Abstract
Background: Waardenburg syndrome (WS) is an inherited heterogeneous auditory pigmentary syndrome, divided into at least four types and characterized by iris heterochromia, white forelock, prominent nasal root, dystopia canthorum, middle eyebrow hypertrichosis, and deafness. Pathogenic variants in the SOX10 gene have been reported to be involved in WS disease. Methods: Whole exome sequencing (WES) was conducted on a 24-year-old male, who originated from Iranian Azeri Turkish ethnic group, with symptoms of deafness and blue eyes from brown-eyed parents. Web-based tools including Mutation Taster, VarSome, SIFT, Human Splicing Finder (HSF), and I-TASSER, were used for bioinformatics analysis. To verify the WES findings, DNAs taken from the blood samples of all family members were subjected to PCR-Sanger sequencing. Results: A novel heterozygous pathogenic variant, NC_000022.11 (NM_006941):c.428+1G>T, located in the second intron of the SOX10 gene and disrupting the splicing site, was identified in the proband. Sanger sequencing was applied on the proband and his parents. The results showed that the variant was a de novo pathogenic variant with an autosomal dominant inheritance pattern. Conclusions: Identification of a novel de novo pathogenic variant, NC_000022.11 (NM_006941):c.428+1G>T, in the second intron of the SOX10 gene with autosomal dominant inheritance pattern.
Journal Section:
Novel Insights from Clinical Practice
References
1.
Amiel
J
, Lyonnet
S
. Hirschsprung disease, associated syndromes, and genetics: a review
. J.Med. Genet
. 2001
;38
:729
–39
.2.
Apaydin
F
, Bereketoglu
M
, Turan
O
, Hribar
K
, Maassen
MM
, Günhan
O
et al. Waardenburg syndrome
. HNO
. 2004
;52
(6
):533
–7
.3.
Baldwin
CT
, Hoth
CF
, Macina
RA
, Milunsky
A
. Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature
. Am J Med Genet
. 1995
;58
(2
):115
–22
.4.
Bolger
AM
, Lohse
M
, Usadel
B
. Trimmomatic: a flexible trimmer for Illumina sequence data
. Bioinformatics
. 2014
;30
(15
):2114
–20
.5.
Bondurand
N
, Dastot-Le Moal
F
, Stanchina
L
, Collot
N
, Baral
V
, Marlin
S
et al. Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4
. Am J Hum Genet
. 2007
;81
:116
–28
.6.
Bremer
M
, Fröb
F
, Kichko
T
, Reeh
P
, Tamm
ER
, Suter
U
et al. Sox10 is required for Schwann-cell homeostasis and myelin maintenance in the adult peripheral nerve
. Glia
. 2011
;59
(7
):1022
–32
.7.
Britsch
S
, Goerich
DE
, Riethmacher
D
, Peirano
RI
, Rossner
M
, Nave
KA
et al. The transcription factor Sox10 is a key regulator of peripheral glial development
. Genes Dev
. 2001
;15
(1
):66
–78
.8.
Carey
JC
, Palumbos
JC
. Advances in the understanding of the genetic causes of hearing loss in children inform a rational approach to evaluation
. Indian J Pediatr
. 2016
;83
(10
):1150
–6
.9.
Chang
X
, Wang
K
. wANNOVAR: annotating genetic variants for personal genomes via the web
. J Med Genet
. 2012
;49
(7
):433
–6
.10.
Chaoui
A
, Watanabe
Y
, Touraine
R
, Baral
V
, Goossens
M
, Pingault
V
et al. Identification and functional analysis of SOX10 missense mutations in different subtypes of waardenburg syndrome
. Hum Mutat
. 2011
;32
(12
):1436
–49
.11.
Cohen
M
, Phillips
JA
. Genetic approach to evaluation of hearing loss
. Otolaryngol Clin North Am
. 2012
;45
(1
):25
–39
.12.
Danecek
P
, Bonfield
JK
, Liddle
J
, Marshall
J
, Ohan
V
, Pollard
MO
et al. Twelve years of SAMtools and BCFtools
. Gigascience
. 2021
10
2
giab008
4
.13.
Desmet
FO
, Hamroun
D
, Lalande
M
, Collod-Béroud
G
, Claustres
M
, Béroud
C
. Human Splicing Finder: an online bioinformatics tool to predict splicing signals
. Nucleic Acids Res
. 2009
;37
(9
):e67
.14.
Eigelshoven
S
, Kameda
G
, Kortüm
AK
, Hübsch
S
, Angerstein
W
, Singh
P
et al. Waardenburg syndrome type I with heterochromia iridis and circumscribed hypopigmentation of the skin
. Pediatr Dermatol
. 2009
;26
(6
):759
–61
.15.
Global Burden of Disease Child and Adolescent Health Collaboration
Kassebaum
N
, Kyu
HH
, Zoeckler
L
, Olsen
HE
, Thomas
K
et al. Child and adolescent health from 1990 to 2015: findings from the global burden of diseases, injuries, and risk factors 2015 study
. JAMA Pediatr
. 2017
;171
(6
):573
–92
.16.
He
D
, Marie
C
, Zhao
C
, Kim
B
, Wang
J
, Deng
Y
et al. Chd7 cooperates with Sox10 and regulates the onset of CNS myelination and remyelination
. Nat Neurosci
. 2016
;19
(5
):678
–89
.17.
Kircher
M
, Witten
DM
, Jain
P
, O’roak
BJ
, Cooper
GM
, Shendure
J
. A general framework for estimating the relative pathogenicity of human genetic variants
. Nat Genet
. 2014
;46
(3
):310
–5
.18.
Kopanos
C
, Tsiolkas
V
, Kouris
A
, Chapple
CE
, Albarca Aguilera
M
, Meyer
R
et al. VarSome: the human genomic variant search engine
. Bioinformatics
. 2019
;35
(11
):1978
–80
.19.
Kuhlbrodt
K
, Herbarth
B
, Sock
E
, Hermans-Borgmeyer
I
, Wegner
M
. Sox10, a novel transcriptional modulator in glial cells
. J Neurosci
. 1998
;18
(1
):237
–50
.20.
Landrum
MJ
, Lee
JM
, Benson
M
, Brown
GR
, Chao
C
, Chitipiralla
S
et al. ClinVar: improving access to variant interpretations and supporting evidence
. Nucleic Acids Res
. 2018
46
D1
D1062
7
.21.
Li
H
, Durbin
R
. Fast and accurate long-read alignment with Burrows–Wheeler transform
. Bioinformatics
. 2010
;26
(5
):589
–95
.22.
Li
H
, Durbin
R
. Fast and accurate short read alignment with Burrows–Wheeler transform
. Bioinformatics
. 2009
;25
(14
):1754
–60
.23.
Li
H
, Handsaker
B
, Wysoker
A
, Fennell
T
, Ruan
J
, Homer
N
et al. The sequence alignment/map format and SAMtools
. Bioinformatics
. 2009
;25
(16
):2078
–9
.24.
Li
W
, Mei
L
, Chen
H
, Cai
X
, Liu
Y
, Men
M
et al. New genotypes and phenotypes in patients with 3 subtypes of waardenburg syndrome identified by diagnostic next-generation sequencing
. Neural Plast
. 2019
;2019
:7143458
.25.
Masood
S
, Jalil
P
, Ahmed Jan
N
, Sadique
M
. Waardenburg syndrome type-II in twin siblings: an unusual audio-pigmentary disorder
. Cureus
. 2020
;12
(10
):e10889
.26.
Moldenæs
MF
, Rendtorff
ND
, Hindbæk
LS
, Tørring
PM
, Nilssen
Ø
, Tranebjærg
L
. Clinical manifestations and novel pathogenic variants in SOX10 in eight Danish probands with Waardenburg syndrome
. Eur J Med Genet
. 2021
;64
(9
):104265
.27.
Morton
CC
, Nance
WE
. Newborn hearing screening: a silent revolution
. N Engl J Med
. 2006
;354
(20
):2151
–64
.28.
National Center for Biotechnology Information
. ClinVar [VCV000590850.3]. 2023a. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000590850.3 (accessed April 8, 2023).29.
National Center for Biotechnology Information
. ClinVar [VCV000635541.3]. 2023b
. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000635541.3 (accessed April 8, 2023).30.
National Center for Biotechnology Information
. ClinVar [VCV000995934.3]. 2023c. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000995934.3 (accessed April 8, 2023).31.
Pardono
E
, van Bever
Y
, van den Ende
J
, Havrenne
PC
, Iughetti
P
, Maestrelli
SRP
et al. Waardenburg syndrome: clinical differentiation between types I and II
. Am J Med Genet
. 2003
117A
3
223
35
.32.
Phillips
SJ
, Anderson
RP
, Dudík
M
, Schapire
RE
, Blair
ME
Opening the black box: an open-source release of Maxent
. 2017
. Available from: Ecography.40887-893Http://hollywood.mit.edu/burgelab/maxent/Xmaxentscan_scoreseq.html.33.
Pingault
V
, Bondurand
N
, Kuhlbrodt
K
, Goerich
DE
, Préhu
MO
, Puliti
A
et al. SOX10 mutations in patients with Waardenburg-Hirschsprung disease
. Nat Genet
. 1998
;18
(2
):171
–3
.34.
Pingault
V
, Ente
D
, Dastot-Le Moal
F
, Goossens
M
, Marlin
S
, Bondurand
N
. Review and update of mutations causing Waardenburg syndrome
. Hum Mutat
. 2010
;31
(4
):391
–406
.35.
Schwarz
JM
, Cooper
DN
, Schuelke
M
, Seelow
D
. Mutationtaster2: mutation prediction for the deep-sequencing age
. Nat Methods
. 2014
;11
(4
):361
–2
.36.
Soares de Lima
Y
, Chiabai
M
, Shen
J
, Córdoba
MS
, Versiani
BR
, Benício
ROA
et al. Syndromic hearing loss molecular diagnosis: application of massive parallel sequencing
. Hear Res
. 2018
;370
:181
–8
.37.
Stolt
CC
, Rehberg
S
, Ader
M
, Lommes
P
, Riethmacher
D
, Schachner
M
et al. Terminal differentiation of myelin-forming oligodendrocytes depends on the transcription factor Sox10
. Genes Dev
. 2002
;16
(2
):165
–70
.38.
Vaser
R
, Sikic
M
, Ng
PC
, Adusumalli
S
, Leng
SN
. SIFT missense predictions for genomes
. Nat Protoc
. 2016
;11
:1
–9
.39.
Waardenburg
PJ
. A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentarydefects of the iris and head hair and with congenital deafness
. Am J Hum Genet
. 1951
;3
:195
–253
.40.
Yang
H
, Robinson
PN
, Wang
K
. Phenolyzer: phenotype-based prioritization of candidate genes for human diseases
. Nat Methods
. 2015
;12
(9
):841
–3
.41.
Yu
Y
, Liu
W
, Chen
M
, Yang
Y
, Yang
Y
, Hong
E
et al. Two novel mutations of PAX3 and SOX10 were characterized as genetic causes of Waardenburg Syndrome
. Mol Genet Genomic Med
. 2020
;8
(5
):e1217
.© 2023 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2023
You do not currently have access to this content.
