Histone-modification disorders

Recommended panel testing at Breda Genetics for this condition:

Histone-modification disorders and their differential diagnosis (incl. Wiedemann-Steiner, Kabuki, Coffin-Siris, Nicolaides-Baraitser, and Cornelia de Lange syndromes) (ARID1A, ARID1B, HDAC8, NIPBL, KMT2A, KMT2D, KDM6A, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SMC1A, SMC3, RAD21)


Histone modification is a epigenetic mechanism by which more than 100 different post-translational modifications may occur at the amino-terminal ends of the histone tails in nucleosomes. Such modifications include methylation, acetylation, ubiquitination, phosphorylation, among others. These modifications can result in the activation or repression of gene transcription,  depending on the identity and location of the amino acid residue that is modified. Histones are key players in epigenetics and many diseases develop when anomalies emerge in the epigenetic mechanisms.

Detailed clinical description

Wiedemann-Steiner syndrome: clinics and causes of a histone modification disorder

Wiedemann-Steiner syndrome (WDSTS), first described in 1989 by Wiedemann et al., is a complex congenital syndrome with a variable phenotypic spectrum which can be characterized by pre- and postnatal growth deficiency, psychomotor developmental delay, generalized hypotonia, facial dysmorphisms (round and flat face, facial asymmetry with right/left hemi-hypoplasia, dolichocephaly, telecanthus, thick eyebrows, mild synophrys, short nose, hypertelorism, long philtrum, heavy jaw, short and downslanting palpebral fissures, ptosis, low-set ears, epicanthal folds, high-arched palate, and mild clinodactyly), alternating convergent squint, short stature, hypertrichosis cubiti (elbow), small kidneys dilatation of the renal calyces, sacral dimple, and short and thick limbs.

Wiedemann-Steiner syndrome is autosomal dominant and is caused by heterozygous de novo mutation causing haploinsufficiency in the KMT2A gene (also known as MLL), a gene encoding a histone methyltransferase. The syndrome is sporadic (i.e. the parents are not affected and the syndrome arises because of a mutation in the spermatozoa or in the oocyte). The mutant transcripts of the KMT2A gene have been found to be subject to nonsense-mediated decay.

Differential diagnosis

It has been found that patients with Wiedemann-Steiner syndrome may show significant clinical overlap with other disorders, in particular with Cornelia de Lange syndrome, atypical Kabuki syndrome (also caused by mutations in genes involved in histone modification) and BRG1- and BRM-associated factor (BAF) complex mutations (Coffin-Siris and Nicolaides-Baraitser syndromes). In fact, some patients with a tentative diagnosis of one of these disorders have been later found to be affected by another one of the same group through molecular confirmation.

Cornelia de Lange syndrome is a congenital syndrome with a variable clinical spectrum (characteristic facial dysmorphism with synophrys, intellectual deficit, pre- and postnatal growth retardation, marked digital defects in hands and feet and various splanchnic malformations. About 65% of patients with Cornelia de Lange syndrome harbor mutations in one of the following five genes: NIPBL, SMC1A, SMC3, RAD21, and HDAC8.

Kabuki syndrome is a congenital syndrome characterized by mental retardation, postnatal dwarfism, facial dysmorphisms (reminiscent of the make-up of actors of Kabuki, a Japanese theatrical form), scoliosis, short fifth finger, persistence of finger pads, and radiographic skeleton abnormalities. Kabuki syndrome 1 (KABUK1) is autosomal dominant and caused by heterozygous mutation in the KMT2D gene. Kabuki syndrome 2 (KABUK2) is X-linked and caused by mutation in the KDM6A gene.

Coffin-Siris syndrome (also known as Mental retardation, autosomal dominant 16, MRD16SMARCA4 gene mutation) and Nicolaides-Baraitser syndrome (NCBRSSMARCA2 gene mutation) are rare intellectual disability/congenital malformation syndromes which may show clinical overlap with Wiedemann-Steiner syndrome. Coffin-Siris syndrome patients may show developmental delay, hypotonia, microcephaly, seizures, Dandy-Walker malformation, vision/hearing problems, finger defects, thick eyebrows, sparse scalp hair and hirsutism. Nicolaides-Baraitser syndrome is characterized by severe mental retardation, early-onset seizures, short stature, dysmorphic facial features, and sparse hair.

Due to its overlap with Cornelia de Lange syndrome, we may also take into account Roberts syndrome (ESCO2 gene mutations). Also Adams-Oliver syndrome (ARHGAP31, RBPJ, NOTCH1, DOCK6, or EOGT gene mutations) has been reported as possibly partially overlapping with histone modification disorders, although the clinical features of these two syndromes may be more easily distinguishable.

Recommended panel testing at Breda Genetics for this condition:

Histone-modification disorders and their differential diagnosis (incl. Wiedemann-Steiner, Kabuki, Coffin-Siris, Nicolaides-Baraitser, and Cornelia de Lange syndromes) (ARID1A, ARID1B, HDAC8, NIPBL, KMT2A, KMT2D, KDM6A, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SMC1A, SMC3, RAD21)


The molecular hallmarks of epigenetic effects mediated by antiepileptic drugs. Navarrete-Modesto V, Orozco-Suárez S2, Feria-Romero IA, Rocha L. Epilepsy Res. 2018 Nov 16;149:53-65. PMID: 30476813

Epigenetic modifications and human disease. Portela A, Esteller M. Nat Biotechnol. 2010 Oct;28(10):1057-68. PMID: 20944598

A de novo Mutation in KMT2A (MLL) in monozygotic twins with Wiedemann-Steiner syndrome. Dunkerton S, Field M, Cho V, Bertram E, Whittle B, Groves A, Goel H. Am J Med Genet A. 2015 Sep;167A(9):2182-7. PMID: 25929198

Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations. Miyake N, Tsurusaki Y, Koshimizu E, Okamoto N, Kosho T, Brown NJ, Tan TY, Yap PJ, Suzumura H, Tanaka T, Nagai T, Nakashima M, Saitsu H, Niikawa N, Matsumoto N. Clin Genet. 2016 Jan;89(1):115-9. PMID: 25810209

Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin-Siris and Nicolaides-Baraitser syndromes. Bramswig NC, Lüdecke HJ, Alanay Y, Albrecht B, Barthelmie A, Boduroglu K, Braunholz D, Caliebe A, Chrzanowska KH, Czeschik JC, Endele S, Graf E, Guillén-Navarro E, Kiper PÖ, López-González V, Parenti I, Pozojevic J, Utine GE, Wieland T, Kaiser FJ, Wollnik B, Strom TM, Wieczorek D. Hum Genet. 2015 Jun;134(6):553-68. PMID: 25724810

OMIM: 605130

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