Human Gene Module / Chromosome 19 / LDLR

LDLRlow density lipoprotein receptor

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
3 / 4
Rare Variants / Common Variants
11 / 0
Aliases
LDLR, FH,  FHC,  FHCL1,  LDLCQ2
Associated Syndromes
-
Chromosome Band
19p13.2
Associated Disorders
-
Relevance to Autism

Integration of familial whole-exome datasets of 3,531 individuals from 1,704 simplex ASD families and 50 multiplex ASD families and expression data from the BrainSpan Atlas of the Developmental Human Brain in Luo et al., 2020 identified a neurodevelopmentally co-regulated, sex-differentially expressed cluster of exons enriched with ASD-segregating deleterious variants in the LDLR gene (Bonferroni-corrected cluster P-value of 1.68-05).

Molecular Function

The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. Low density lipoprotein (LDL) is normally bound at the cell membrane and taken into the cell ending up in lysosomes where the protein is degraded and the cholesterol is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to LDLR (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary A multidimensional precision medicine approach identifies an autism subtype characterized by dyslipidemia Luo Y et al. (2020) Yes -
2 Support - Zhou X et al. (2022) Yes -
3 Support - Cirnigliaro M et al. (2023) Yes -
4 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.94T>A p.Phe32Ile missense_variant Familial - - 32778826 Luo Y et al. (2020)
c.81C>T p.Cys27= synonymous_variant Familial - - 32778826 Luo Y et al. (2020)
c.90C>T p.Asn30= synonymous_variant Familial - - 32778826 Luo Y et al. (2020)
c.1113G>A p.Leu371%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.81C>G p.Cys27Trp missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.268G>A p.Asp90Asn missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.811G>A p.Val271Ile missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.2054C>T p.Pro685Leu missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1977C>A p.Thr659%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2229C>T p.Thr743%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1448G>A p.Trp483Ter stop_gained Familial Paternal Extended multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49303754425595

Ranking 4311/25841 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 2.5926607371831E-16

Ranking 17774/18225 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 0.92448258840308

Ranking 9999/18665 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 -0.071194826376213

Ranking 11232/20870 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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