- Email: [email protected]
Wiedemann-Steiner syndrome: Novel pathogenic variant and review of literature
Accepted Manuscript Wiedemann-Steiner Syndrome: Novel pathogenic variant and review of literature Anjali Aggarwal, David F. Rodriguez-Buritica, Hope Northrup PII:
S1769-7212(16)30244-0
DOI:
10.1016/j.ejmg.2017.03.006
Reference:
EJMG 3268
To appear in:
European Journal of Medical Genetics
Received Date: 10 August 2016 Revised Date:
30 January 2017
Accepted Date: 15 March 2017
Please cite this article as: A. Aggarwal, D.F. Rodriguez-Buritica, H. Northrup, Wiedemann-Steiner Syndrome: Novel pathogenic variant and review of literature, European Journal of Medical Genetics (2017), doi: 10.1016/j.ejmg.2017.03.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Wiedemann-Steiner Syndrome: Novel Pathogenic Variant and Review of
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Literature
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Authors: Anjali Aggarwal, David F. Rodriguez-Buritica, Hope Northrup
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Division of Medical Genetics, Department of Pediatrics, McGovern Medical School, University
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of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, Texas 77030
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Running title: Novel pathogenic variant in KMT2A resulting in Wiedemann-Steiner syndrome
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Conflict of interest disclosures: None.
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Correspondence to: Anjali Aggarwal, MD. Department of Pediatrics, McGovern Medical
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School, 6431 Fannin Street, Houston, TX 77030. Ph.: 1 (832)-217-9035. Fax: 713-383-1475.
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Email: [email protected]
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ABSTRACT
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Wiedemann-Steiner syndrome (WDSTS) is a very rare genetic disorder characterized by short
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stature, intellectual disability and distinctive facial appearance. We present a five-year-old boy
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who was diagnosed with WDSTS based on identification of a novel de novo pathogenic variant
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in the KMT2A gene (OMIM: 159555) by Whole Exome Sequencing and supported by some
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characteristic clinical features. Genotype and phenotype of the patient is compared with the
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earlier reported patients in the literature, in an attempt to broaden our knowledge of this rare
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syndrome.
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KEY WORDS: Wiedemann-Steiner syndrome; KMT2A; novel pathogenic variant
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TEXT
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INTRODUCTION
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Wiedemann-Steiner Syndrome (WDSTS) is a rare autosomal dominant disorder first described
72
by Wiedemann et al. in 1989 who reported a Caucasian boy with pre- and postnatal growth
73
deficiency, psychomotor delay, and a round and flat face, short nose, widely spaced eyes, long
74
philtrum, short palpebral fissures, low-set ears, and high-arched palate. Other findings included
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an alternating convergent squint, dilatation of the renal calyces, and short and thick limbs.
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Over the next decade, more authors described patients with similar clinical features [MacDermot et al. 1989, Flannery et al. 1989, and Edwards et al. 1994]. In 2000, Steiner et al
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described an 8-year-old girl with growth deficiency, mental retardation, unusual facies and
79
hypertrichosis and compared with the one described by Wiedemann et al. Additional authors
80
including Visser at al., 2002; Polizzi et al., 2005; Koc et al., 2007 and Koenig et al., 2010
81
reported children with WDSTS since that time. WDSTS appears to be present among all
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populations, affecting males and females equally, typically arising from a de novo occurrence.
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The genetic underpinning of WDSTS was identified in 2012, when Jones et al. performed
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whole-exome sequencing in four patients with Wiedemann-Steiner syndrome and identified
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heterozygous de novo truncating pathogenic variants in the MLL gene in three of the four
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patients. They concluded that haploinsufficiency of MLL (now known as KMT2A) causes
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WDSTS and pathogenic variants were de novo in occurrence.
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KMT2A (Lysine Methyltransferase 2A) encodes a histone methyltransferase that has been demonstrated to regulate chromatin-mediated transcription and is widely expressed in most
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human tissues. Pathogenic variants in KMT2A lead to defects in chromatin remodeling [Milne et
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al., 2002] and are thought to result in global changes in gene expression throughout development
92
leading to abnormalities in multiple body systems. KMT2A contains 36 exons and has three
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known mRNA isoforms.
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To the best of our knowledge, less than 30 KMT2A pathogenic variant-positive patients have been reported in WDSTS literature. Complete phenotype and genotype-phenotype
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correlation is not fully understood. We discuss the clinical features and genetic findings in our
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patient in comparison to the earlier reported patients with a limited attempt at the genotype-
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phenotype correlation.
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CASE REPORT
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We report a five-year-old boy who was born to a 28-year-old gravida 3 mother and
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nonconsanguineous 24-year-old father. Family history is significant for 2 maternal half siblings
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with history of attention deficit disorder. There were no known exposures during pregnancy.
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Pregnancy was uncomplicated and the antenatal ultrasounds were normal. Baby was born at 39
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weeks gestation via vaginal delivery. Birth weight was 2.8 kg (3rd- 10th percentile), length was
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47.6 cm (3rd-10th percentile), and head circumference was 31.5 cm (<3rd percentile; -2.5SD).
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APGAR scores were 8 and 9 at 1 and 5 minutes, respectively. Neonatal course was uneventful
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and he was discharged home on third day of life.
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Around the age of seven months he started falling off the growth charts for both height
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and weight. Because of loss of growth velocity, he was evaluated for endocrine and
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gastroenterological problems. Upon testing, subclinical hypothyroidism was detected. A bone
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age performed at three years was normal. He was on appropriate nutrition supplementation. He
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crawled at the age of nine months, and walked at fifteen months old. His parents did not
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recognize any speech issues until attempted enrollment into a day school. Evaluators at school
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suggested speech therapy. The patient has difficulty with expressive and receptive language, and
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was noted to have mild learning disability. No formal IQ test was performed. He was toilet
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trained at five years old.
Bilateral ptosis (left> right) was noted since birth and he underwent ptosis surgery at the
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age of four years. He underwent adenoidectomy for snoring and obstructive sleep apnea at the
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age of four years. He was referred for Genetics evaluation due to history of developmental delay
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and poor growth. At five years of age, weight was 13.6 kg (< 5th percentile; -2.5SD), height 90.7
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cm (<5th percentile; -3.8 SD), and head circumference 51 cm (25-50th percentile). Physical
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examination demonstrated mild bilateral ptosis, downslanting palpebral fissures, long eyelashes,
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long philtrum, and downturned corners of mouth (Fig. 1a). Hirsutism was noted throughout back
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(Fig. 1b). He is in pre-kindergarten currently and making progress with appropriate assistance
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and therapies. He is noted to be sensitive to excessive noise and gets easily frustrated, but has no
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attention deficit or hyperactivity.
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Chromosomal microarray was normal. The patient was further investigated with whole
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exome sequencing (WES) that was performed as a clinical test using a trio approach. Genome
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DNA was fragmented by using sonicating genomic DNA and ligating to multiplexing PE
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adaptors. The adaptor-ligated DNA was then PCR amplified using primers with sequencing
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barcodes. For target enrichment/ exome capture procedure, the pre-capture library is enriched by
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hybridizing to biotin labelled VCRome 2.1 in- solution exome probes at 47 degree C for 64-72
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hours. Additional probes for over 3600 Mendelian genes were also included in the capture in
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order to improve the exome coverage. For massively parallel sequencing, the post capture library
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DNA was subjected to sequence analysis on Illumina HiSeq platform for 100 bp paired-end
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results. The output data from Illumina HiSeq were converted from bcl file to FastQ file by
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Illumina CASAVA 1.8 software, and mapped by BWA program to the reference haploid human
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genome sequence. The variant cells were performed using the Atlas-SNP and Atlas-indel
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developed in –house by HGSC. The variant annotations were performed using in-house
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developed software: HGSC-SNP anno and HGSC-indel-anno. WES revealed a Sanger validated
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novel de novo frameshift pathogenic variant: NM_001197104 (KMT2A_v001):c.152_186del (p.
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Pro51Argfs*84). No additional variants were identified.
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DISCUSSION
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The constellation of clinical features described in WDSTS is broad and the clinical diagnosis is often challenging. Characteristic clinical findings in pathogenic variant positive
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patients with WDTS reported in the literature (including currently reported patient) is shown in
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Table 1.
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As seen in the currently reported patient, the clinical phenotype of WDSTS includes a variable degree of prenatal and postnatal growth restriction as well as unusual facial features
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including: flat face, low set and dysmorphic ears, widely spaced eyes, synophrys, long eyelashes,
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broad nose, long philtrum, thin upper lip, high arched palate and micrognathia. The facial
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features become more pronounced with age [Koenig et al, 2010]. Described dental abnormalities
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include hypodontia, premature dental eruption and widely spaced teeth. Skin findings can
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include sacral dimple, localized or generalized hypertrichosis. Hypertrichosis cubiti has been
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regarded as the most prominent but not a universal feature of this syndrome.
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Neuropsychiatric manifestations include variable degree of intellectual disability, developmental delay that can improve over time, epilepsy, wide-based gait, absent corpus
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callosum, aggressive behavior, autistic features, hyperactivity and poor sleep [Vissers et al.,
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2016]. Musculoskeletal features including short stature, thin built, delayed or advanced bone age,
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short and tapering fingers, clinodactyly, syndactyly, hypotonia and pectus excavatum have been
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described. Currently reported patient has speech delay and learning issues.
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Failure to thrive is an important symptom in the first few years. Constipation and feeding difficulty have been reported in some patients. Three patients have been described to have
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urinary problems [Wiedemann et al., 1989; Mendelsohn et al., 2014; Dunkerton et al., 2015].
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Cardiac abnormalities that have been noted include patent ductus arteriosus and atrial septal
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defect in one patient each [Jones et al., 2012].
Pathogenic variants have been described in WDSTS literature since 2012. Pathogenic
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variants causing WDSTS appear to be distributed along the entire gene. Among the 26 patients
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described, most pathogenic variants causing WDSTS (7 patients) were clustered in exon 27,
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which can be considered a pathogenic variantal hotspot. Five patients each had a pathogenic
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variant in exon 3 and 5. Identical twins reported by Dunkerton et al. had a pathogenic variant in
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exon 4. One patient each harbored a pathogenic variant in intron 8, exon 11, 13, 15 or 26. The
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patient described by Mendelsohn et al. had an intragenic deletion involving exons 2-10. Majority
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of these pathogenic variants in KMT2A results in a null allele/ loss-of function (18/25) (Fig. 2).
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The identical twins described above were found to have small kidneys with normal
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function [Dunkerton et al., 2015]. The patient with an intragenic deletion involving exons 2-10
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had recurrent urinary tract infections, unilateral ureterocele and grade IV vesicouretral reflux
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[Mendelsohn et al., 2014]. The renal ultrasound in currently reported patient (pathogenic variant
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in exon 1) revealed a unilateral mild left hydronephrosis and mild right pelviectasis with the plan
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being to monitor with a repeat renal ultrasound in a year.
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All three of the patients with renal manifestations had pathogenic variants involving earlier exons of the KMT2A. Since the number of reported patients with WDSTS is small, it is
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difficult to draw a statistically significant genotype-phenotype correlation. With the available
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information and small number of individuals with WDSTS identified so far, we suggest a
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screening renal ultrasound in all WDSTS patients. With increasing awareness about this rare
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disorder and wider availability of genetic testing, we anticipate additional reports of WDSTS
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patients. Further study of individuals with KMT2A pathogenic variants will be needed to fully
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understand the phenotypic spectrum and draw more discrete genotype-phenotype correlations.
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ACKNOWLEDGEMENT
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We would like to thank the family for their participation in this study.
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The novel variant has been submitted to the Leiden Open Variation Database (LOVD).
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Individual #00089138 .
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Fig. 1 (a): Front profile at the age of 3 years showing long philtrum, low set ears, widely spaced
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eyes, strabismus, bilateral ptosis (left>right), epicanthal folds, narrow palpebral fissures,
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downslanting palpebral fissures, thick eyebrows, broad nose and thin upper lip
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(b): Back showing hypertrichosis which is more prominent along the midline
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Fig. 2: KMT2A protein structure and location of KMT2A reported in literature (including the
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currently reported patient). The upper panel shows nonsense pathogenic variants and the lower
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panel shows missense pathogenic variants. Domain key has been shown in the lower half of the
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figure. Refer to the supplementary table for details of the published pathogenic variants.
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Table 1: Frequency of clinical features in the KMT2A pathogenic variant positive patients with WDSTS in literature (including currently reported patient).
222 Clinical feature Developmental delay Post-natal growth retardation
(n = 26) Percentage (%) 23 88 22 85
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Hypertrichosis (generalized/ localized) 21
81
Thick eyebrows Long eyelashes Wide nasal bridge Downslanting palpebral fissures Narrow palpebral fissures Hypertelorism Broad nasal tip Thin vermilion border Thick hair Feeding problems 5th finger clinodactyly
62 62 62 58 54 46 46 46 42 35 35
16 16 16 15 14 12 12 12 11 9 9
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SUPPLEMENTAL DATA DESCRIPTION
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Supplementary Table: KMT2A pathogenic variants causing Wiedemann Steiner syndrome that
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have bene reported to date (including currently reported patient).
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EJMG signed publication permit
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PÖ, López-González V, Parenti I, Pozojevic J, Utine GE, Wieland T, Kaiser FJ, Wollnik B,
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Strom TM, Wieczorek D. Exome sequencing unravels unexpected differential diagnoses in
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Dysgenesis. Sex Dev. 2015; 9(5):289-295.
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variants: Variable Severity in PsychomotorDevelopment and Musculoskeletal Manifestation.
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9. Koenig R, Meinecke P, Kuechler A, Schäfer D, Müller D. Wiedemann-Steiner syndrome: three further cases. Am J Med Genet A. 2010 Sep; 152A (9):2372-2375. 10. Steel D, Salpietro V, Phadke R, Pitt M, Gentile G, Massoud A, Batten L, Bashamboo A, Mcelreavey K, Saggar A, Kinali M. Whole exome sequencing reveals a MLL de novo
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11. Stellacci E, Onesimo R, Bruselles A, Pizzi S, Battaglia D, Leoni C, Zampino G, Tartaglia
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12. Strom SP, Lozano R, Lee H, Dorrani N, Mann J, O'Lague PF, Mans N, Deignan JL, Vilain E,
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Nelson SF, Grody WW, Quintero-Rivera F. De Novo variants in the KMT2A (MLL) gene
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13. Yu Sun, Guorui Hu, Huili Liu, Xia Zhang, Zhuo Huang, Hui Yan, Lili Wang, Yanjie Fan,
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Xuefan Gu,and Yongguo Yu. Further Delineation of the Phenotype of Truncating KMT2A
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14. Vissers LE, Gilissen C, Veltman JA. .Genetic studies in intellectual disability and related
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15. Yuan Bo, Pehlivan Davut, Karaca Ender, Patel Nisha, Charng Wu-Lin, Gambin Tomasz,
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Koparir Asuman, Koparir Erkan, Beck Christine R., Gu Shen, Aslan Huseyin, Yuregir Ozge
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Ozalp, Rubeaan Khalid Al, Alnaqeb Dhekra, Alshammari Muneera J., Bayram Yavuz, Atik
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Mehmed M., Aydin Hatip, Geckinli B. Bilge, Seven Mehmet, Ulucan Hakan, Elif
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Fenercioglu, Ozen Mustafa, Jhangiani Shalini, Muzny Donna M., Boerwinkle Eric, Beyhan
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S1769-7212(16)30244-0
DOI:
10.1016/j.ejmg.2017.03.006
Reference:
EJMG 3268
To appear in:
European Journal of Medical Genetics
Received Date: 10 August 2016 Revised Date:
30 January 2017
Accepted Date: 15 March 2017
Please cite this article as: A. Aggarwal, D.F. Rodriguez-Buritica, H. Northrup, Wiedemann-Steiner Syndrome: Novel pathogenic variant and review of literature, European Journal of Medical Genetics (2017), doi: 10.1016/j.ejmg.2017.03.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
1
Wiedemann-Steiner Syndrome: Novel Pathogenic Variant and Review of
2
Literature
RI PT
3
Authors: Anjali Aggarwal, David F. Rodriguez-Buritica, Hope Northrup
5
Division of Medical Genetics, Department of Pediatrics, McGovern Medical School, University
6
of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, Texas 77030
SC
4
8
Running title: Novel pathogenic variant in KMT2A resulting in Wiedemann-Steiner syndrome
9
11
Conflict of interest disclosures: None.
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Correspondence to: Anjali Aggarwal, MD. Department of Pediatrics, McGovern Medical
13
School, 6431 Fannin Street, Houston, TX 77030. Ph.: 1 (832)-217-9035. Fax: 713-383-1475.
14
Email: [email protected]
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ABSTRACT
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Wiedemann-Steiner syndrome (WDSTS) is a very rare genetic disorder characterized by short
23
stature, intellectual disability and distinctive facial appearance. We present a five-year-old boy
24
who was diagnosed with WDSTS based on identification of a novel de novo pathogenic variant
25
in the KMT2A gene (OMIM: 159555) by Whole Exome Sequencing and supported by some
26
characteristic clinical features. Genotype and phenotype of the patient is compared with the
27
earlier reported patients in the literature, in an attempt to broaden our knowledge of this rare
28
syndrome.
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KEY WORDS: Wiedemann-Steiner syndrome; KMT2A; novel pathogenic variant
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TEXT
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INTRODUCTION
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Wiedemann-Steiner Syndrome (WDSTS) is a rare autosomal dominant disorder first described
72
by Wiedemann et al. in 1989 who reported a Caucasian boy with pre- and postnatal growth
73
deficiency, psychomotor delay, and a round and flat face, short nose, widely spaced eyes, long
74
philtrum, short palpebral fissures, low-set ears, and high-arched palate. Other findings included
75
an alternating convergent squint, dilatation of the renal calyces, and short and thick limbs.
SC
M AN U
76
RI PT
69
Over the next decade, more authors described patients with similar clinical features [MacDermot et al. 1989, Flannery et al. 1989, and Edwards et al. 1994]. In 2000, Steiner et al
78
described an 8-year-old girl with growth deficiency, mental retardation, unusual facies and
79
hypertrichosis and compared with the one described by Wiedemann et al. Additional authors
80
including Visser at al., 2002; Polizzi et al., 2005; Koc et al., 2007 and Koenig et al., 2010
81
reported children with WDSTS since that time. WDSTS appears to be present among all
82
populations, affecting males and females equally, typically arising from a de novo occurrence.
EP
The genetic underpinning of WDSTS was identified in 2012, when Jones et al. performed
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84
whole-exome sequencing in four patients with Wiedemann-Steiner syndrome and identified
85
heterozygous de novo truncating pathogenic variants in the MLL gene in three of the four
86
patients. They concluded that haploinsufficiency of MLL (now known as KMT2A) causes
87
WDSTS and pathogenic variants were de novo in occurrence.
ACCEPTED MANUSCRIPT 5 88
KMT2A (Lysine Methyltransferase 2A) encodes a histone methyltransferase that has been demonstrated to regulate chromatin-mediated transcription and is widely expressed in most
90
human tissues. Pathogenic variants in KMT2A lead to defects in chromatin remodeling [Milne et
91
al., 2002] and are thought to result in global changes in gene expression throughout development
92
leading to abnormalities in multiple body systems. KMT2A contains 36 exons and has three
93
known mRNA isoforms.
SC
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To the best of our knowledge, less than 30 KMT2A pathogenic variant-positive patients have been reported in WDSTS literature. Complete phenotype and genotype-phenotype
96
correlation is not fully understood. We discuss the clinical features and genetic findings in our
97
patient in comparison to the earlier reported patients with a limited attempt at the genotype-
98
phenotype correlation.
99
CASE REPORT
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We report a five-year-old boy who was born to a 28-year-old gravida 3 mother and
101
nonconsanguineous 24-year-old father. Family history is significant for 2 maternal half siblings
102
with history of attention deficit disorder. There were no known exposures during pregnancy.
103
Pregnancy was uncomplicated and the antenatal ultrasounds were normal. Baby was born at 39
104
weeks gestation via vaginal delivery. Birth weight was 2.8 kg (3rd- 10th percentile), length was
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47.6 cm (3rd-10th percentile), and head circumference was 31.5 cm (<3rd percentile; -2.5SD).
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APGAR scores were 8 and 9 at 1 and 5 minutes, respectively. Neonatal course was uneventful
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and he was discharged home on third day of life.
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Around the age of seven months he started falling off the growth charts for both height
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and weight. Because of loss of growth velocity, he was evaluated for endocrine and
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gastroenterological problems. Upon testing, subclinical hypothyroidism was detected. A bone
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age performed at three years was normal. He was on appropriate nutrition supplementation. He
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crawled at the age of nine months, and walked at fifteen months old. His parents did not
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recognize any speech issues until attempted enrollment into a day school. Evaluators at school
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suggested speech therapy. The patient has difficulty with expressive and receptive language, and
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was noted to have mild learning disability. No formal IQ test was performed. He was toilet
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trained at five years old.
Bilateral ptosis (left> right) was noted since birth and he underwent ptosis surgery at the
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age of four years. He underwent adenoidectomy for snoring and obstructive sleep apnea at the
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age of four years. He was referred for Genetics evaluation due to history of developmental delay
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and poor growth. At five years of age, weight was 13.6 kg (< 5th percentile; -2.5SD), height 90.7
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cm (<5th percentile; -3.8 SD), and head circumference 51 cm (25-50th percentile). Physical
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examination demonstrated mild bilateral ptosis, downslanting palpebral fissures, long eyelashes,
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long philtrum, and downturned corners of mouth (Fig. 1a). Hirsutism was noted throughout back
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(Fig. 1b). He is in pre-kindergarten currently and making progress with appropriate assistance
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and therapies. He is noted to be sensitive to excessive noise and gets easily frustrated, but has no
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attention deficit or hyperactivity.
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Chromosomal microarray was normal. The patient was further investigated with whole
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exome sequencing (WES) that was performed as a clinical test using a trio approach. Genome
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DNA was fragmented by using sonicating genomic DNA and ligating to multiplexing PE
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adaptors. The adaptor-ligated DNA was then PCR amplified using primers with sequencing
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barcodes. For target enrichment/ exome capture procedure, the pre-capture library is enriched by
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hybridizing to biotin labelled VCRome 2.1 in- solution exome probes at 47 degree C for 64-72
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hours. Additional probes for over 3600 Mendelian genes were also included in the capture in
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order to improve the exome coverage. For massively parallel sequencing, the post capture library
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DNA was subjected to sequence analysis on Illumina HiSeq platform for 100 bp paired-end
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results. The output data from Illumina HiSeq were converted from bcl file to FastQ file by
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Illumina CASAVA 1.8 software, and mapped by BWA program to the reference haploid human
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genome sequence. The variant cells were performed using the Atlas-SNP and Atlas-indel
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developed in –house by HGSC. The variant annotations were performed using in-house
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developed software: HGSC-SNP anno and HGSC-indel-anno. WES revealed a Sanger validated
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novel de novo frameshift pathogenic variant: NM_001197104 (KMT2A_v001):c.152_186del (p.
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Pro51Argfs*84). No additional variants were identified.
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DISCUSSION
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The constellation of clinical features described in WDSTS is broad and the clinical diagnosis is often challenging. Characteristic clinical findings in pathogenic variant positive
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patients with WDTS reported in the literature (including currently reported patient) is shown in
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Table 1.
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As seen in the currently reported patient, the clinical phenotype of WDSTS includes a variable degree of prenatal and postnatal growth restriction as well as unusual facial features
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including: flat face, low set and dysmorphic ears, widely spaced eyes, synophrys, long eyelashes,
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broad nose, long philtrum, thin upper lip, high arched palate and micrognathia. The facial
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features become more pronounced with age [Koenig et al, 2010]. Described dental abnormalities
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include hypodontia, premature dental eruption and widely spaced teeth. Skin findings can
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include sacral dimple, localized or generalized hypertrichosis. Hypertrichosis cubiti has been
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regarded as the most prominent but not a universal feature of this syndrome.
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Neuropsychiatric manifestations include variable degree of intellectual disability, developmental delay that can improve over time, epilepsy, wide-based gait, absent corpus
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callosum, aggressive behavior, autistic features, hyperactivity and poor sleep [Vissers et al.,
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2016]. Musculoskeletal features including short stature, thin built, delayed or advanced bone age,
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short and tapering fingers, clinodactyly, syndactyly, hypotonia and pectus excavatum have been
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described. Currently reported patient has speech delay and learning issues.
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Failure to thrive is an important symptom in the first few years. Constipation and feeding difficulty have been reported in some patients. Three patients have been described to have
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urinary problems [Wiedemann et al., 1989; Mendelsohn et al., 2014; Dunkerton et al., 2015].
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Cardiac abnormalities that have been noted include patent ductus arteriosus and atrial septal
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defect in one patient each [Jones et al., 2012].
Pathogenic variants have been described in WDSTS literature since 2012. Pathogenic
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variants causing WDSTS appear to be distributed along the entire gene. Among the 26 patients
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described, most pathogenic variants causing WDSTS (7 patients) were clustered in exon 27,
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which can be considered a pathogenic variantal hotspot. Five patients each had a pathogenic
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variant in exon 3 and 5. Identical twins reported by Dunkerton et al. had a pathogenic variant in
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exon 4. One patient each harbored a pathogenic variant in intron 8, exon 11, 13, 15 or 26. The
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patient described by Mendelsohn et al. had an intragenic deletion involving exons 2-10. Majority
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of these pathogenic variants in KMT2A results in a null allele/ loss-of function (18/25) (Fig. 2).
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The identical twins described above were found to have small kidneys with normal
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function [Dunkerton et al., 2015]. The patient with an intragenic deletion involving exons 2-10
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had recurrent urinary tract infections, unilateral ureterocele and grade IV vesicouretral reflux
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[Mendelsohn et al., 2014]. The renal ultrasound in currently reported patient (pathogenic variant
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in exon 1) revealed a unilateral mild left hydronephrosis and mild right pelviectasis with the plan
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being to monitor with a repeat renal ultrasound in a year.
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All three of the patients with renal manifestations had pathogenic variants involving earlier exons of the KMT2A. Since the number of reported patients with WDSTS is small, it is
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difficult to draw a statistically significant genotype-phenotype correlation. With the available
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information and small number of individuals with WDSTS identified so far, we suggest a
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screening renal ultrasound in all WDSTS patients. With increasing awareness about this rare
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disorder and wider availability of genetic testing, we anticipate additional reports of WDSTS
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patients. Further study of individuals with KMT2A pathogenic variants will be needed to fully
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understand the phenotypic spectrum and draw more discrete genotype-phenotype correlations.
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ACKNOWLEDGEMENT
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We would like to thank the family for their participation in this study.
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The novel variant has been submitted to the Leiden Open Variation Database (LOVD).
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Individual #00089138 .
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Fig. 1 (a): Front profile at the age of 3 years showing long philtrum, low set ears, widely spaced
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eyes, strabismus, bilateral ptosis (left>right), epicanthal folds, narrow palpebral fissures,
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downslanting palpebral fissures, thick eyebrows, broad nose and thin upper lip
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(b): Back showing hypertrichosis which is more prominent along the midline
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Fig. 2: KMT2A protein structure and location of KMT2A reported in literature (including the
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currently reported patient). The upper panel shows nonsense pathogenic variants and the lower
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panel shows missense pathogenic variants. Domain key has been shown in the lower half of the
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figure. Refer to the supplementary table for details of the published pathogenic variants.
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Table 1: Frequency of clinical features in the KMT2A pathogenic variant positive patients with WDSTS in literature (including currently reported patient).
222 Clinical feature Developmental delay Post-natal growth retardation
(n = 26) Percentage (%) 23 88 22 85
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Hypertrichosis (generalized/ localized) 21
81
Thick eyebrows Long eyelashes Wide nasal bridge Downslanting palpebral fissures Narrow palpebral fissures Hypertelorism Broad nasal tip Thin vermilion border Thick hair Feeding problems 5th finger clinodactyly
62 62 62 58 54 46 46 46 42 35 35
16 16 16 15 14 12 12 12 11 9 9
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SUPPLEMENTAL DATA DESCRIPTION
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Supplementary Table: KMT2A pathogenic variants causing Wiedemann Steiner syndrome that
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have bene reported to date (including currently reported patient).
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EJMG signed publication permit
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