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.

Waardenburg Syndrome Type 2 (WS2) is a rare hereditary condition with a low prevalence, characterized by abnormalities in both auditory function and pigmentation. We present a case of a 2-year-old female child who exhibited reduced vocalizations, delayed speech development, and distinctive heterochromic irides. Initial auditory assessments revealed bilateral severe to profound hearing loss. Subsequent MRI findings confirmed bilateral aplasia of the posterior semicircular canals, consistent with a diagnosis of Waardenburg syndrome type 2. While standard treatments using bilateral Behind-The-Ear (BTE) power hearing aids yielded only modest improvements, cochlear implantation significantly enhanced auditory perception and speech abilities within 18 months. This report underscores the diagnostic intricacies of WS2 and highlights the profound benefits of cochlear implantation in addressing associated auditory challenges.

Waardenburg syndrome (WS) is a rare genetic disorder characterized by varying combinations of sensorineural hearing loss and abnormal pigmentation involving the hair, skin and iris. WS is classified into 4 subtypes (WS1-WS4) based on additional symptoms. WS2 is characterized by the absence of additional symptoms and is mainly attributed to variants in the microphthalmia-associated transcription factor (MITF) gene. We detected a novel frameshift variant c.1025_1032delGGAACAAG (NM_198159) of MITF in 5 patients with WS2 from the same Chinese family by using targeted next-generation sequencing and Sanger sequencing. Phenotypic and genotypic analyses of the family members suggested that this novel variants was pathogenic. Our finding expands the spectrum of MITF variants.

Waardenburg syndrome (WS) is a neurocristopathy with an autosomal dominant mode of inheritance, and considerable clinical and genetic heterogeneity. WS type II is the most common type of WS in many populations presenting with sensorineural hearing impairment, heterochromia iridis, hypoplastic blue eye, and pigmentary abnormalities of the hair and skin. To date, mutations of MITF, SOX10, and SNAI2 have been implicated in the pathogenesis of WS2. Although different pathogenic mutations have been reported in many ethnic groups, the data on Iranian WS2 patients is insufficient. 31 WS2 patients, including 22 men and 9 women from 14 families were included. Waardenburg consortium guidelines were employed for WS2 diagnosis. WS2 patients underwent screening for MITF, SOX10, and SNAI2 mutations using direct sequencing and MLPA analysis. Clinical evaluation revealed prominent phenotypic variability in Iranian WS2 patients. Sensorineural hearing impairment and heterochromia iridis were the most common features (67% and 45%, respectively), whereas anosmia was the least frequent phenotype. Molecular analysis revealed a de novo heterozygous c.640C>T (p.R214X) in MITF and a de novo heterozygous SOX10 gross deletion in the study population. Our data help illuminate the phenotypic and genotypic spectrum of WS2 in an Iranian series of patients, and could have implications for the genetic counseling of WS in Iran.

Waardenburg syndrome (WS) is a rare genetic disorder characterized by abnormal pigmentation of the hair, skin, and iris as well as sensorineural hearing loss. WS is subdivided into 4 major types (WS1-4), where WS2 is characterized by the absence of dystopia canthorum. This study was launched to investigate clinical and molecular characteristics of WS in an extended Iranian WS2 family. A comprehensive clinical investigation was performed. Peripheral blood samples were collected and genomic DNA was extracted. Affected members of the family were studied for possible mutations within the SOX10, MITF, and SNAI2 genes. Six WS2 individuals affected from a large Iranian WS2 kindred were enrolled. All affected members carried the novel substitution c.877C>T at exon 9 in the MITF gene, which resulted in p.Arg293* at the protein level. None of the healthy members and also of 50 ethnically matched controls had this variant. In addition, a spectrum of unique ocular findings, including nystagmus, chorioretinal degeneration, optic disc hypoplasia, astigmatism, and myopia, was segregated with the mutant allele in the pedigree. Our data provide insight into the genotypic and phenotypic spectrum of WS2 in an Iranian family and could further expand the spectrum of MITF mutations and have implications for genetic counseling on WS in Iran.