Waardenburg Syndrome Research Articles

Application of next generation sequencing in 3 Waardenburg syndrome

Objective:To test the gene sequence of 3 patients with Waardenburg syndrome（WS） using the next generation sequencing technology in order to explore the possible mechanism of molecular genetics. Methods:Medical histories of the family members were collected. Physical examination, audiological evaluation and CT examination were performed. Peripheral blood was collected and DNA was extracted. The exon region of 159 deafness genes, 6 mitochondrial genes and 3 miRNAs of the proband were tested by next generation sequencing. The mutation sites of the possible pathogenic genes were obtained, subsequently, Sanger sequencing verification was performed on the proband and family members. Results:The first proband had a heterozygous mutation in exon 7 of MITF gene（NM_000248）: c.641_643delGAA; The second proband had a heterozygous mutation in exon 10 of MITF gene（NM_001354605）: c.1177-1G>A; The third proband had a heterozygous mutation in exon 5 of PAX3 gene（NM_181457）: c.587_593delCCTCAGC; The parents of the three probands verified by Sanger sequencing that there was no variation at the corresponding sites, and the above mutations were spontaneous mutations. Conclusion:Next generation sequencing can more comprehensively analyze information of the carried status and genetic rules of the disease-associated gene in WS families, and provide guidance for family reproductives.

Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss.

Hearing loss is one of the most common sensory defects, affecting 5.5% of the worldwide population and significantly impacting health and social life. It is mainly attributed to genetic causes, but their relative contribution reflects the geographical region's socio-economic development. Extreme genetic heterogeneity with hundreds of deafness genes involved poses challenges for molecular diagnosis. Here we report the investigation of 542 hearing-impaired subjects from all Brazilian regions to search for genetic causes. Biallelic GJB2/GJB6 causative variants were identified in 12.9% (the lowest frequency was found in the Northern region, 7.7%), 0.4% carried GJB2 dominant variants, and 0.6% had the m.1555A > G variant (one aminoglycoside-related). In addition, other genetic screenings, employed in selected probands according to clinical presentation and presumptive inheritance patterns, identified causative variants in 2.4%. Ear malformations and auditory neuropathy were diagnosed in 10.8% and 3.5% of probands, respectively. In 3.8% of prelingual/perilingual cases, Waardenburg syndrome was clinically diagnosed, and in 71.4%, these diagnoses were confirmed with pathogenic variants revealed; seven out of them were novel, including one CNV. All these genetic screening strategies revealed causative variants in 16.2% of the cases. Based on causative variants in the molecular diagnosis and genealogy analyses, a probable genetic etiology was found in ~ 50% of the cases. The present study highlights the relevance of GJB2/GJB6 as a cause of hearing loss in all Brazilian regions and the importance of screening unselected samples for estimating frequencies. Moreover, when a comprehensive screening is not available, molecular diagnosis can be enhanced by selecting probands for specific screenings.

Waardenburg syndrome type 2A in a large Iranian family with a novel MITF gene mutation

BackgroundThe characteristics of Waardenburg syndrome (WS) as a scarce heritable disorder are sensorineural hearing loss and deficits of pigmentation in the skin, hair, and eye. Here, clinical features and detection of the mutation in the MITF gene of WS2 patients are reported in a sizable Iranian family.MethodsA man aged 28-years represented with symptoms of mild unilateral hearing loss (right ear), complete heterochromia iridis, premature graying prior to 30 years of age, and synophrys. In this research, there was a sizable family in Iran comprising three generations with seven WS patients and two healthy members. Whole exome sequencing was applied for proband for the identification of the candidate genetic mutations associated with the disease. The detected mutation in proband and investigated family members was validated by PCR-Sanger sequencing.ResultsA novel heterozygous mutation, NM_198159.3:c.1026dup p.(Asn343Glufs*27), in exon 9 of the MITF gene co-segregated with WS2 in the affected family members. The variant was forecasted as a disease-causing variant by the Mutation Taster. According to the UniProt database, this variant has been located in basic helix-loop-helix (bHLH) domain of the protein with critical role in DNA binding.ConclusionsA frameshift was caused by a nucleotide insertion, c.1026dup, in exon 9 of the MITF gene. This mutation is able to induce an early termination, resulting in forming a truncated protein capable of affecting the normal function of the MITF protein. Helpful information is provided through an exactly described mutations involved in WS to clarify the molecular cause of clinical characteristics of WS and have a contribution to better genetic counseling of WS patients.

Feedback-Related Beta-Band Power Predicts Risky Choices in a Probabilistic Gambling Task

SOX10 variants previously implicated in Waardenburg syndrome (WS) have now been linked to Kallmann syndrome (KS), the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders.Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population.Thirty-seven SOX10-associated IHH cases were identified as follows: current study: 16 KS; 4 nIHH; literature: 16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease states versus gnomAD.SOX10 variants contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.

SOX10 ablation severely impairs the generation of postmigratory neural crest from human pluripotent stem cells

Animal studies have indicated that SOX10 is one of the key transcription factors regulating the proliferation, migration and differentiation of multipotent neural crest (NC), and mutation of SOX10 in humans may lead to type 4 Waardenburg syndrome (WS). However, the exact role of SOX10 in human NC development and the underlying molecular mechanisms of SOX10-related human diseases remain poorly understood due to the lack of appropriate human model systems. In this study, we successfully generated SOX10-knockout human induced pluripotent stem cells (SOX10−/− hiPSCs) by the CRISPR-Cas9 gene editing tool. We found that loss of SOX10 significantly inhibited the generation of p75highHNK1+/CD49D+ postmigratory neural crest stem cells (NCSCs) and upregulated the cell apoptosis rate during NC commitment from hiPSCs. Moreover, we discovered that both the neuronal and glial differentiation capacities of SOX10−/− NCSCs were severely compromised. Intriguingly, we showed that SOX10−/− hiPSCs generated markedly more TFAP2C+nonneural ectoderm cells (NNE) than control hiPSCs during neural crest differentiation. Our results indicate that SOX10 is crucial for the transition of premigratory cells to migrating NC and is vital for NC survival. Taken together, these results provide new insights into the function of SOX10 in human NC development, and the SOX10-knockout hiPSC lines may serve as a valuable cell model to study the pathogenesis of SOX10-related human neurocristopathies.

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.

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.

Nerve-associated Schwann cell precursors contribute extracutaneous melanocytes to the heart, inner ear, supraorbital locations and brain meninges

Melanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans.

Clinical phenocopies of albinism

To present a series of patients diagnosed with oculocutaneous albinism (OCA) based on clinical presentation who were later proven to have a different diagnosis. The medical records of patients seen at the Pediatric Inherited Eye Disease Clinic of the University of Iowa from 1980 to 2018 who were eventually discovered to have an incorrect diagnosis of OCA were reviewed retrospectively. Eight pediatric patients presenting with clinical features suggestive of OCA which changed to a different diagnosis over time were identified. Presenting clinical features included fair pigmentation of the skin and adnexa (8/8), congenital nystagmus (6/8), decreased visual acuity (8/8), iris transillumination defects (8/8), and foveal hypoplasia (7/8). Of the 8 patients, 4 manifested progressive, preschool-age-onset myopia. Other associated clinical features included hearing loss (3), seizures (1), abnormal chest x-ray (1) and easy bruising (2). During follow-up, additional clinical features and genetic testing proved that they have different clinical entities, namely, Knobloch syndrome, Jeune syndrome, Donnai-Barrow syndrome, Waardenburg syndrome, Aniridia syndrome, Stickler syndrome, and Hermansky-Pudlak syndrome, one of the syndromic types of OCA. Clinical features used to diagnose OCA also occur in other disorders. For a definitive diagnosis of OCA, ancillary/genetic testing must be performed. Clinical features not typically found in association with albinism, such as hearing loss, or early onset, or progressive myopia, may indicate the need for more extensive investigation.

Psychometric Properties of the Wechsler Intelligence Scale, WISC-IV for Deaf Intelligence with Wardenburg Syndrome and Level of Intelligence for Different Mental States

This study aimed to investigate the psychometric characteristics of the Wechsler-4 scale of the intelligence of deaf people with Waardenburg syndrome and the level of intelligence according to the mental state. To achieve the objectives of the study, a descriptive survey method was used. The sample of the study consisted of (17) students from all deaf schools in Jordan, whose ages ranged between (8-17) years, and (WISC-IV) was applied in sign language. Indicators are reached for Construct Validity (2.741 - 0.243). And indications for reliability, where the correlation coefficients ranged between (0.487 - 0.898). The results showed that there were no differences in the IQ level of deaf people with Waardenburg syndrome due to gender. The absence of differences in the IQ level of deaf people with Waardenburg syndrome is due to the mental state variable in favor of the deaf group of those with the borderline between Gifted and Superior, but the overall IQ level of the deaf person with Waardenburg syndrome is within the lower limits (IQ = 71), which is Learning Disability. There are also differences in the level of the sub-tests of the scale for deaf people with Waardenburg syndrome, as the (Cancellation) test was the highest score and then (coding) in second place. The study recommends including this syndrome as part of the hearing impairment categories. Studies have been carried out on the development of the functional section of the Wechsler-4 scale to suit the visual perception of deaf people with Waardenburg syndrome. Received: 27 February 2021 / Accepted: 5 June 2021 / Published: 8 July 2021

Waardenburg Syndrome

Background: Waardenburg syndrome (WS) is an autosomal dominant inherited genetic condition that manifests with sensorineural deafness and pigmentation defects of the skin, hair, and iris. This genetically and clinically heterogeneous disease accounts for 2% of the congenitally deaf population. Objectives: The aim of our study is to determine epidemiological and clinical characteristics of this group to improve the management, especially for the hearing impairment. Methods: Seven cases were diagnosed during the examination of children with suspected congenital deafness. Results: The age of our children ranged from 1.3 to 5 years, with a median age of 3.6 years, with female predominance; no consanguineous marriage and fetal or perinatal history have been reported; there was family history of premature greying in four cases and deafness in two cases. Two patients had WS Type 1 with a dystopia canthorum, while four cases had WS Type 2. There was one patient with Waardenburg Klein or Shah syndrome. The otoscopy was normal in all children. Evoked auditory potentials, otoacoustic emissions, and tonal audiometry were performed; they had shown a congenital, sensorineural bilateral, and profound hearing loss >100 dB in all cases. All children had received a cochlear implantation followed by speech reeducation. A genetic consultation was carried out for all our children. Conclusion: WS is a relatively common genetic cause of sensorineural hearing loss. Early diagnosis and improvement of hearing impairment are most important for psychological and intellectual development of the children with WS.

Genotype and phenotype analysis of a family with Waardenburg syndrome type Ⅰcaused by a novel mutation in PAX3 gene

Objective:To identify gene mutation and analysis the association between clinical characterizes and the mutations in a family of Waardenburg syndrome （WS） type I in Yunnan, China. Methods:With informed consent, the proband with WS phenotype and his family members were given medical history collection, physical examination and audiological evaluation. Peripheral blood was obtained, genomic DNA was extracted, and deafness related genes were detected by high-throughput sequencing. Sanger sequencing was used to verify the mutation sites of proband and his family members. Results:C. 602C>G mutation in exon 5 of PAX3 gene was identified, which is nonsense mutation and may cause a truncated protein. The mutation cause 201 amino acid of the protein changed from serine to stop codon. According to the American College of Medical Genetics and Genomics （ACMG）, it is considered as Pathogenicity（PVS1+PM2+PP3）. This mutation has not been included in the database also not been reported in the literature. Conclusion:Combined with the results of clinical diagnosis and gene diagnosis, this mutation was considered as the cause of the disease. This study enriched mutation spectrum of PAX3 gene.

A novel case of concurrent occurrence of demyelinating-polyneuropathy-causing PMP22 duplication and SOX10 gene mutation producing severe hypertrophic neuropathy

BackgroundHereditary motor and sensory neuropathy, also referred to as Charcot–Marie–Tooth disease (CMT), is most often caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. This duplication causes CMT type 1A (CMT1A). CMT1A rarely occurs in combination with other hereditary neuromuscular disorders. However, such rare genetic coincidences produce a severe phenotype and have been reported in terms of “double trouble” overlapping syndrome. Waardenburg syndrome (WS) is the most common form of a hereditary syndromic deafness. It is primarily characterized by pigmentation anomalies and classified into four major phenotypes. A mutation in the SRY sex determining region Y-box 10 (SOX10) gene causes WS type 2 or 4 and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease. We describe a 11-year-old boy with extreme hypertrophic neuropathy because of a combination of CMT1A and WS type 2. This is the first published case on the co-occurrence of CMT1A and WS type 2.Case presentationThe 11-year-old boy presented with motor developmental delay and a deterioration in unstable walking at 6 years of age. In addition, he had congenital hearing loss and heterochromia iridis. The neurological examination revealed weakness in the distal limbs with pes cavus. He was diagnosed with CMT1A by the fluorescence in situ hybridization method. His paternal pedigree had a history of CMT1A. However, no family member had congenital hearing loss. His clinical manifestation was apparently severe than those of his relatives with CMT1A. In addition, a whole-body magnetic resonance neurography revealed an extreme enlargement of his systemic cranial and spinal nerves. Subsequently, a genetic analysis revealed a heterozygous frameshift mutation c.876delT (p.F292Lfs*19) in the SOX10 gene. He was eventually diagnosed with WS type 2.ConclusionsWe described a patient with a genetically confirmed overlapping diagnoses of CMT1A and WS type 2. The double trouble with the genes created a significant impact on the peripheral nerves system. Severe phenotype in the proband can be attributed to the cumulative effect of mutations in both PMP22 and SOX10 genes, responsible for demyelinating neuropathy.

Juvenile type II Waardenburg syndrome: a rare case report in Kerala

<p class="abstract">Rare diseases are many in number but their treatments are less, as most of these rare diseases are genetical and there is no complete cure for a genetic disorder. Waardenburg syndrome (WS) is one among that type of rare genetic disorder thus the treatment is limited but the number of cases are increasing. This was the case report of a newborn baby showing major symptoms of WS. The patient got it through paternally. To make a final conclusion, various diagnostic tests were conducted including the family history as the patient's father had premature grey hairs and white patches on the body. Even though there is no complete cure for this disease condition, the sign and symptoms can be controlled before making it into a major disability. This case report typically dealt with the major types, clinical presentation, diagnosis and supportive therapy for a patient diagnosed with WS. Also showed the crucial role of consanguineous parents on this syndrome because the children affecting this rare syndrome are increasing. This report showed that further studies are required to check how the colour of the hair is changing in WS patients and what is happening to the gene involved in the production of melanin. Also, studies are required the find why WS typically affecting the major sensory organs such as eyes, ears, nose and skin.</p>

Clinical manifestations and novel pathogenic variants in SOX10 in eight Danish probands with Waardenburg syndrome

The SRY-related HMG box gene 10 (SOX10), located on 22q13.1, encodes a member of the SOX family of transcription factors involved in the regulation of embryonic development and in the determination of cell fate and differentiation. SOX10 is one of the six causal genes for Waardenburg syndrome, which is a dominantly inherited auditory-pigmentary disorder characterized by sensorineural hearing impairment and abnormal pigmentation of the hair, skin and iris. Waardenburg syndrome is categorized into four subtypes based on clinical features (WS1-WS4). Here we present eight families (eleven patients) harboring pathogenic variants in SOX10. The patients displayed both allelic and clinical variability: bilateral profound hearing impairment (11/11), malformations of the semicircular canals (5/11), motor skill developmental delay (5/11), pigmentary defects (3/11) and Hirschsprung's disease (3/11) were some of the clinical manifestations observed. The patients demonstrate a spectrum of pathogenic SOX10 variants, of which six were novel (c.267del, c.299_300insA, c.335T >C, c.366_376del, c.1160_1179dup, and exon 3–4 deletion), and two were previously reported (c.336G>A and c.422T>C). Six of the variants occurred de novo whereas two were dominantly inherited. The pathogenic SOX10 variants presented here add novel information to the allelic variability of Waardenburg syndrome and illustrate the considerable clinical heterogeneity.

Waardenburg syndrome type II in a Chinese pedigree caused by frameshift mutation in the SOX10 gene.

Waardenburg syndrome (WS) is a congenital hereditary disease, attributed to the most common symptoms of sensorineural deafness and iris hypopigmentation. It is also known as the hearing-pigmentation deficient syndrome. Mutations on SOXl0 gene often lead to congenital deafness and has been shown to play an important role in the pathogenesis of WS. We investigated one family of five members, with four patients exhibiting the classic form of WS2, whose DNA samples were analyzed by the technique of Whole-exome sequencing (WES). From analysis of WES data, we found that both the mother and all three children in the family have a heterozygous mutation on the Sex Determining Region Y - Box 10 (SOX10) gene. The mutation was c.298_300delinsGG in exon 2 of SOX10 (NM_006941), which leads to a frameshift of nine nucleotides, hence the amino acids (p. S100Rfs*9) are altered and the protein translation may be terminated prematurely. Further flow cytometry confirmed significant down-regulation of SOX10 protein, which indicated the SOX10 gene mutation was responsible for the pathogenesis of WS2 patients. In addition, we speculated that some other mutated genes might be related to disease phenotype in this family, which might also participate in promoting the progression of WS2.

Analysis of genotype-phenotype relationships in 90 Chinese probands with Waardenburg syndrome.

Waardenburg syndrome (WS) is a phenotypically and genetically heterogeneous disorder characterised by hearing loss and pigmentary abnormalities. We clarified the clinical and genetic features in 90 Chinese WS probands. Disease-causing variants were detected in 55 probands, for a molecular diagnosis rate of 61%, including cases related to PAX3 (14.4%), MITF (24.4%), and SOX10 (22.2%). Altogether, 48 variants were identified, including 44 single-nucleotide variants and 4 copy number variants. By parental genotyping, de novo variants were observed in 60% of probands and 15.4% of the de novo variation was associated with mosaicism. Statistical analyses revealed that brown freckles on the skin were more frequently seen in probands with MITF variants; patchy depigmented skin, asymmetric hearing loss, and white forelocks occurred more often in cases with PAX3 variants; and congenital inner ear malformations were more common and cochlear hypoplasia III was exclusively observed in those with SOX10 variants. In addition, we found that ranges of W-index values overlapped between WS probands with different genetic variants, and the use of the W-index as a tool for assessing dystopia canthorum may be problematic in Chinese. Herein, we report the spectrum of a cohort of WS probands and elucidate the relationship between genotype and phenotype.

High Genetic Heterogeneity in Chinese Patients With Waardenburg Syndrome Revealed by Next-Generation Sequencing.

ObjectiveThis study aimed to explore the genetic causes of probands who were diagnosed with Waardenburg syndrome (WS) or congenital sensorineural hearing loss.MethodsA detailed physical and audiological examinations were carried out to make an accurate diagnosis of 14 patients from seven unrelated families. We performed whole-exome sequencing in probands to detect the potential genetic causes and further validated them by Sanger sequencing in the probands and their family members.ResultsThe genetic causes for all 14 patients with WS or congenital sensorineural hearing loss were identified. A total of seven heterozygous variants including c.1459C > T, c.123del, and c.959-409_1173+3402del of PAX3 gene (NM_181459.4), c.198_262del and c.529_556del of SOX10 gene (NM_006941.4), and c.731G > A and c.970dup of MITF gene (NM_000248.3) were found for the first time. Of these mutations, we had confirmed two (c.1459C > T and c.970dup) are de novo by Sanger sequencing of variants in the probands and their parents.ConclusionWe revealed a total of seven novel mutations in PAX3, SOX10, and MITF, which underlie the pathogenesis of WS. The clinical and genetic characterization of these families with WS elucidated high heterogeneity in Chinese patients with WS. This study expands the database of PAX3, SOX10, and MITF mutations and improves our understanding of the causes of WS.

A Rare Case of Waardenburg-Shah Syndrome without Family History

BACKGROUND: Waardenburg syndrome (WS) is an uncommon genetic disorder that is most often characterized by pigmentary disturbance and lateral displacement of inner iris with variety of sensorineural deafness. The prevalence of this syndrome is about 1/42.000–1/50.000 on population. There are approximately 48 cases of WS with Hirschsprung disease (HD) which were being reported up to 2002. CASE REPORTS: A 7-year-old, Asian boy, routine patient of Pediatric-Surgery Department with HD was transferred from Pediatric-Surgery Department of Haji Adam Malik Hospital Medan to Ophthalmology Department of Universitas Sumatera Utara Hospital Medan with progressive abdominal distance and first ophthalmic evaluation. The patient is accompanied by a history of Hirschsprung disease, malnutrition, and sensorineural hearing loss. There was no family history being discovered. He is responding to visual command. Anterior segment examination showed that there were two different colors of iris – blue colored of the whole left iris and partial right iris. Fundoscopy showed pale retina on both eyes. CONCLUSION: This patient is diagnosed with Waardenburg-Shah syndrome type IV. It is directly reality with a kind of other congenital disease like HD and no further treatment is needed.

CRISPR/Cas9-mediated correction of MITF homozygous point mutation in a Waardenburg syndrome 2A pig model

Gene therapy for curing congenital human diseases is promising, but the feasibility and safety need to be further evaluated. In this study, based on a pig model that carries the c.740T>C (L247S) mutation in MITF with an inheritance pattern and clinical pathology that mimics Waardenburg syndrome 2A (WS2A), we corrected the point mutation by the CRISPR-Cas9 system in the mutant fibroblast cells using single-stranded oligodeoxynucleotide (ssODN) and long donor plasmid DNA as the repair template. By using long donor DNA, precise correction of this point mutation was achieved. The corrected cells were then used as the donor cell for somatic cell nuclear transfer (SCNT) to produce piglets, which exhibited a successfully rescued phenotype of WS2A, including anophthalmia and hearing loss. Furthermore, engineered base editors (BEs) were exploited to make the correction in mutant porcine fibroblast cells and early embryos. The correction efficiency was greatly improved, whereas substantial off-targeting mutations were detected, raising a safety concern for their potential applications in gene therapy. Thus, we explored the possibility of precise correction of WS2A-causing gene mutation by the CRISPR-Cas9 system in a large-animal model, suggesting great prospects for its future applications in treating human genetic diseases.

A de novo mutation of the SOX10 gene associated with inner ear malformation in a Guangxi family with Waardenburg syndrome type II

ObjectiveWaardenburg syndrome type 2 (WS2) is a rare neural-crest disorder, characterized by heterochromic irides or blue eyes and sensorineural hearing loss. The aim of this study was to analyze the clinical features and investigate the genetic cause of WS2 in a small family from Guangxi Zhuang Autonomous region. MethodsWhole-exome sequencing and mutational analysis were used to identify disease-causing genes in this family. ResultsA de novo missense mutation, C.355C > T (p. Arg119Cys), in exon 2 of SOX10 was related to inner ear malformation in the proband and identified by whole exon sequencing, but this mutation was absent in normal controls and any public databases. According to nucleic acid sequence and protein bioinformatic analysis, this mutation is considered the cause of WS2 without neurologic involvement in the proband. ConclusionsOur findings provide an accurate genetic diagnosis, counseling, and rehabilitation for family members and may contribute to further genotype-phenotype correlation studies of the SOX10 gene.