UNASSIGNED: In addition to sensorineural hearing loss, Waardenburg Syndrome (WS) may present with variable pigmentation of skin and choroid, which may simulate other life-threating conditions (e.g. melanoma).
UNASSIGNED: Two siblings ostensibly presented with unilateral choroidal pigmentary abnormalities concerning for choroidal tumour. Serial ophthalmic examination documented no lesion growth (base or height) whilst the apparent syndromic features (i.e. iris hypochromia, profound sensorineural hearing loss, SNHL), family history (autosomal dominant inheritance) and positive genetic testing (pathogenic MITF variant) led to a revised diagnosis of Waardenburg Syndrome type 2A.
UNASSIGNED: Sectoral preservation of choroidal pigmentation in WS is rarely associated with choroidal malignancy. Awareness of syndromic features (e.g. SNHL) and access to genetic testing may facilitate early accurate diagnosis (i.e. allay concern for malignancy), enable treatment of modifiable features (e.g. SNHL) and identify other affected relatives.

BACKGROUND: Waardenburg syndrome (WS) is a rare genetic disorder mainly characterized by hearing loss and pigmentary abnormalities. Currently, seven causative genes have been identified for WS, but clinical genetic testing results show that 38.9% of WS patients remain molecularly unexplained. In this study, we performed multi-data integration analysis through protein-protein interaction and phenotype-similarity to comprehensively decipher the potential causative factors of undiagnosed WS. In addition, we explored the association between genotypes and phenotypes in WS with the manually collected 443 cases from published literature.
RESULTS: We predicted two possible WS pathogenic genes (KIT, CHD7) through multi-data integration analysis, which were further supported by gene expression profiles in single cells and phenotypes in gene knockout mouse. We also predicted twenty, seven, and five potential WS pathogenic variations in gene PAX3, MITF, and SOX10, respectively. Genotype-phenotype association analysis showed that white forelock and telecanthus were dominantly present in patients with PAX3 variants; skin freckles and premature graying of hair were more frequently observed in cases with MITF variants; while aganglionic megacolon and constipation occurred more often in those with SOX10 variants. Patients with variations of PAX3 and MITF were more likely to have synophrys and broad nasal root. Iris pigmentary abnormality was more common in patients with variations of PAX3 and SOX10. Moreover, we found that patients with variants of SOX10 had a higher risk of suffering from auditory system diseases and nervous system diseases, which were closely associated with the high expression abundance of SOX10 in ear tissues and brain tissues.
CONCLUSIONS: Our study provides new insights into the potential causative factors of WS and an alternative way to explore clinically undiagnosed cases, which will promote clinical diagnosis and genetic counseling. However, the two potential disease-causing genes (KIT, CHD7) and 32 potential pathogenic variants (PAX3: 20, MITF: 7, SOX10: 5) predicted by multi-data integration in this study are all computational predictions and need to be further verified through experiments in follow-up research.

暂无摘要。

BACKGROUND: Waardenburg syndrome type 2 (WS2) has been reported to be a rare hereditary disorder, which is distinguished by vivid blue eyes, varying degrees of hearing impairment, and abnormal pigment deposition in the skin and hair. Variants in the sex-determining region Y-box containing gene 10 (SOXl0) gene may cause congenital deafness and have been demonstrated to be important during the development of WS2.
METHODS: Complete clinical data of the proband and her family members (her parents and 2 sisters) was collected and physical examinations were performed in the hospital. The laboratory examination including hemoglobin, Coomb\'s test, urine protein, ENA, autoimmune hepatitis-related autoantibodies and ultrasonography were all conducted. We obtained the peripheral blood samples from all the participants and performed whole exome sequencing and sanger sequencing validation.
RESULTS: The present study identified a family of 5 members, and only the proband exhibited typical WS2. Beyond the characteristics of WS2, the proband also manifested absence of puberty. The proband and her younger sister manifested systemic lupus erythematosus (SLE). Whole exome sequencing revealed a de novo variant in the SOX10 gene. The variant c.175 C > T was located in exon 2 of the SOX10 gene, which is anticipated to result in early termination of protein translation.
CONCLUSIONS: The present study is the first to report a case of both WS2 and SLE, and the present findings may provide a new insight into WS2.

OBJECTIVE: This study aimed to identify the causative variants in a patient with Waardenburg syndrome (WS) type 2 using whole exome sequencing (WES).
METHODS: The clinical features of the patient were collected. WES was performed on the patient and his parents to screen causative genetic variants and Sanger sequencing was performed to validate the candidate mutation. The AlphaFold2 software was used to predict the changes in the 3D structure of the mutant protein. Western blotting and immunocytochemistry were used to determine the SOX10 mutant in vitro.
RESULTS: A de novo variant of SOX10 gene, NM_006941.4: c.707_714del (p. H236Pfs*42), was identified, and it was predicted to disrupt the wild-type DIM/HMG conformation in SOX10. In-vitro analysis showed an increased level of expression of the mutant compared to the wild-type.
CONCLUSIONS: Our findings helped to understand the genotype-phenotype association in WS2 cases with SOX10 mutations.

暂无摘要。

Tietz albinism-deafness syndrome (TADS) is a rare and severe manifestation of Waardenburg syndrome that is primarily linked to mutations in MITF. In this report, we present a case of TADS resulting from a novel c.637G>C mutation in MITF (p.Glu213Gln; GenBank Accession number: NM_000248). A 3-year-old girl presented with congenital generalized hypopigmentation of the hair, skin, and irides along with complete sensorineural hearing loss. Histopathological and electron microscopy investigations indicated that this variant did not alter the number of melanocytes in the skin but significantly impaired melanosome maturation within melanocytes. Comprehensive melanin analysis revealed marked reductions in both eumelanin (EM) and pheomelanin (PM) rather than changes in the EM-to-PM ratio observed in oculocutaneous albinism. We conducted an electrophoretic mobility shift assay to investigate the binding capability of the identified variant to DNA sequences containing the E-box motif along with other known variants (p.Arg217del and p.Glu213Asp). Remarkably, all three variants exhibited dominant-negative effects, thus providing novel insights into the pathogenesis of TADS. This study sheds light on the genetic mechanisms underlying TADS and offers a deeper understanding of this rare condition and its associated mutations in MITF.

OBJECTIVE: To explore the molecular etiology of Waardenburg syndrome type II (WS2) in a family from Yunnan province, China.
METHODS: A total of 406 genes related to hereditary hearing loss were sequenced using next-generation sequencing. DNA samples were isolated from the peripheral blood DNA of probands. Those pathogenic mutations detected by next-generation sequencing in probands and their parents were validated by Sanger sequencing. The conservatism of variation sites in genes was also analyzed. The protein expression was detected by flow cytometry.
RESULTS: A heterozygous mutation c.178delG (p.D60fs*49) in the SOX10 gene was identified in the proband, which is a frameshift mutation and may cause protein loss of function and considered to be a pathogenic mutation. This was determined to be a de novo mutation because her family were demonstrated to be wild-type and symptom free. SOX10, FGFR3, SOX2, and PAX3 protein levels were reduced as determined by flow cytometry.
CONCLUSIONS: A novel frameshift mutation in SOX10 gene was identified in this study, which may be the cause of WS2 in proband. In addition, FGFR3, SOX2, and PAX3 might also participate in promoting the progression of WS2.

暂无摘要。

Waardenburg syndrome (WS) is characterized by hearing loss and pigmentary abnormalities of the eyes, hair, and skin. The condition is genetically heterogeneous, and is classified into four clinical types differentiated by the presence of dystopia canthorum in type 1 and its absence in type 2. Additionally, limb musculoskeletal abnormalities and Hirschsprung disease differentiate types 3 and 4, respectively. Genes PAX3, MITF, SOX10, KITLG, EDNRB, and EDN3 are already known to be associated with WS. In WS, a certain degree of molecularly undetected patients remains, especially in type 2. This study aims to pinpoint causative variants using different NGS approaches in a cohort of 26 Brazilian probands with possible/probable diagnosis of WS1 (8) or WS2 (18). DNA from the patients was first analyzed by exome sequencing. Seven of these families were submitted to trio analysis. For inconclusive cases, we applied a targeted NGS panel targeting WS/neurocristopathies genes. Causative variants were detected in 20 of the 26 probands analyzed, these being five in PAX3, eight in MITF, two in SOX10, four in EDNRB, and one in ACTG1 (type 2 Baraitser-Winter syndrome, BWS2). In conclusion, in our cohort of patients, the detection rate of the causative variant was 77%, confirming the superior detection power of NGS in genetically heterogeneous diseases.