Human Gene Module / Chromosome 6 / H1-4

H1-4H1.4 linker histone, cluster member

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
4 / 10
Rare Variants / Common Variants
37 / 0
Aliases
-
Associated Syndromes
Rahman syndrome, ID, Rahman syndrome, DD, Rahman syndrome, DD, ID, Rahman syndrome, ASD, DD, ID
Chromosome Band
6p22.2
Associated Disorders
-
Relevance to Autism

Heterozygous mutations in the H1-4 gene are responsible for Rahman syndrome (OMIM 617537), a disorder characterized by mild to severe intellectual disability associated with variable somatic overgrowth manifest as increased birth length, height, weight, and/or head circumference (Tatton-Brown et al., 2017). Autism spectrum disorder has been observed in a subset of individuals with H1-4 variants (Duffney et al., 2018; Burkardt et al., 2019; Tremblay et al., 2021).

Molecular Function

Histones are basic nuclear proteins responsible for nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H1 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
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Reports related to H1-4 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability Tatton-Brown K , et al. (2017) No -
2 Primary - Duffney LJ et al. (2018) Yes -
3 Support - Burkardt DD et al. (2019) No ASD or autistic features, stereotypy, epilepsy/sei
4 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
5 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
6 Recent Recommendation - Tremblay MW et al. (2021) No ASD or autistic features
7 Support - Indugula SR et al. (2022) No -
8 Support - Zhao J et al. (2022) No -
9 Support - Singh T et al. (2022) No -
10 Support - Zhao W et al. (2023) Yes -
Rare Variants   (37)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.430dupG - frameshift_variant De novo - - 28475857 Tatton-Brown K , et al. (2017)
c.441dupC - frameshift_variant De novo - - 28475857 Tatton-Brown K , et al. (2017)
c.441dupC - frameshift_variant Unknown - - 28475857 Tatton-Brown K , et al. (2017)
c.1A>G p.Met1? initiator_codon_variant De novo - - 34788807 Tremblay MW et al. (2021)
c.436_458del23 - frameshift_variant De novo - - 28475857 Tatton-Brown K , et al. (2017)
c.392dup p.Ala132SerfsTer64 frameshift_variant - - - 34788807 Tremblay MW et al. (2021)
c.430dup p.Ala144GlyfsTer52 frameshift_variant - - - 34788807 Tremblay MW et al. (2021)
c.431dup p.Ala145GlyfsTer51 frameshift_variant - - - 34788807 Tremblay MW et al. (2021)
c.435dup p.Thr146HisfsTer50 frameshift_variant - - - 34788807 Tremblay MW et al. (2021)
c.430dupG p.Ala144GlyfsTer52 frameshift_variant - - - 34788807 Tremblay MW et al. (2021)
c.447G>C p.Lys149Asn missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.441dup p.Lys148GlnfsTer48 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.441dup p.Lys148GlnfsTer48 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.435dupC p.Thr146HisfsTer50 frameshift_variant De novo - - 29704315 Duffney LJ et al. (2018)
c.365dup p.Ala123GlyfsTer73 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.407dup p.Lys137GlufsTer59 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.416dup p.Lys140GlufsTer56 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.433dup p.Ala145GlyfsTer51 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.435dup p.Thr146HisfsTer50 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.441dup p.Lys148GlnfsTer48 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.265del p.Ser89AlafsTer140 frameshift_variant De novo - - 34788807 Tremblay MW et al. (2021)
c.430dupG p.Ala144GlyfsTer52 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.430dupG p.Ala144GlyfsTer52 frameshift_variant Unknown - - 31400068 Burkardt DD et al. (2019)
c.431dupC p.Ala145GlyfsTer51 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.435dupC p.Thr146HisfsTer50 frameshift_variant Unknown - - 31400068 Burkardt DD et al. (2019)
c.441dupC p.Lys148GlnfsTer48 frameshift_variant Unknown - - 31400068 Burkardt DD et al. (2019)
c.233del p.Ser78ThrfsTer11 frameshift_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.368dup p.Gly124ArgfsTer72 frameshift_variant Familial Maternal - 35156329 Zhao J et al. (2022)
c.436_458del p.Thr146AspfsTer42 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.440_441del p.Pro147GlnfsTer48 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.444_466del p.Lys149GlufsTer39 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.406_407insT p.Lys136IlefsTer60 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.454_455insT p.Lys152IlefsTer44 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.416_419dup p.Ala141GlufsTer56 frameshift_variant De novo - Simplex 37605493 Zhao W et al. (2023)
c.425_431del7ins8 p.Thr142LysfsTer54 frameshift_variant De novo - - 31400068 Burkardt DD et al. (2019)
c.505_506insT p.Lys169IlefsTer27 frameshift_variant De novo - Simplex 35154720 Indugula SR et al. (2022)
c.100_101insT p.Lys34IlefsTer13 frameshift_variant Familial Maternal - 34788807 Tremblay MW et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

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."

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