<i>HIST1H1E</i> heterozygous protein‐truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

Burkardt, Deepika D’Cunha; Zachariou, Anna; Loveday, Chey; Allen, Clare L.; Amor, David J.; Ardissone, Anna; Banka, Siddharth; Bourgois, Alexia; Coubes, Christine; Cytrynbaum, Cheryl; Faivre, Laurence; Gérard, Marion; Horton, Rachel; Kotzot, Dieter; Lay-Son, Guillermo; Lees, Melissa; Low, Karen; Luk, Ho Ming; Mark, Paul R.; McConkie‐Rosell, Allyn; McDonald, Marie; Pappas, John; Phillipe, Christophe; Shears, Deborah; Skotko, Brian G.; Stewart, Fiona; Stewart, Helen; Temple, I. Karen; Mau‐Them, Frédéric Tran; Verdugo, Ricardo A.; Weksberg, Rosanna; Zárate, Yuri A.; Graham, John M.; Tatton‐Brown, Katrina

doi:10.1002/ajmg.a.61321

Cited by 16 publications

(22 citation statements)

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“…Of 8 patients considered to have a syndromic clinical presentation, 1 (subject 5944) was excluded from further consideration owing to confounding by two additional DNMs likely to contribute to the phenotype, which had been separately identified by exome sequencing. 28 Of the remaining seven syndromic subjects, five had congenital heart defects (comprising atrioventricular septal defect, atrial septal defect [ASD] with patent foramen ovale, two ASD with ventricular septal defect, and bicuspid aortic valve with right bundle branch block; only the first of these required corrective surgery), three had brain anomalies (comprising ventriculomegaly and absent corpus callosum, macrocephaly, and mild microcephaly), and one had duodenal atresia. Seven children had delayed developmental/intellectual or educational attainment, classified as mild-moderate in one case and mild in the remainder.…”

Section: Phenotypic Characterization Of Smad6-positive Individualsmentioning

confidence: 99%

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

Calpena

Cuellar

Bala

et al. 2020

Genetics in Medicine

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Purpose Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism nearBMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. Methods We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. Results We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10−7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. Conclusion Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.

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Section: Phenotypic Characterization Of Smad6-positive Individualsmentioning

confidence: 99%

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

Calpena

Cuellar

Bala

et al. 2020

Genetics in Medicine

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“…Notably, patients also exhibited a characteristic overgrowth during infancy, which was no longer observable in adulthood. Further clinical manifestations of Rahman syndrome encompass behavioral problems, hypotonia, abnormal dentition, cardiac and skeletal anomalies, hypothyroidism, cryptorchidism, and corpus callosum abnormalities 123‐125 . Rahman syndrome is caused by protein‐truncating variants in HIST1H1E , encoding the widely expressed human linker histone H1.4.…”

Section: Pathogenesis and Clinical Phenotypes Of Selected Premature Amentioning

confidence: 99%

Premature aging disorders: A clinical and genetic compendium

2020

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Progeroid disorders make up a heterogeneous group of very rare hereditary diseases characterized by clinical signs that often mimic physiological aging in a premature manner. Apart from Hutchinson-Gilford progeria syndrome, one of the bestinvestigated progeroid disorders, a wide spectrum of other premature aging phenotypes exist, which differ significantly in their clinical presentation and molecular pathogenesis. Next-generation sequencing (NGS)-based approaches have made it feasible to determine the molecular diagnosis in the early stages of a disease. Nevertheless, a broad clinical knowledge on these disorders and their associated symptoms is still fundamental for a comprehensive patient management and for the interpretation of variants of unknown significance from NGS data sets. This review provides a detailed overview on characteristic clinical features and underlying molecular genetics of well-known as well as only recently identified premature aging disorders and also highlights novel findings towards future therapeutic options. K E Y W O R D S characteristic clinical features, hereditary, premature aging, progeroid disorders 1 | INTRODUCTION Aging is a general biological phenomenon that affects all human beings and results in a functional decline of physiological systems accompanied by an increased risk for chronic ailments with advancing chronological age. 1,2 At the molecular level, aging is for example associated with genomic instability, loss of heterochromatin, and the accumulation of macromolecular damage leading to reduced (stem) cell function and tissue regeneration. 3 Progeroid disorders show many clinical features of aging-associated pathologies and signs similar to physiological aging; however, they occur at earlier ages and often progress rapidly. In many aspects progeria therefore represents a timelapse form of aging. Premature aging processes are mostly segmental in that they involve one or more organs, but do not exhibit all aspects associated with physiological aging. Premature aging signs include, among others, alopecia, hair graying, lipodystrophy, osteoporosis, joint contractures, cataract, hearing loss, atherosclerosis, cardiovascular diseases, diabetes mellitus and malignancies at an early age. In addition to these typical aging phenotypes, progeria patients may also present with growth retardation, developmental delay, and intellectual disability. A more modular view of segmental premature aging syndromes hypothesizes that a cluster of symptoms appearing in several disorders might be due to a common underlying cause-for example, alopecia, osteoporosis and nail atrophy have been proposed to be related to telomere shortening. 4 Research into premature aging disorders aims at understanding the pathogenesis and to develop novel treatment strategies, but also intends to unshadow physiological aging processes since premature aging phenotypes mirror many of the clinical aspects of physiological aging. 3 One of the best-known premature aging disorders is the Hutchinson-Gilford progeria syndr...

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“…In addition to these findings, he shared similar dysmorphic facial features, developmental delay, and macrocephaly as other patients described formerly. 2,3,8 This infant underwent mandibular distraction with improvement in obstructive sleep apnea, although central apnea worsened. We hypothesized that his hypotonia is the major contributing factor to his central apnea, and it is expected to improve over time as his hypotonia improves.…”

Section: Resultsmentioning

confidence: 99%

Exome sequencing identified a novel HIST1H1E heterozygous protein‐truncating variant in a 6‐month‐old male patient with Rahman syndrome: A case report

Indugula

Ayala

Vetrini

et al. 2022

Clinical Case Reports

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Rahman syndrome is a rare autosomal-dominant intellectual disability syndrome caused by monoallelic pathogenic frameshift variants affecting the C-terminal domain (CTD) of the HIST1H1E gene. HIST1H1E is a single-exon, intronless gene located on chromosome 6p22.2. It encodes the linker histone H1.4, a member of the H1 histone family, and functions as a structural component of chromatin to control DNA compaction, gene expression regulation, DNA replication, recombination, and repair. The HIST1H1E protein contains an N-terminus region enriched in basic amino acids, a central conserved globular H15 domain involved in DNA binding, and a long Cterminal tail enriched in lysine, serine, and proline. 1 This condition, also known as HIST1H1E syndrome, was first described in 2014 and is characterized by overgrowth, distinctive facial features (full cheeks, high frontal hairline, hypertelorism, telecanthus, deep-set eyes, downslanting palpebral fissures, micrognathia, etc.), intellectual disability (mostly moderate severity), and behavioral problems. Other symptoms include strabismus, hypothyroidism, cryptorchidism, skeletal and cardiac anomalies, abnormal dentition, hypotonia, and abnormal brain MRI with corpus callosum abnormalities being the most frequent finding. 2,3 Additionally, autism spectrum

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HIST1H1E heterozygous protein‐truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

Cited by 16 publications

References 10 publications

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

Premature aging disorders: A clinical and genetic compendium

Exome sequencing identified a novel HIST1H1E heterozygous protein‐truncating variant in a 6‐month‐old male patient with Rahman syndrome: A case report

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