Whole exome sequencing reveals a MLL de novo mutation associated with mild developmental delay and without ‘hairy elbows’: expanding the phenotype of Wiedemann–Steiner syndrome

Steel, Dora; Salpietro, Vincenzo; Phadke, Rahul; Pitt, M. A. T. T. H. E. W.; Gentile, Giulia; Massoud, A. H. M. E. D.; Batten, L. E. I. G. H.; Bashamboo, Anu; McElreavey, Kenneth; Saggar, Anand; Kinali, Maria

doi:10.1007/s12041-015-0578-x

Cited by 29 publications

(18 citation statements)

References 14 publications

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“…Immune dysfunction, including early‐onset combined variable immune deficiency, recurrent pulmonary infection, and death from sepsis have been reported (Bogaert et al, 2017; Bramswig et al, 2015; Stellacci et al, 2016). Other rare neurological findings, such as syringomyelia (Pavone et al, 2015) periventricular nodular heterotopia (Baer et al, 2018), and cerebral hemisphere asymmetry (Steel et al, 2015) have been noted. Outcomes of two adults have been detailed (Feldman et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

Sheppard

Campbell

Harr

et al. 2021

American J of Med Genetics Pt A

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Wiedemann‐Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype–phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty‐nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants. This study identifies genotype–phenotype correlations as well as race‐facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long‐term outcomes in individuals with WSS.

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Section: Introductionmentioning

confidence: 99%

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

Sheppard

Campbell

Harr

et al. 2021

American J of Med Genetics Pt A

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“…Eight different nonsense mutations were found in 8 different patients. Six were new (p.Ser90*, p.Arg160*, p.Arg1101*, p.Arg2163*, p.Glu2544* and p.Arg2659*) and 2 had already been reported (p.Arg1633*) and (p.Arg2480*). We also found one new splice mutation: c.4696+1G>A.…”

Section: Resultsmentioning

confidence: 99%

Wiedemann‐Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases

et al. 2018

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Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

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“…Cubiti hypertrichosis was the distinct phenotype to recruit samples. Since then, additional KMT2A mutations were discovered by exome sequencing in atypical WDSTS patients [Mendelsohn et al, ; Strom et al, ; Calvel et al, ; Steel et al, ]. To further delineate the phenotype of WDSTS, we summarized the phenotypes of cases with KMT2A mutations in literatures together with the present two boys (Table and Supplementary Table SI for detail).…”

Section: Resultsmentioning

confidence: 99%

Further delineation of the phenotype of truncating KMT2A mutations: The extended Wiedemann–Steiner syndrome

Sun

Liu

et al. 2016

American J of Med Genetics Pt A

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KMT2A mutations cause Wiedemann-Steiner syndrome (WDSTS), which is characterized by hypertrichosis cubiti, short stature, and distinct facial features in general. Here, we report two Chinese boys with novel nonsense KMT2A mutations. Most of their phenotypes are concordant with WDSTS. They, however, lack the key WDSTS feature-hypertrichosis cubiti. Additionally, their transverse palmar creases are absent. We further summarized the genotypes and phenotypes of the KMT2A mutation carriers. The consensus phenotypes include postnatal growth retardation, developmental delay, short stature, and intellectual disability. The common facial features include thick eyebrows, long eyelashes, downslanting, and narrow palpebral fissures, wide nasal bridge, and broad nasal tip. They have generalized hypertrichosis. A hairy back can be observed as frequently as hairy elbows in patients with KMT2A mutations. Absent palmar proximal transverse creases are only observed in these two Chinese boys. This might be due to the difference in ethnic background. Thus far, all mutations in KMT2A are located before the FYRC domain. They would truncate KMT2A mRNA transcripts. Haploinsufficiency of the histone methyltransferase activity would therefore influence transcriptional regulation. © 2016 Wiley Periodicals, Inc.

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Whole exome sequencing reveals a MLL de novo mutation associated with mild developmental delay and without ‘hairy elbows’: expanding the phenotype of Wiedemann–Steiner syndrome

Cited by 29 publications

References 14 publications

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

Wiedemann‐Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases

Further delineation of the phenotype of truncating KMT2A mutations: The extended Wiedemann–Steiner syndrome

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