Human Gene Module / Chromosome 11 / HEPACAM

HEPACAMhepatic and glial cell adhesion molecule

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 12
Rare Variants / Common Variants
29 / 0
Aliases
HEPACAM, GlialCAM,  MLC2A,  MLC2B
Associated Syndromes
-
Chromosome Band
11q24.2
Associated Disorders
ID, ASD
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 in the HEPACAM gene have been found to cause either macrocephaly and mental retardation with or without autism or benign familial macrocephaly (Lpez-Hernndez et al., 2011).

Molecular Function

Involved in regulating cell motility and cell-matrix interactions. May inhibit cell growth through suppression of cell proliferation

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HEPACAM (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma Chung Moh M , et al. (2005) No -
2 Recent Recommendation Structural and functional analyses of a novel ig-like cell adhesion molecule, hepaCAM, in the human breast carcinoma MCF7 cells Moh MC , et al. (2005) No -
3 Primary Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism Lpez-Hernndez T , et al. (2011) No ASD, ID
4 Highly Cited HepaCAM induces G1 phase arrest and promotes c-Myc degradation in human renal cell carcinoma Zhang QL , et al. (2011) No -
5 Highly Cited Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts Lpez-Hernndez T , et al. (2011) No -
6 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
7 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
8 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
9 Recent Recommendation Megalencephalic leukoencephalopathy with subcortical cysts: Characterization of disease variants Hamilton EMC , et al. (2018) No -
10 Support Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations Zhou WZ , et al. (2019) Yes -
11 Support - Baldwin KT et al. (2021) No -
12 Support - Hosneara Akter et al. () No -
Rare Variants   (29)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.478C>G p.Leu160Val missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.803+1G>A - splice_site_variant Familial Paternal - 30763456 Zhou WZ , et al. (2019)
c.505T>C p.Ser169Pro missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.437C>T p.Ser146Leu missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.274C>T p.Arg92Trp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.68T>A p.Leu23His missense_variant De novo - Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.265G>A p.Gly89Ser missense_variant De novo - Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.274C>T p.Arg92Trp missense_variant De novo - Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.274C>T p.Arg92Trp missense_variant Unknown - Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.292C>T p.Arg98Cys missense_variant Unknown - Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.382G>A p.Asp128Asn missense_variant Unknown - Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.587C>A p.Ser196Tyr missense_variant Unknown - Multiplex 21419380 Lpez-Hernndez T , et al. (2011)
c.742G>T p.Gly248Ter stop_gained Familial Paternal Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.789G>A p.Trp263Ter stop_gained Familial Maternal Multiplex 21419380 Lpez-Hernndez T , et al. (2011)
c.265G>A p.Gly89Ser missense_variant Familial Maternal Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.265G>A p.Gly89Ser missense_variant Familial Paternal Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.266G>A p.Gly89Asp missense_variant Familial Paternal Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.274C>T p.Arg92Trp missense_variant Familial Maternal Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.275G>A p.Arg92Gln missense_variant Familial Paternal Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.382G>A p.Asp128Asn missense_variant Familial Paternal Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.631G>A p.Asp211Asn missense_variant Familial Maternal Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.862C>T p.Arg288Cys missense_variant Familial Paternal Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.265G>A p.Gly89Ser missense_variant Familial Paternal Multiplex 21419380 Lpez-Hernndez T , et al. (2011)
c.274C>T p.Arg92Trp missense_variant Familial Maternal Multiplex 21419380 Lpez-Hernndez T , et al. (2011)
c.442C>T p.Pro148Ser missense_variant Familial Both parents Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.404_406del p.Lys135del inframe_deletion Familial Paternal Simplex 21419380 Lpez-Hernndez T , et al. (2011)
c.292C>T p.Arg98Cys missense_variant Familial Both parents Multiplex 21419380 Lpez-Hernndez T , et al. (2011)
c.461_462del p.Ser154TyrfsTer17 frameshift_variant Familial Paternal Simplex 21419380 Lpez-Hernndez T , et al. (2011)
NM_152722.5:c.580delC,582C>T p.Leu194PhefsTer60 frameshift_variant Familial Both parents Simplex 21419380 Lpez-Hernndez T , et al. (2011)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Rare mutations in the HEPACAM gene have been found to cause megalencephalic leukoencephalopathy with subcortical cysts (MLC) (Lopez-Hernandez et al., 2011); multiple individuals with MLC caused by heterozygous HEPACAM mutations (also known as remitting megalencephalic leukoencephalopathy with subcortical cysts-2B or MLC2B; OMIM 613926) were found to meet DSM-IV criteria for autism or PDD-NOS in this report. Phenotypic characterization of 38 patients with MLC2B in Hamilton et al., 2018 determined that autistic features were present in 25% of cases (9/36). A de novo potentially damaging missense variant in the HEPACAM gene (p.Arg92Trp) was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was also observed in multiple individuals with MLC2B in Lopez-Hernandez et al., 2011. An inherited missense variant in this gene that was predicted to be potentially damaging was observed in a Chinese ASD proband in Li et al., 2017.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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
S

Score remained at S

New Scoring Scheme
Description

Rare mutations in the HEPACAM gene have been found to cause megalencephalic leukoencephalopathy with subcortical cysts (MLC) (Lopez-Hernandez et al., 2011); multiple individuals with MLC caused by heterozygous HEPACAM mutations (also known as remitting megalencephalic leukoencephalopathy with subcortical cysts-2B or MLC2B; OMIM 613926) were found to meet DSM-IV criteria for autism or PDD-NOS in this report. Phenotypic characterization of 38 patients with MLC2B in Hamilton et al., 2018 determined that autistic features were present in 25% of cases (9/36). A de novo potentially damaging missense variant in the HEPACAM gene (p.Arg92Trp) was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was also observed in multiple individuals with MLC2B in Lopez-Hernandez et al., 2011. An inherited missense variant in this gene that was predicted to be potentially damaging was observed in a Chinese ASD proband in Li et al., 2017.

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

Score remained at S

Description

Rare mutations in the HEPACAM gene have been found to cause megalencephalic leukoencephalopathy with subcortical cysts (MLC) (Lopez-Hernandez et al., 2011); multiple individuals with MLC caused by heterozygous HEPACAM mutations (also known as remitting megalencephalic leukoencephalopathy with subcortical cysts-2B or MLC2B; OMIM 613926) were found to meet DSM-IV criteria for autism or PDD-NOS in this report. Phenotypic characterization of 38 patients with MLC2B in Hamilton et al., 2018 determined that autistic features were present in 25% of cases (9/36). A de novo potentially damaging missense variant in the HEPACAM gene (p.Arg92Trp) was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was also observed in multiple individuals with MLC2B in Lopez-Hernandez et al., 2011. An inherited missense variant in this gene that was predicted to be potentially damaging was observed in a Chinese ASD proband in Li et al., 2017.

Reports Added
[Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...2019]
10/1/2017
S
icon
S

Score remained at S

Description

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations in the HEPACAM gene have been found to cause Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) (L?pez-Hern?ndez et al., 2011). No other evidence exists that implicates this gene in autism.

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
7/1/2016
S
icon
S

Score remained at S

Description

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations in the HEPACAM gene have been found to cause Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) (L?pez-Hern?ndez et al., 2011). No other evidence exists that implicates this gene in autism.

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
1/1/2016
S
icon
S

Score remained at S

Description

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations in the HEPACAM gene have been found to cause Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) (L?pez-Hern?ndez et al., 2011). No other evidence exists that implicates this gene in autism.

Reports Added
[Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation ...2011] [Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma.2005] [Structural and functional analyses of a novel ig-like cell adhesion molecule, hepaCAM, in the human breast carcinoma MCF7 cells.2005] [HepaCAM induces G1 phase arrest and promotes c-Myc degradation in human renal cell carcinoma.2011] [Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts.2011] [The contribution of de novo coding mutations to autism spectrum disorder2014]
Krishnan Probability Score

Score 0.45015572875907

Ranking 10942/25841 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 0.6306448609469

Ranking 4843/18225 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 0.68013592065638

Ranking 1041/18665 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 -0.29044847828777

Ranking 17070/20870 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
Cfp complement factor properdin Mouse Protein Binding 5199 P27918
CLCN2 chloride channel, voltage-sensitive 2 Human Protein Binding 1181 P51788
HEPACAM hepatic and glial cell adhesion molecule Human Autoregulation 220296 Q14CZ8
Mbl2 mannose-binding lectin (protein C) 2 Mouse Protein Binding 17195 P41317
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