 17 subjects (53%) meeting the diagnostic criteria for autistic disorder using ADI-R. Using 3 different diagnostic measures of autism to evaluate 14 children with SLOS ranging from 3 to 16 years, Sikora et al., 2006 found that three-fourths of the children with SLOS (71-86% depending on the evaluation method) had ASD. A recent assessment of 33 individuals with Smith-Lemli-Optiz syndrome aged 4 to 23 years using ADOS and ADI-R resulted in 18 individuals (55%) being assigned a diagnosis of ASD (Thurm et al., 2016). A mouse model of Smith-Lemli-Optiz syndrome (Dhcr7 -/- mice) displayed commissural deficiencies, hippocampal abnormalities, and hypermorphic development of serotonin (5-HT) neurons (Waage-Baudet et al., 2003). However, there is no evidence linking this gene to idiopathic autism.

Reports Added
[Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders.2019]
10/1/2017
S
icon
S

Increased from S to S

Description

Mutations in DHCR7 are responsible for Smith-Lemli-Optiz syndrome (SLOS). Evaluation of the behavioral phenotype in 56 subjects with SLOS in Tierney et al., 2001 concluded that individuals with SLOS manifested a behavioral profile of cognitive delay, sensory hyperreactivity, irritability, language impairment, sleep-cycle disturbance, self-injurious behavior, syndrome-specific motor movements, and autistic behaviors, with nine of 17 subjects (53%) meeting the diagnostic criteria for autistic disorder using ADI-R. Using 3 different diagnostic measures of autism to evaluate 14 children with SLOS ranging from 3 to 16 years, Sikora et al., 2006 found that three-fourths of the children with SLOS (71-86% depending on the evaluation method) had ASD. A recent assessment of 33 individuals with Smith-Lemli-Optiz syndrome aged 4 to 23 years using ADOS and ADI-R resulted in 18 individuals (55%) being assigned a diagnosis of ASD (Thurm et al., 2016). A mouse model of Smith-Lemli-Optiz syndrome (Dhcr7 -/- mice) displayed commissural deficiencies, hippocampal abnormalities, and hypermorphic development of serotonin (5-HT) neurons (Waage-Baudet et al., 2003). However, there is no evidence linking this gene to idiopathic autism.

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017] [Expanding the genetic heterogeneity of intellectual disability.2017]
4/1/2016
S
icon
S

Increased from S to S

Description

Mutations in DHCR7 are responsible for Smith-Lemli-Optiz syndrome (SLOS). Evaluation of the behavioral phenotype in 56 subjects with SLOS in Tierney et al., 2001 concluded that individuals with SLOS manifested a behavioral profile of cognitive delay, sensory hyperreactivity, irritability, language impairment, sleep-cycle disturbance, self-injurious behavior, syndrome-specific motor movements, and autistic behaviors, with nine of 17 subjects (53%) meeting the diagnostic criteria for autistic disorder using ADI-R. Using 3 different diagnostic measures of autism to evaluate 14 children with SLOS ranging from 3 to 16 years, Sikora et al., 2006 found that three-fourths of the children with SLOS (71-86% depending on the evaluation method) had ASD. A recent assessment of 33 individuals with Smith-Lemli-Optiz syndrome aged 4 to 23 years using ADOS and ADI-R resulted in 18 individuals (55%) being assigned a diagnosis of ASD (Thurm et al., 2016). A mouse model of Smith-Lemli-Optiz syndrome (Dhcr7 -/- mice) displayed commissural deficiencies, hippocampal abnormalities, and hypermorphic development of serotonin (5-HT) neurons (Waage-Baudet et al., 2003). However, there is no evidence linking this gene to idiopathic autism.

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014] [Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome.1998] [Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome.2001] [The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome.2006] [Molecular cloning and expression of the human delta7-sterol reductase.1998] [Negative regulation of Hedgehog signaling by the cholesterogenic enzyme 7-dehydrocholesterol reductase.2006] [Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith-Lemli-Opitz syndrome mouse.2007] [Social approach in genetically engineered mouse lines relevant to autism.2008] [Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015] [Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/-catenin defects in neuronal cholesterol syn...2016] [Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update.2016] [Abnormal serotonergic development in a mouse model for the Smith-Lemli-Opitz syndrome: implications for autism.2003]
1/1/2016
S
icon
S

Increased from S to S

Description

Candidate gene based on role in Smith-Lemli-Optiz syndrome (up to 75% manifest ASD; PMID: 14659996). No evidence for a role in idiopathic autism.

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014] [Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome.1998] [Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome.2001] [The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome.2006] [Molecular cloning and expression of the human delta7-sterol reductase.1998] [Negative regulation of Hedgehog signaling by the cholesterogenic enzyme 7-dehydrocholesterol reductase.2006] [Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith-Lemli-Opitz syndrome mouse.2007] [Social approach in genetically engineered mouse lines relevant to autism.2008] [Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015]
1/1/2015
S
icon
S

Increased from S to S

Description

Candidate gene based on role in Smith-Lemli-Optiz syndrome (up to 75% manifest ASD; PMID: 14659996). No evidence for a role in idiopathic autism.

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

Score 0.40961727702289

Ranking 22787/25841 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 5.0426643876391E-8

Ranking 15838/18225 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 0.94983715498619

Ranking 18252/18665 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 -0.5061388037864

Ranking 19306/20870 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
ACP6 acid phosphatase 6, lysophosphatidic Human Protein Binding 51205 Q9NPH0
CYP24A1 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial Human Protein Binding 1591 Q07973
SREBP-2 "<span title=""The name recommended by the UniProt consortium for this chain/part."" class=""tooltipped RECOMMENDED""><a href=""#PRO_0000314033"" onclick=""uniprot.entryViews.openSectionForInternalLink('PRO_0000314033');"">Processed sterol regulatory element-binding protein 2</a>" Human DNA Binding 6721 Q12772
Zfp110 zinc finger protein 110 Mouse DNA Binding 65020 Q923B3
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