Human Gene Module / Chromosome X / HCFC1

HCFC1host cell factor C1

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
6 / 12
Rare Variants / Common Variants
23 / 0
Aliases
HCFC1, CFF,  HCF,  HCF-1,  HCF1,  HFC1,  MRX3,  PPP1R89,  VCAF
Associated Syndromes
-
Chromosome Band
Xq28
Associated Disorders
DD/NDD, ASD, EPS, ID
Relevance to Autism

A variant in the 5'UTR of the HCFC1 gene was found to completely segregate with intellectual disability in the MRX3 pedigree. This variant, which resided in the binding site of the transcription factor YY1, abolished YY1 binding and led to increased HCFC1 expression. Two additional unique HCFC1 variants were identified in follow-up exome sequencing of probands from unresolved families affected by intellectual disability, one of which was shown to segregate with ID (Huang et al., 2012).

Molecular Function

Involved in control of the cell cycle.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HCFC1 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability Huang L , et al. (2012) No -
2 Support Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals Piton A , et al. (2012) Yes -
3 Recent Recommendation An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1 Yu HC , et al. (2013) No DD, epilepsy
4 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing Redin C , et al. (2014) No -
5 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
6 Support A novel HCFC1 variant in male siblings with intellectual disability and microcephaly in the absence of cobalamin disorder Koufaris C , et al. (2016) No Microcephaly
7 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No Autistic features
8 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes ID
9 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children Long S , et al. (2019) Yes -
10 Support - Woodbury-Smith M et al. (2022) Yes -
11 Support - Hu C et al. (2022) Yes -
12 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
Rare Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.5261-4C>T - splice_region_variant Unknown - - 35741772 Hu C et al. (2022)
c.218C>T p.Ala73Val missense_variant De novo - Simplex 24011988 Yu HC , et al. (2013)
c.202C>G p.Gln68Glu missense_variant Unknown - Unknown 24011988 Yu HC , et al. (2013)
c.217G>A p.Ala73Thr missense_variant Unknown - Unknown 24011988 Yu HC , et al. (2013)
c.218C>T p.Ala73Val missense_variant Unknown - Unknown 24011988 Yu HC , et al. (2013)
c.343G>A p.Ala115Thr missense_variant Unknown - Unknown 24011988 Yu HC , et al. (2013)
c.344C>T p.Ala115Val missense_variant Unknown - Unknown 24011988 Yu HC , et al. (2013)
c.5114C>G p.Ala1705Gly missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.4106T>C p.Met1369Thr missense_variant Familial Maternal - 35741772 Hu C et al. (2022)
c.2860G>A p.Val954Met missense_variant Familial Maternal - 31139143 Long S , et al. (2019)
c.722C>T p.Thr241Met missense_variant Unknown - Multiplex 23169495 Piton A , et al. (2012)
c.5305G>A p.Val1769Met missense_variant Familial Maternal - 31031587 Xiong J , et al. (2019)
c.4296G>A p.Thr1432%3D synonymous_variant De novo - - 35205252 Woodbury-Smith M et al. (2022)
c.1429G>A p.Ala477Thr missense_variant Familial Maternal - 28554332 Bowling KM , et al. (2017)
c.344C>T p.Ala115Val missense_variant Familial Maternal Simplex 24011988 Yu HC , et al. (2013)
c.3980C>T p.Thr1327Met missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.2626G>A p.Gly876Ser missense_variant Familial Maternal Simplex 23000143 Huang L , et al. (2012)
c.218C>T p.Ala73Val missense_variant Familial Maternal Multiplex 25167861 Redin C , et al. (2014)
c.5267C>T p.Ala1756Val missense_variant Unknown - Multi-generational 23000143 Huang L , et al. (2012)
c.-970T>C - 5_prime_UTR_variant Familial Maternal Multi-generational 23000143 Huang L , et al. (2012)
c.2690C>T p.Ala897Val missense_variant Familial Maternal Multiplex 26893841 Koufaris C , et al. (2016)
c.674G>A p.Ser225Asn missense_variant Familial Maternal Multi-generational 23000143 Huang L , et al. (2012)
c.2285C>T p.Thr762Ile missense_variant Familial Maternal Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

A variant in the 5'UTR of the HCFC1 gene was found to completely segregate with intellectual disability in the MRX3 pedigree. This variant, which resided in the binding site of the transcription factor YY1, abolished YY1 binding and led to increased HCFC1 expression. Two additional unique HCFC1 variants were identified in follow-up exome sequencing of probands from unresolved families affected by intellectual disability, one of which was shown to segregate with ID (Huang et al., 2012). Yu et al., 2013 identified 5 different hemizygous missense mutations in the HCFC1 gene in 14 unrelated males with X-linked intellectual disability and a cobalamin disorder identified through laboratory studies (cblX). Autistic disorder or autistic features have been observed in two individuals with HCFC1-associated intellectual disability (Redin et al., 2014; Bowling 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

A variant in the 5'UTR of the HCFC1 gene was found to completely segregate with intellectual disability in the MRX3 pedigree. This variant, which resided in the binding site of the transcription factor YY1, abolished YY1 binding and led to increased HCFC1 expression. Two additional unique HCFC1 variants were identified in follow-up exome sequencing of probands from unresolved families affected by intellectual disability, one of which was shown to segregate with ID (Huang et al., 2012). Yu et al., 2013 identified 5 different hemizygous missense mutations in the HCFC1 gene in 14 unrelated males with X-linked intellectual disability and a cobalamin disorder identified through laboratory studies (cblX). Autistic disorder or autistic features have been observed in two individuals with HCFC1-associated intellectual disability (Redin et al., 2014; Bowling et al., 2017).

Reports Added
[New Scoring Scheme]
7/1/2019
icon
S

Score remained at S

Description

A variant in the 5'UTR of the HCFC1 gene was found to completely segregate with intellectual disability in the MRX3 pedigree. This variant, which resided in the binding site of the transcription factor YY1, abolished YY1 binding and led to increased HCFC1 expression. Two additional unique HCFC1 variants were identified in follow-up exome sequencing of probands from unresolved families affected by intellectual disability, one of which was shown to segregate with ID (Huang et al., 2012). Yu et al., 2013 identified 5 different hemizygous missense mutations in the HCFC1 gene in 14 unrelated males with X-linked intellectual disability and a cobalamin disorder identified through laboratory studies (cblX). Autistic disorder or autistic features have been observed in two individuals with HCFC1-associated intellectual disability (Redin et al., 2014; Bowling et al., 2017).

Reports Added
[The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.2019]
Krishnan Probability Score

Score 0.49166912456193

Ranking 5268/25841 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 0.99999593449913

Ranking 384/18225 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 0.94948846140826

Ranking 18111/18665 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 0.45042558027932

Ranking 917/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
DDAH2 N(G),N(G)-dimethylarginine dimethylaminohydrolase 2 Human Protein Binding 23564 O95865
HCFC1R1 Host cell factor C1 regulator 1 Human Protein Binding 54985 Q9NWW0-2
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