Human Gene Module / Chromosome 8 / CLN8

CLN8Ceroid-lipofuscinosis, neuronal 8 (epilepsy, progressive with mental retardation)

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
9 / 0
Aliases
CLN8, C8orf61,  EPMR
Associated Syndromes
-
Chromosome Band
8p23.3
Associated Disorders
-
Relevance to Autism

A missense variant in the CLN8 gene segregated with ASD in a multi-generational Japanese family consisting of a father diagnosed with PDD-NOS and three affected male offspring diagnosed with Asperger syndrome (Egawa et al., 2015).

Molecular Function

This gene encodes a transmembrane protein belonging to a family of proteins containing TLC domains, which are postulated to function in lipid synthesis, transport, or sensing. Mutations in this gene are associated with progressive epilepsy with mental retardation (EMPR; OMIM 600143), which is a subtype of neuronal ceroid lipofuscinoses (NCL).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to CLN8 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8 Ranta S , et al. (1999) No -
2 Primary Novel rare missense variations and risk of autism spectrum disorder: whole-exome sequencing in two families with affected siblings and a two-stage follow-up study in a Japanese population Egawa J , et al. (2015) Yes -
3 Negative Association Resequencing and Association Analysis of CLN8 with Autism Spectrum Disorder in a Japanese Population Inoue E , et al. (2015) Yes -
4 Support - Woodbury-Smith M et al. (2022) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Tamam Khalaf et al. (2024) No -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.117T>G p.Phe39Leu missense_variant - - - 26657971 Inoue E , et al. (2015)
c.290G>A p.Arg97His missense_variant - - - 26657971 Inoue E , et al. (2015)
c.323C>T p.Thr108Met missense_variant - - - 26657971 Inoue E , et al. (2015)
c.455A>G p.Asn152Ser missense_variant - - - 26657971 Inoue E , et al. (2015)
c.523G>A p.Val175Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.71G>A p.Arg24His missense_variant Unknown Not maternal - 25806950 Egawa J , et al. (2015)
c.609C>T p.Cys203%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.71G>A p.Arg24His missense_variant Familial Paternal Multiplex 25806950 Egawa J , et al. (2015)
c.570G>T p.Trp190Cys missense_variant Familial Both parents - 38438125 Tamam Khalaf et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Missense variants in the CLN8 gene have been identified in Japanese ASD cases, including a p.Arg24His variant observed in three siblings with Asperger syndrome and their father diagnosed with PDD-NOS. However, the variants identified in these studies were frequently also observed either in Japanese control populations or in external databases, and no significant association between these variants and ASD was found (Egawa et al., 2015; Inoue et al., 2015). Mutations in this gene are associated with progressive epilepsy with mental retardation (EMPR; OMIM 600143), which is a subtype of neuronal ceroid lipofuscinoses (NCL).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Missense variants in the CLN8 gene have been identified in Japanese ASD cases, including a p.Arg24His variant observed in three siblings with Asperger syndrome and their father diagnosed with PDD-NOS. However, the variants identified in these studies were frequently also observed either in Japanese control populations or in external databases, and no significant association between these variants and ASD was found (Egawa et al., 2015; Inoue et al., 2015). Mutations in this gene are associated with progressive epilepsy with mental retardation (EMPR; OMIM 600143), which is a subtype of neuronal ceroid lipofuscinoses (NCL).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Missense variants in the CLN8 gene have been identified in Japanese ASD cases, including a p.Arg24His variant observed in three siblings with Asperger syndrome and their father diagnosed with PDD-NOS. However, the variants identified in these studies were frequently also observed either in Japanese control populations or in external databases, and no significant association between these variants and ASD was found (Egawa et al., 2015; Inoue et al., 2015). Mutations in this gene are associated with progressive epilepsy with mental retardation (EMPR; OMIM 600143), which is a subtype of neuronal ceroid lipofuscinoses (NCL).

Reports Added
[New Scoring Scheme]
1/1/2016
icon
4

Increased from to 4

Description

Missense variants in the CLN8 gene have been identified in Japanese ASD cases, including a p.Arg24His variant observed in three siblings with Asperger syndrome and their father diagnosed with PDD-NOS. However, the variants identified in these studies were frequently also observed either in Japanese control populations or in external databases, and no significant association between these variants and ASD was found (Egawa et al., 2015; Inoue et al., 2015). Mutations in this gene are associated with progressive epilepsy with mental retardation (EMPR; OMIM 600143), which is a subtype of neuronal ceroid lipofuscinoses (NCL).

Reports Added
[Novel rare missense variations and risk of autism spectrum disorder: whole-exome sequencing in two families with affected siblings and a two-stage ...2015] [The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8.1999] [Resequencing and Association Analysis of CLN8 with Autism Spectrum Disorder in a Japanese Population.2015]
Krishnan Probability Score

Score 0.41279435142499

Ranking 21998/25841 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 0.0007470732501025

Ranking 11968/18225 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 0.94078470399902

Ranking 14693/18665 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 -0.091399327641524

Ranking 12031/20870 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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