Genetic insights, disease mechanisms, and biological therapeutics for Waardenburg syndrome

Huang, Sida; Song, Jian; He, Chufeng; Cai, Xinzhang; Yuan, Kai; Mei, Lingyun; Feng, Yong

doi:10.1038/s41434-021-00240-2

Cited by 26 publications

(43 citation statements)

References 188 publications

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“…A DNA library was constructed from the fragments using a TruSeq Library Preparation Kit (Illumina Inc., San Diego, CA). Probe capture-based target enrichment was achieved with a SeqCap EZ Hybridization and Wash Kit (Roche NimbleGen, Madison, WI) using probes designed to target the coding regions of 30 common deafness-associated genes in the Taiwanese population, including the six genes ( PAX3, MITF, EDNRB, EDN3, SOX10, SNAI2 ) reported to be causative of WS (Supplemental Table S1) [15, 21]. The total target region size was approximately 317 kb, and the DNA samples were sequenced with a MiSeq platform (Illumina Inc., San Diego, CA) to produce 300-nucleotide paired-end reads with a 150x average read depth.…”

Section: Methodsmentioning

confidence: 99%

“…Variants in PAX3 are primarily responsible for WS1 and WS3, while SOX10, EDN3 , and EDNRB variants are involved in WS4. Genetic studies have linked WS2 to variants in MITF, SOX10, EDN3, EDNRB , and SNAI2 [15]. Interactions between the six WS-associated genes are believed to form a MITF -centered regulatory framework responsible for controlling the differentiation and development of neural crest cells (NCCs), particularly melanocytes derived from NCCs [15, 16].…”

Section: Introductionmentioning

confidence: 99%

“…Genetic studies have linked WS2 to variants in MITF, SOX10, EDN3, EDNRB , and SNAI2 [15]. Interactions between the six WS-associated genes are believed to form a MITF -centered regulatory framework responsible for controlling the differentiation and development of neural crest cells (NCCs), particularly melanocytes derived from NCCs [15, 16]. An abnormality in this framework could lead to the development of WS and related diseases [16].…”

Section: Introductionmentioning

confidence: 99%

“…As such, the identification of novel variants will contribute to a better understanding of WS pathogenesis. Meanwhile, phenotypic analysis of WS patients is also crucial for better determining the correlations between genotypes and phenotypes for each WS subtype, in turn providing guidance for genetic counseling, diagnosis, and treatment choices for patients [15]. In this study, we examined in detail the clinical phenotypes in a cohort of individuals with suspected WS and performed comprehensive genetic analyses using a targeted next-generation sequencing (NGS) approach.…”

Section: Introductionmentioning

confidence: 99%

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Identification of eight novel variants acrossPAX3, SOX10, EDNRBandMITFgenes in Waardenburg syndrome with next-generation sequencing

Lee

Chen

et al. 2022

Preprint

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Background: Waardenburg syndrome (WS) is a hereditary, genetically heterogeneous disorder characterized by variable presentations of sensorineural hearing impairment and pigmentation anomalies. Objective: This study aimed to investigate the clinical features of WS in detail and determine the genetic causes of patients with clinically suspected WS. Methods: A total of 24 patients from 21 Han Taiwanese families were enrolled and underwent comprehensive physical and audiological examination. We applied targeted next-generation sequencing (NGS) to investigate the potential causative variants in these patients and further validated the candidate variants through Sanger sequencing. Results: We identified 18 causative variants of WS in our cohort. Of these variants, eight were novel and discovered in PAX3, SOX10, EDNRB, MITF genes, including missense, nonsense, deletion, and splice site variants. Several patients presented skeletal deformities, hypotonia, megacolon, and neurological disorders that were rarely seen in WS. Conclusion: This study revealed highly phenotypic variability in Taiwanese WS patients and demonstrated that targeted NGS allowed us to clarify the genetic diagnosis and extend the genetic variant spectrum of WS.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Identification of eight novel variants acrossPAX3, SOX10, EDNRBandMITFgenes in Waardenburg syndrome with next-generation sequencing

Lee

Chen

et al. 2022

Preprint

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“…In addition, iPSC technology is promising for personalized cell therapies ( Takahashi et al, 2007 ; Tang et al, 2020 ; Zhang et al, 2020a ). It is currently thought that a global disturbance of transcriptional regulation due to SOX10 deficiency, which is still not fully understood, may be one cause of the aberrant phenotypes found in WS patients ( Huang et al, 2021 ). Because SOX10 functions as a DNA-binding protein, the likelihood that SOX10 may directly modulate transcription in the nucleus is high.…”

Section: Introductionmentioning

confidence: 99%

A Model of Waardenburg Syndrome Using Patient-Derived iPSCs With a SOX10 Mutation Displays Compromised Maturation and Function of the Neural Crest That Involves Inner Ear Development

Wen

Song

Bai

et al. 2021

Front. Cell Dev. Biol.

Self Cite

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Waardenburg syndrome (WS) is an autosomal dominant inherited disorder that is characterized by sensorineural hearing loss and abnormal pigmentation. SOX10 is one of its main pathogenicity genes. The generation of patient-specific induced pluripotent stem cells (iPSCs) is an efficient means to investigate the mechanisms of inherited human disease. In our work, we set up an iPSC line derived from a WS patient with SOX10 mutation and differentiated into neural crest cells (NCCs), a key cell type involved in inner ear development. Compared with control-derived iPSCs, the SOX10 mutant iPSCs showed significantly decreased efficiency of development and differentiation potential at the stage of NCCs. After that, we carried out high-throughput RNA-seq and evaluated the transcriptional misregulation at every stage. Transcriptome analysis of differentiated NCCs showed widespread gene expression alterations, and the differentially expressed genes (DEGs) were enriched in gene ontology terms of neuron migration, skeletal system development, and multicellular organism development, indicating that SOX10 has a pivotal part in the differentiation of NCCs. It’s worth noting that, a significant enrichment among the nominal DEGs for genes implicated in inner ear development was found, as well as several genes connected to the inner ear morphogenesis. Based on the protein-protein interaction network, we chose four candidate genes that could be regulated by SOX10 in inner ear development, namely, BMP2, LGR5, GBX2, and GATA3. In conclusion, SOX10 deficiency in this WS subject had a significant impact on the gene expression patterns throughout NCC development in the iPSC model. The DEGs most significantly enriched in inner ear development and morphogenesis may assist in identifying the underlying basis for the inner ear malformation in subjects with WS.

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Identification of nine novel variants across PAX3, SOX10, EDNRB, and MITF genes in Waardenburg syndrome with next‐generation sequencing

Lee¹,

Chen

et al. 2022

Molec Gen & Gen Med

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Background: Waardenburg syndrome (WS) is a hereditary, genetically heterogeneous disorder characterized by variable presentations of sensorineural hearing impairment and pigmentation anomalies. This study aimed to investigate the clinical features of WS in detail and determine the genetic causes of patients with clinically suspected WS.Methods: A total of 24 patients from 21 Han-Taiwanese families were enrolled and underwent comprehensive physical and audiological examinations. We applied targeted next-generation sequencing (NGS) to investigate the potential causative variants in these patients and further validated the candidate variants through Sanger sequencing. Results:We identified 19 causative variants of WS in our cohort. Of these variants, nine were novel and discovered in PAX3, SOX10, EDNRB, and MITF genes, including missense, nonsense, deletion, and splice site variants. Several patients presented with skeletal deformities, hypotonia, megacolon, and neurological disorders that were rarely seen in WS. Conclusion:This study revealed highly phenotypic variability in Taiwanese WS patients and demonstrated that targeted NGS allowed us to clarify the genetic diagnosis and extend the genetic variant spectrum of WS.

show abstract

Genetic insights, disease mechanisms, and biological therapeutics for Waardenburg syndrome

Cited by 26 publications

References 188 publications

Identification of eight novel variants acrossPAX3, SOX10, EDNRBandMITFgenes in Waardenburg syndrome with next-generation sequencing

Identification of eight novel variants acrossPAX3, SOX10, EDNRBandMITFgenes in Waardenburg syndrome with next-generation sequencing

A Model of Waardenburg Syndrome Using Patient-Derived iPSCs With a SOX10 Mutation Displays Compromised Maturation and Function of the Neural Crest That Involves Inner Ear Development

Identification of nine novel variants across PAX3, SOX10, EDNRB, and MITF genes in Waardenburg syndrome with next‐generation sequencing

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