Waardenburg Syndrome Research Articles

The first Korean case of Waardenburg-Shah syndrome with novel endothelin receptor type B mutations

The first Korean case of Waardenburg-Shah syndrome with novel endothelin receptor type B mutations

The outcome of cochlear implantation among children with genetic syndromes.

To assess the outcome and efficacy of cochlear implantation in children with genetic syndromes. Study design: case-control study. A cochlear implantation tertiary referral center. All pediatric cochlear implantation recipients with Waardenburg syndrome, Usher syndrome, Dandy-Walker syndrome, or albinism. A control group was appropriately matched to the syndromic group with regard to age at implantation and duration of device use. Cochlear implantation. Subjects' auditory abilities, speech intelligibility, and pure tone thresholds were compared between the syndromic and non-syndromic group. A total of 25 subjects (13 syndromic and 12 non-syndromic) participated in the study. Neither auditory ability nor speech intelligibility scores differed significantly by group. The final PTA of both the groups showed normal-to-mild hearing loss: 26dB HL in the syndromic group and 23dB HL for the control group. Cochlear implant recipients with genetic syndromes achieved similar levels auditory perception and speech intelligibility as their peers with a genetic syndrome. The presence of any of the genetic syndromes described herein should not be a contraindication to cochlear implant provision, as it would have a positive impact on the patients' sensory perception and lifestyle.

Identification and functional analysis of a novel mutation in the PAX3 gene associated with Waardenburg syndrome type I

Waardenburg syndrome type 1 (WS1) is a rare autosomal dominant genetic disorder of neural crest cells (NCC) characterized by congenital sensorineural hearing loss, dystopia canthorum, and abnormal iris pigmentation. WS1 is due to loss-of-function mutations in paired box gene 3 (PAX3). Here, we identified a novel PAX3 mutation (c.808C>G, p.R270G) in a three-generation Chinese family with WS1, and then analyzed its in vitro activities. The R270G PAX3 retained nuclear distribution and normal DNA-binding ability; however, it failed to activate MITF promoter, suggesting that haploinsufficiency may be the underlying mechanism for the mild WS1 phenotype of the study family.

Germinal mosaicism of PAX3 mutation caused Waardenburg syndrome type I

ObjectivesWaardenburg syndrome mutations are most often recurrent or de novo. The rate of familial recurrence is low and families with several affected children are extremely rare. In this study, we aimed to clarify the underlying hereditary cause of Waardenburg syndrome type I in two siblings in a Chinese family, with a mother affected by prelingual mild hearing loss and a father who was negative for clinical symptoms of Waardenburg syndrome and had a normal hearing threshold. MethodsComplete characteristic features of the family members were recorded and genetic sequencing and parent-child relationship analyses were performed. ResultsThe two probands were found to share double mutations in the PAX3/GJB2 genes that caused concurrent hearing loss in Waardenburg syndrome type I. Their mother carried the GJB2 c.109G > A homozygous mutation; however, neither the novel PAX3 c.592delG mutation, nor the Waardenburg syndrome phenotype, was observed in either parent. ConclusionThese previously unreported digenic mutations in PAX3/GJB2 resulted in deafness associated with Waardenburg syndrome type I in this family. To our knowledge, this is the first report describing germinal mosaicism in Waardenburg syndrome. This concept is important because it complicates genetic counseling of this family regarding the risk of recurrence of the mutations in subsequent pregnancies.

Creation of miniature pig model of human Waardenburg syndrome type 2A by ENU mutagenesis.

Human Waardenburg syndrome 2A (WS2A) is a dominant hearing loss (HL) syndrome caused by mutations in the microphthalmia-associated transcription factor (MITF) gene. In mouse models with MITF mutations, WS2A is transmitted in a recessive pattern, which limits the study of hearing loss (HL) pathology. In the current study, we performed ENU (ethylnitrosourea) mutagenesis that resulted in substituting a conserved lysine with a serine (p. L247S) in the DNA-binding domain of the MITF gene to generate a novel miniature pig model of WS2A. The heterozygous mutant pig (MITF +/L247S) exhibits a dominant form of profound HL and hypopigmentation in skin, hair, and iris, accompanied by degeneration of stria vascularis (SV), fused hair cells, and the absence of endocochlear potential, which indicate the pathology of human WS2A. Besides hypopigmentation and bilateral HL, the homozygous mutant pig (MITF L247S/L247S) and CRISPR/Cas9-mediated MITF bi-allelic knockout pigs both exhibited anophthalmia. Three WS2 patients carrying MITF mutations adjacent to the corresponding region were also identified. The pig models resemble the clinical symptom and molecular pathology of human WS2A patients perfectly, which will provide new clues for better understanding the etiology and development of novel treatment strategies for human HL.

A novel mutation of the EYA4 gene associated with post-lingual hearing loss in a proband is co-segregating with a novel PAX3 mutation in two congenitally deaf family members

ObjectivesThis work was aimed at establishing the molecular etiology of hearing loss in a 9-year old girl with post-lingual non-syndromic mild sensorineural hearing loss with a complex family history of clinically heterogeneous deafness. MethodsThe proband's DNA was subjected to NGS analysis of a 59-targeted gene panel, with the use of the Ion Torrent PGM platform. Conventional Sanger sequencing was used for segregation analysis in all the affected relatives. The proband and all the other hearing impaired members of the family underwent a thorough clinical and audiological evaluation. ResultsA new likely pathogenic mutation in the EYA4 gene (c.1154C > T; p.Ser385Leu) was identified in the proband and in her 42-year-old father with post-lingual non-syndromic profound sensorineural hearing loss. The EYA4 mutation was also found in the proband's grandfather and uncle, both showing clinical features of Waardenburg syndrome type 1. A novel pathogenic splice-site mutation (c.321+1G > A) of the PAX3 gene was found to co-segregate with the EYA4 mutation in these two subjects. ConclusionThe identified novel EYA4 mutation can be considered responsible of the hearing loss observed in the proband and her father, while a dual molecular diagnosis was reached in the relatives co-segregating the EYA4 and the PAX3 mutations. In these two subjects the DFNA10 phenotype was masked by Waardenburg syndrome.The use of NGS targeted gene-panel, in combination with an extensive clinical and audiological examination led us to identify the genetic cause of the hearing loss in members of a family in which different forms of autosomal dominant deafness segregate. These results provide precise and especially important prognostic and follow-up information for the future audiologic management in the youngest affected member.

Prenatal diagnosis and genetic counseling�for Waardenburg syndrome type�I and II in Chinese families

Waardenburg syndrome (WS) is an auditory-pigmentary disorder with varying combinations of sensorineural hearing loss and abnormal pigmentation. The present study aimed to investigate the underlying molecular pathology and provide a method of prenatal diagnosis of WS in Chinese families. A total of 11 patients with WS from five unrelated Chinese families were enrolled. A thorough clinical examination was performed on all participants. Furthermore, patients with WS underwent screening for mutations in the following genes: Paired box 3 (PAX3), melanogenesis associated transcription factor (MITF), SRY-box 10, snail family transcriptional repressor 2 and endothelin receptor type B using polymerase chain reaction sequencing. Array-based comparative genomic hybridization was used for specific patients whose sequence results were normal. Following identification of the genotype of the probands and their parents, prenatal genetic diagnosis was performed for family 01 and 05. According to the diagnostic criteria for WS, five cases were diagnosed as WS1, while the other six cases were WS2. Genetic analysis revealed three mutations, including a nonsense mutation PAX3 c.583C>T in family 01, a splice-site mutation MITF c.909G>A in family 03 and an in-frame deletion MITF c.649_651delGAA in family 05. To the best of the authors' knowledge the mutations (c.583C>T in PAX3 and c.909G>A in MITF) were reported for the first time in Chinese people. Mutations in the gene of interest were not identified in family 02 and 04. The prenatal genetic testing of the two fetuses was carried out and demonstrated that the two babies were normal. The results of the present study expanded the range of known genetic mutations in China. Identification of genetic mutations in these families provided an efficient way to understand the causes of WS and improved genetic counseling.

Waardenburg Syndrome Expression and Penetrance

Through a combination of in silico research and reviews of previous work, mechanisms by which nonsense-mediated mRNA decay (NMD) affects the inheritance and expressivity of Waardenburg syndrome is realized. While expressivity and inheritance both relate to biochemical processes underlying a gene's function, this research explores how alternative splicing and premature termination codons (PTC's) within mRNAs mutated in the disease are either translated into deleterious proteins or decayed to minimize expression of altered proteins. Elucidation of splice variants coupled with NMD perpetuating the various symptoms and inheritance patterns of this disease represent novel findings. By investigating nonsense mutations that lie within and outside the NMD boundary of these transcripts we can evaluate the effects of protein truncation versus minimized protein expression on the variable expressivity found between Type I and Type III Waardenburg syndrome, PAX3, while comparatively evaluating EDN3 and SOX10's role in inheritance of Type IV subtypes of the disease. This review will demonstrate how alternative splicing perpetuates or limits NMD activity by way of PTC positioning, thereby affecting the presentation of Waardenburg syndrome.

Novel PAX3 mutations causing Waardenburg syndrome type 1 in Tunisian patients

Waardenburg syndrome (WS) is an auditory-pigmentary disease characterized by a clinical and genetic variability. WS is classified into four types depending on the presence or absence of additional symptoms: WS1, WS2, WS3 and WS4. Type 1 and 3 are mostly caused by PAX3 mutations, while type 2 and type 4 are genetically heterogeneous.The aims of this study are to confirm the diagnostic of WS1 by the sequencing of PAX3 gene and to evaluate the genotype phenotype correlation.A clinical classification was established for 14 patients WS, as proposed by the Waardenburg Consortium, and noted a predominance of type 1 and type 2 with 6 patients WS1, 7 patients WS2 and 1 patient WS3. A significant inter and intra-familial clinical heterogeneity was also observed.A sequencing of PAX3 gene in the 6 patients WS1 confirmed the diagnosis in 4 of them by revealing three novel mutations that modify two functional domains of the protein: the c.942delC; the c.933_936dupTTAC and the c.164delTCCGCCACA. These three variations are most likely responsible for the phenotype, however their pathogenic effects need to be confirmed by functional studies. The MLPA analysis of the 2 patients who were sequence negative for PAX3 gene revealed, in one of them, a heterozygous deletion of exons 5 to 9 confirming the WS1 diagnosis.Both clinical and molecular approaches led to the conclusion that there is a lack of genotype-phenotype correlation in WS1, an element that must be taken into account in genetic counseling. The absence of PAX3 mutation in one patient WS1 highlights the fact that the clinical classification is sometimes insufficient to distinguish WS1 from other types WS hence the interest of sequencing the other WS genes in this patient.

Functional analysis of a SOX10 gene mutation associated with Waardenburg syndrome II

Waardenburg syndrome (WS) is an autosomal dominant inherited non-syndromic type of hereditary hearing loss characterized by varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four subtypes (WS1–WS4) based on additional symptoms. WS2 is characterized by the absence of additional symptoms. Recently, we identified a SOX10 missense mutation c.422T > C (p.L141P) associated with WS2. We performed functional assays and found the mutant loses DNA-binding capacity, shows aberrant cytoplasmic and nuclear localization, and fails to interact with PAX3. Therefore, the mutant cannot transactivate the MITF promoter effectively, inhibiting melanin synthesis and leading to WS2. Our study confirmed haploinsufficiency as the underlying pathogenesis for WS2.

Genetic analysis of a Chinese family with members affected with Usher syndrome type II and Waardenburg syndrome type IV

AimsThe purpose of this study was to identify the genetic causes of a family presenting with multiple symptoms overlapping Usher syndrome type II (USH2) and Waardenburg syndrome type IV (WS4). MethodsTargeted next-generation sequencing including the exon and flanking intron sequences of 79 deafness genes was performed on the proband. Co-segregation of the disease phenotype and the detected variants were confirmed in all family members by PCR amplification and Sanger sequencing. ResultsThe affected members of this family had two different recessive disorders, USH2 and WS4. By targeted next-generation sequencing, we identified that USH2 was caused by a novel missense mutation, p.V4907D in GPR98; whereas WS4 due to p.V185M in EDNRB. This is the first report of homozygous p.V185M mutation in EDNRB in patient with WS4. ConclusionThis study reported a Chinese family with multiple independent and overlapping phenotypes. In condition, molecular level analysis was efficient to identify the causative variant p.V4907D in GPR98 and p.V185M in EDNRB, also was helpful to confirm the clinical diagnosis of USH2 and WS4.

Identification of rare paired box 3 variant in strabismus by whole exome sequencing.

To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. Whole exome sequencing and filtering identified a nonsynonymous mutation c.434G-T transition in paired box 3 (PAX3) in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. Our results report that the c.434G-T mutation (p.R145L) in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.

Waardenburg Syndrome: An Unusual Indication of Cochlear Implantation Experienced in 11 Patients.

The aim of this study was to present the surgical findings of children with Waardenburg syndrome (WS) and investigate speech development after cochlear implantation in this unique group of patients. A retrospective chart review of the patients diagnosed with WS and implanted between 1998 and 2015 was performed. Categories of auditory performance (CAP) test were used to assess the auditory skills of these patients. CAP is a nonlinear hierarchical scale used to rate a child's developing auditory abilities. Preoperative test results and intraoperative surgical findings of these patients have been presented. In total, 1835 cases were implanted a tour institution, and 1210 of these were children. Among these implantees, 11 were diagnosed with WS (0.59% of all implantees). Four of the 11 patients showed incomplete partition type 2bony labyrinth abnormality (Mondini deformity) and all patients showed intraoperative gusher during cochleostomy, which was subsided through routine interventions. No other complications occurred during surgery, and all patients showed satisfactory CAP results in the late postoperative period. Our experiences with cochlear implantation in patients with WS showed that the procedure is safe and effective in this group of patients. Surgeons should be aware of possible labyrinth malformations and intraoperative problems such as gusher in these patients. In long term, auditory performances may exhibit satisfactory results with optimal postoperative educational and supportive measures.

Study of gene mutation and pathogenetic mechanism for a family with Waardenburg syndrome

To explore the pathogenetic mechanism of a family affected with Waardenburg syndrome. Clinical data of the family was collected. Potential mutation of the MITF, SOX10 and SNAI2 genes were screened. Plasmids for wild type (WT) and mutant MITF proteins were constructed to determine their exogenous expression and subcellular distribution by Western blotting and immunofluorescence assay, respectively. A heterozygous c.763C>T (p.R255X) mutation was detected in exon 8 of the MITF gene in the proband and all other patients from the family. No pathological mutation of the SOX10 and SNAI2 genes was detected. The DNA sequences of plasmids of MITFwild and mutant MITFR255X were confirmed. Both proteins were detected with the expected size. WT MITF protein only localized in the nucleus, whereas R255X protein showed aberrant localization in the nucleus as well as the cytoplasm. The c.763C>T mutation of the MITF gene probably underlies the disease in this family. The mutation can affect the subcellular distribution of MITF proteins in vitro, which may shed light on the molecular mechanism of Waardenburg syndrome caused by mutations of the MITF gene.

English

INTRODUCTION ; Neurocutaneous disorders are genetically determined disorders showing both cutaneous and neurologic involvement. The definition includes both hereditary and nonhereditary phenotypes but excludes acquired disorders. Either they follow the established Mendelian modes of inheritance or they represent lethal mutations surviving by mosaicism, or they belong to the group of chromosomal disorders. Some clinicians still use phacomatosis to categorize particular neurocutaneous diseases characterized by patchy lesions involving the skin and the nervous system. Unfortunately, this term has diminished rather than increased our understanding of these disorders because the group of phacomatoses has never been well defined. Today, this term should no longer be used for the classification of neurocutaneous diseases but may be applied, together with a specifying adjective, to some genetically determined diseases characterized by the presence of multiple nevi, such as phacomatosis pigmentovascularis. AIM OF THE STUDY : 1. To study the incidence of Neurocutaneous disorders in the outpatients attending the Department of Dermatology in Government General Hospital, Chennai, from July 2006 to September 2008. 2. To determine the age and sexwise distribution of Neurocutaneous disorders. 3. To study the clinical morphology and distribution of lesions. 4. To correlate the morphological lesions with the histopathological freatures. 5. To evaluate incidence of associated systemic abnormalities. 6. To determine the involvement in other family members. CONCLUSION 1. In the study of 109 cases of Neurocutaneous syndromes, Neurofibromatosis topped the list followed by Tuberous sclerosis complex. 2. NF – Type –I accounted for the maximum number of Neurofibromatosis. 3. The most common clinical sign in NF was CALM followed by mollusca fibrosa. 4. Axillary, inguinal, palmar and plantar freckling were the notable pigmentary changes in NF. 5. Lisch nodules accounted for 81.3% of the cases in NF. 6. Skeletal abnormalities in the form of kyphoscoliosis, local gigantism and facial asymmetry were reported. 7. One case of sarcoma complicating NF was observed. 8. A case of NF-II with multiple intracranial tumours in MRI was detected. 9. Tuberous sclerosis complex is the second most common neurocutaneous disorder. 10. Angiofibroma was observed in 100% cases followed by ash leaf macules (85%). 11. Few patients had sub-ependymal nodules and cortical tubers. 12. One patient with astrocytoma and one patient with renal angiomyolipoma were observed. 13. Classical features of XP were observed in a patient who also had cutaneous malignancies – BCC over the nose and SCC over the cheek. 14. Sturge – Weber syndrome with unilateral port wine stain with seizures was reported in our study. 15. One case of unilateral naevus comedonicus was reported. 16. Two cases of Waardenburg syndrome ( mother and child ) was observed in our study. Both had white forelock, heterochromia iridis and deafness. 17. Two cases of epidermal naevus syndrome with extensive involvement and seizures were noted. 18. Two cases of giant congential melanocytic naevus were reported. 19. A case of Elejalde syndrome with typical clinical manifestations was observed. 20. One case of oculocutaneous albinism was reported. 21. One case of Adams Oliver syndrome with Dandy Walker malformation has been reported.

Whole-exome sequencing analysis of Waardenburg syndrome in a Chinese family

Waardenburg syndrome (WS) is a dominantly inherited, genetically heterogeneous auditory-pigmentary syndrome characterized by non-progressive sensorineural hearing loss and iris discoloration. By whole-exome sequencing (WES), we identified a nonsense mutation (c.598C>T) in PAX3 gene, predicted to be disease causing by in silico analysis. This is the first report of genetically diagnosed case of WS PAX3 c.598C>T nonsense mutation in Chinese ethnic origin by WES and in silico functional prediction methods.

The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology

Certain transcription factors have vital roles in lineage development, including specification of cell types and control of differentiation. Microphthalmia-associated transcription factor (MITF) is a key transcription factor for melanocyte development and differentiation. MITF regulates expression of numerous pigmentation genes to promote melanocyte differentiation, as well as fundamental genes for maintaining cell homeostasis, including genes encoding proteins involved in apoptosis (eg, BCL2) and the cell cycle (eg, CDK2). Loss-of-function mutations of MITF cause Waardenburg syndrome type IIA, whose phenotypes include depigmentation due to melanocyte loss, whereas amplification or specific mutation of MITF can be an oncogenic event that is seen in a subset of familial or sporadic melanomas. In this article, we review basic features of MITF biological function and highlight key unresolved questions regarding this remarkable transcription factor.

Homozygous EDNRB mutation in a patient with Waardenburg syndrome type 1

ObjectiveTo examine and expand the genetic spectrum of Waardenburg syndrome type 1 (WS1). MethodsClinical features related to Waardenburg syndrome (WS) were examined in a five-year old patient. Mutation analysis of genes related to WS was performed in the proband and her parents. Molecular modeling of EDNRB and the p.R319W mutant was conducted to predict the pathogenicity of the mutation. ResultsThe proband showed sensorineural hearing loss, heterochromia iridis, and dystopia canthorum, fulfilling the clinical criteria of WS1. Genetic analyses revealed that the proband had no mutation in PAX3 which has been known as the cause of WS1, but had a homozygous missense mutation (p.R319W) in endothelin receptor type B (EDNRB) gene. The asymptomatic parents had the mutation in a heterozygote state. This mutation has been previously reported in a heterozygous state in a patient with Hirschsprung’s disease unaccompanied by WS, but the patient and her parents did not show any symptoms in gastrointestinal tract. Molecular modeling of EDNRB with the p.R319W mutation demonstrated reduction of the positively charged surface area in this region, which might reduce binding ability of EDNRB to G protein and lead to abnormal signal transduction underlying the WS phenotype. ConclusionsOur findings suggested that autosomal recessive mutation in EDNRB may underlie a part of WS1 with the current diagnostic criteria, and supported that Hirschsprung’s disease is a multifactorial genetic disease which requires additional factors. Further molecular analysis is necessary to elucidate the gene interaction and to reappraise the current WS classification.

The blue-eyed man: A case of Waardenburg syndrome type 1 associated with mania and autistic spectrum disorder

Waardenburg syndrome (WS) is a rare genetic disorder characterised by varying degrees of sensorineural deafness, dystopia canthorum, musculokeletal defects, pigmentation anomalies such as bright blue iris, greying hair and in some cases intestinal pathology.A 21-year-old Chinese gentleman, diagnosed with WS type 1 (Figs. 1 and 2) at the age of two, presented at the emergency unit with manic symptoms for the past one month such as irritability, grandiosity, flight of ideas and reduced need for sleep. With regards to social integration, he had features suggestive of autism spectrum disorder (ASD). He often played by himself and was fixated on particular toys. He was eventually admitted to the psychiatric ward for acute management of mania. He was stabilised on olanzapine 10 mg BD and sodium valproate 600 mg BD. His sodium valproate was cross-titrated with lithium in the ward and his manic features gradually subsided. He was discharged well after 2 weeks of admission with lithium 300 mg BD and olanzapine 10 mg BD. WS type 1 has been localised to the locus 2q35 and researchers have identified that a tetranucleotide repeat marker on 2q35 is strongly associated with recurrent mood symptoms.In conclusion, it is important to note that individuals with WS may be at higher risk to develop ASD and mood disorders.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Functional analysis of a nonstop mutation in MITF gene identified in a patient with Waardenburg syndrome type 2

Waardenburg syndrome (WS) is an autosomal dominant inherited neurogenic disorder with the combination of various degrees of sensorineural deafness and pigmentary abnormalities affecting the skin, hair and eye. The four subtypes of WS were defined on the basis of the presence or absence of additional symptoms. Mutation of human microphthalmia-associated transcription factor (MITF) gene gives rise to WS2. Here, we identified a novel WS-associated mutation at the stop codon of MITF (p.X420Y) in a Chinese WS2 patient. This mutation resulted in an extension of extra 33 amino-acid residues in MITF. The mutant MITF appeared in both the nucleus and the cytoplasm, whereas the wild-type MITF was localized in the nucleus exclusively. The mutation led to a reduction in the transcriptional activities, whereas the DNA-binding activity was not altered. We show that the foremost mechanism was haploinsufficiency for the mild phenotypes of WS2 induced in X420Y MITF.