ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

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Select assembly: (NC_000006.11) (NC_000006.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
28475857 Tatton-Brown et al. 2017: Exome sequencing 710 individuals with Rahman syndrome (OMIM: mild to severe intellectual disability and an increase in height, weight, or head size [overgrowth]). 323 individuals with both parents available. Five unrelated probands with heterozygous HIST1H1E protein truncating variants. All the five patients had full cheeks and high hairline. In four probands the variants were de novo, parental samples were not available for the fifth child. The mutations identified in these five individuals represent three different mutations: 2 unrelated patients carried de novo c.430dupG; 2 unrelated patients carried c.441dupC (one is de novo, the other one is unknown); and a 1.9-year-old girl Rahman syndrome carried de novo c.436_458del23. All those three variants were identified cluster significantly (p= 2.0 3x10-9) to a 12-bp region in the carboxyterminal domain (CTD) that is involved in chromatin binding and protein-protein interactions. None of the mutations are present in the ExAC dataset, nor in 11,677 exomes analyzed in-house with similar pipelines. Of note, Takenouchi et al. 2018 comment on this study mentioned that the growth pattern of these five patients appeared complex that 4/5 patients had a decreasing height percentile over time, and three of these patients began with above-average heights but exhibited reductions to average heights or below when they were older. Therefore, the overgrowth phenotype is controversial and main phenotype associated with HIST1H1E remains intellectual disability.
29704315 Duffney et al., 2018: A de novo deleterious mutation of HIST1H1E (c.435dupC; p.Thr146Hisfs*50) was identified by WES in a 10-year-old boy with autism, intellectual disability, and potential overgrowth [his weight is 54.5kg (98th percentile), height is 144.8cm (70th percentile), and head circumference is 53cm (45th percentile)]. He has minor dysmorphic facial features, including downward-slanting palpebral fissures, hypertelorism, light eyebrows, micro and retrognathia, and wide philtrumwith. The c.435dupC at the 3' end of the mRNA leads to a frameshift and truncation of the positive charge in the carboxy-terminus of the protein. An expression study demonstrates the mutation leads to reduced protein expression, supporting haploinsufficiency of HIST1H1E protein and loss of function as an underlying mechanism of dysfunction in the brain. This variant was not found in ExAc, dbSNP, 1000G, or ESP.
29383847 Takenouchi et al. 2018: A female patient with intellectual disability (ID) and distinctive facial features including a wide nasal bridge and prominent cheek bones. She did not exhibit skeletal overgrowth, but she had a short stature at 21 years of age. An exome analysis identified a de novo heterozygous 1-bp duplication in HIST1H1E, that is, c.433dup/chr6 (GRCh37): g.26157051dup, which predicted a premature termination of the protein, p. Ala145Glyfs*51. This duplication was located within the 12-bp, (chr6 (GRCh37):g.26157048-g.26157059), region in the carboxyl terminal domain of HIST1H1E gene. This author also summarized the growth pattern of seven patients with HIST1H1E mutations and concluded that skeletal overgrowth is not an essential feature of HIST1H1E-related disorder. This HIST1H1E-related disorder is suggested to be referred to as Rahman syndrome.

Haploinsufficiency phenotype comments:

Additional supporting evidence includes: Helsmoortel C et al. 2015 (PMID: 25081361) had 0.15 points. Patient #8 carried a de novo heterozygous frameshift insertion of 1?bp in HIST1H1E, resulting in a premature stop codon 46 amino acids downstream. This patient had mild ID, normal growth with a relative macrocephaly (OFC on 97th centile for length on 25th centile) and dysmorphic features: scaphocephaly, a high hairline with frontal upsweep of the hair, mild downslant of the palpebral fissures and small teeth. Rahman syndrome is characterized by mild to severe intellectual disability associated with variable somatic overgrowth manifest as increased birth length, height, weight, and/or head circumference. The overgrowth is apparent in infancy and may lessen with time or persist. The phenotype is highly variable; some individuals may have other minor anomalies, including dysmorphic facial features, strabismus, or camptodactyly. (Takenouchi T, Uehara T, Kosaki K, Mizuno S. Growth pattern of Rahman syndrome. Am J Med Genet Part A. 2018;176A:712?714.)

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity