HIST1H1E – Rahman syndrome

Rahman syndrome (RMNS) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous HIST1H1E variants and defined by the Rahman syndrome phenotype. Affected individuals exhibit a distinctive facial gestalt including macrocephaly, full cheeks, short neck, and low-set ears, accompanied by intellectual disability, hypotonia, anxiety, and autism spectrum behaviors.

The inheritance pattern is autosomal dominant, with most cases arising de novo and one documented mother–child transmission. To date, 48 unrelated probands (21 male, 27 female) with heterozygous frameshift mutations in the C-terminal tail of HIST1H1E have been reported (PMID:35156329). These variants uniformly truncate the protein, leading to loss of the normal C-terminal domain and generation of a novel frameshift tail.

Segregation analysis identified one additional affected first-degree relative, confirming familial transmission (PMID:35156329). The variant spectrum comprises exclusively small insertions or deletions creating a shared frameshift (e.g., c.368dup (p.Gly124ArgfsTer72)), consistent with a haploinsufficiency or dominant-negative mechanism.

A recent review curated 23 distinct HIST1H1E variants in 52 individuals, further delineating genotype–phenotype correlations. Common features included intellectual disability, hypotonia, anxiety, autism spectrum behaviors, and craniofacial dysmorphism, while variable expressivity was observed across different mutation sites (PMID:37605493).

Functional assays in rat hippocampal neurons expressing truncated H1.4 CTF proteins revealed dysregulation of ~400 transcripts enriched for synaptic and neuropeptide signaling pathways, alongside reduced neuronal firing rates on multielectrode arrays, supporting pathogenicity of C-terminal frameshift tails (PMID:34788807).

Collectively, the robust genetic and functional evidence meets a ClinGen “Strong” gene–disease association. Identification of frameshift HIST1H1E mutations should prompt clinical genetic testing for Rahman syndrome, enabling precise diagnosis and early intervention. Key take-home: HIST1H1E C-terminal frameshift variants underlie a distinct autosomal dominant neurodevelopmental syndrome with consistent facial, cognitive, and neurophysiological phenotypes.

References

• Molecular genetics & genomic medicine • 2022 • Expanding the mutational spectrum of Rahman syndrome: A rare disorder with severe intellectual disability and particular facial features in two Chinese patients. PMID:35156329
• Human molecular genetics • 2022 • Mutations of the histone linker H1-4 in neurodevelopmental disorders and functional characterization of neurons expressing C-terminus frameshift mutant H1.4. PMID:34788807
• Molecular genetics & genomic medicine • 2023 • A case report of a novel HIST1H1E mutation and a review of the bibliography to evaluate the genotype-phenotype correlations. PMID:37605493

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