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 / 20
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.

SFARI Genomic Platforms
Reports related to DHCR7 (20 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 - et al. () No -
19 Highly Cited Molecular cloning and expression of the human delta7-sterol reductase Moebius FF , et al. (1998) No -
20 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.1328G>A p.Arg443His missense_variant Familial Both parents - 38438125 et al. ()
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.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

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.

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.

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.

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.

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.

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.

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.

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.
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
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).
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.
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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