Genetic insights into Tietz albinism-deafness syndrome: A new dominant-negative mutation in MITF.

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.

Modeling of pigmentation disorders associated with MITF mutation in Waardenburg syndrome revealed an impaired melanogenesis pathway in iPS-derived melanocytes.

Waardenburg Syndrome (WS) is a rare genetic disorder that leads to congenital hearing loss and pigmentation defects. Microphthalmia-associated transcription factor (MITF) is one of its significant pathogenic genes. Despite the comprehensive investigation in animal models, the pathogenic mechanism is still poorly described in humans due to difficulties accessing embryonic tissues. In this work, we used induced pluripotent stem cells derived from a WS patient carrying a heterozygous mutation in the MITF gene c.626A>T (p.His209Leu), and differentiated toward melanocyte lineage, which is the most affected cell type involved in WS. Compared with the wild-type cell line, the MITFmut cell line showed a reduced expression of the characteristic melanocyte-related genes and a lesser proportion of mature, fully pigmented melanosomes. The transcriptome analysis also revealed widespread gene expression changes at the melanocyte stage in the MITFmut cell line. The differentially expressed genes were enriched in melanogenesis and cell proliferation-related pathways. Interestingly, ion transport-related genes also showed a significant difference in MITFmut -induced melanocytes, indicating that the MITF mutant may lead to the dysfunction of potassium channels and transporters produced by intermediate cells in the cochlea, further causing the associated phenotype of deafness. Altogether, our study provides valuable insights into how MITF mutation affects WS patients, which might result in defective melanocyte development and the related phenotype based on the patient-derived iPSC model.

[Analysis of molecular genetics and clinical characteristics of 3 children with Waardenburg syndrome].

Objective:To analyze the molecular genetics and clinical characteristics of 3 children with syndromic deafness were analyzed to clarify their causative genes and genetic characteristics. Methods:The medical records of 3 children and their parents were collected and analyzed, including physical examination, hearing evaluation, temporal bone CT, and cranial MRI. Whole-exome sequencing（WES） was used to screen for pathogenic gene variants, and Sanger sequencing was used to verify the candidate positive variants in the probands and their parents. Results:All 3 patients were female with normal intelligence. Patient 1 and 3 had a family history of deafness, which conformed to the pattern of autosomal dominant inheritance. All three patients had bilateral profound sensorineural hearing impairment with bright-blue sclera. Other phenotypes included hypertelorism（patient 1）, multiple dyschromatosis（patient 2）, and yellowish hair（patient 2）, blepharoptosis（patient 3）. Patient 3 had bilateral vestibular enlargement, internal auditory canal enlargement, and bilateral inner ear malformations. Mother of patient 1 had only left mild hearing impairment; mother of patient 3 had bilateral hearing impairment with unilateral bright-blue sclera and yellowish hair. WES detected heterozygous variants, PAX3 c.811C>T, MITF c.632T>C, and SOX10 c.1359_1360 insGCCCCACA, in patient 1, 2, and 3, respectively. The variants in patient 1 and 3 were inherited from their mothers who had hearing impairment, and MITFvariant in patient 2 may be a spontaneous variation. The final diagnoses were that patient 1 with Waardenburg syndrome type 1（WS1）, and the mother of patient 1, patient 2, patient 3, and the mother of patient 3 with WS2. Conclusion:WS is a syndromic deafness, and the main clinical features include autosomal dominant inheritance and scleral pigment abnormalities. However, the findings of this study show that there is still phenotypic heterogeneity in WS even caused by the same gene variant, so it depends on genetic tests to confirm the diagnosis; The gene variant of patient 1 and 2 was never been reported in other patients, which expands the pathogenic variant spectrum of WS.

NR2F1 regulates a Schwann cell precursor-vs-melanocyte cell fate switch in a mouse model of Waardenburg syndrome type IV.

Waardenburg syndrome type 4 (WS4) combines abnormal development of neural crest cell (NCC)-derived melanocytes (causing depigmentation and inner ear dysfunction) and enteric nervous system (causing aganglionic megacolon). The full spectrum of WS4 phenotype is present in Spot mice, in which an insertional mutation close to a silencer element leads to NCC-specific upregulation of the transcription factor-coding gene Nr2f1. These mice were previously found to develop aganglionic megacolon because of NR2F1-induced premature differentiation of enteric neural progenitors into enteric glia. Intriguingly, this prior work also showed that inner ear dysfunction in Spot mutants specifically affects balance but not hearing, consistent with the absence of melanocytes in the vestibule only. Here, we report an analysis of the effect of Nr2f1 upregulation on the development of both inner ear and skin melanocytes, also taking in consideration their origin relative to the dorsolateral and ventral NCC migration pathways. In the trunk, we found that NR2F1 overabundance in Spot NCCs forces dorso-laterally migrating melanoblasts to abnormally adopt a Schwann cell precursor (SCP) fate and conversely prevents ventrally migrating SCPs to normally adopt a melanoblast fate. In the head, Nr2f1 upregulation appears not to be uniform, which might explain why SCP-derived melanocytes do colonize the cochlea while non-SCP-derived melanocytes cannot reach the vestibule. Collectively, these data point to a key role for NR2F1 in the control of SCP-vs-melanocyte fate choice and unveil a new pathogenic mechanism for WS4. Moreover, our data argue against the proposed existence of a transit-amplifying compartment of melanocyte precursors in hair follicles.

Diagnosis and genetic analysis of a case of Waardenburg syndrome type 2 with hypogonadotropic hypogonadism caused by SOX10 gene deletion.

Hypogonadotropic hypogonadism (HH) is a disease defined by dysfunction of the hypothalamic- pituitary-gonadal hormone axis, leading to low sex hormone levels and impaired fertility. HH with anosmia or hyposmia is known as Kallmann syndrome (KS). Waardenburg syndrome (WS) is a rare autosomal dominant genetic disorder characterized by sensorineural hearing loss and abnormal pigmentation. In this report, we collected the clinical data of a patient with hypogonadotropic hypogonadism and congenital hearing loss of unknown cause. The patient had no obvious secondary sexual characteristics development after puberty, and had a heterozygous deletion (at least 419 kb) in 22q13.1 region (Chr.22:38106433-38525560), which covered the SOX10 gene. The abnormalities were not found in gene sequencing analysis of both the parents and sister of the proband. By summarizing and analyzing the characteristics of this case, we further discussed the molecular biological etiological association between HH and WS type 2. This case also enriches the clinical data of subsequent genetic studies, and provides a reference for the diagnosis and treatment of such diseases.

SOX10: 20 years of phenotypic plurality and current understanding of its developmental function.

SOX10 belongs to a family of 20 SRY (sex-determining region Y)-related high mobility group box-containing (SOX) proteins, most of which contribute to cell type specification and differentiation of various lineages. The first clue that SOX10 is essential for development, especially in the neural crest, came with the discovery that heterozygous mutations occurring within and around SOX10 cause Waardenburg syndrome type 4. Since then, heterozygous mutations have been reported in Waardenburg syndrome type 2 (Waardenburg syndrome type without Hirschsprung disease), PCWH or PCW (peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, with or without Hirschsprung disease), intestinal manifestations beyond Hirschsprung (ie, chronic intestinal pseudo-obstruction), Kallmann syndrome and cancer. All of these diseases are consistent with the regulatory role of SOX10 in various neural crest derivatives (melanocytes, the enteric nervous system, Schwann cells and olfactory ensheathing cells) and extraneural crest tissues (inner ear, oligodendrocytes). The recent evolution of medical practice in constitutional genetics has led to the identification of SOX10 variants in atypical contexts, such as isolated hearing loss or neurodevelopmental disorders, making them more difficult to classify in the absence of both a typical phenotype and specific expertise. Here, we report novel mutations and review those that have already been published and their functional consequences, along with current understanding of SOX10 function in the affected cell types identified through in vivo and in vitro models. We also discuss research options to increase our understanding of the origin of the observed phenotypic variability and improve the diagnosis and medical care of affected patients.

[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.

[Genotype and phenotype analysis of a family with Waardenburg syndrome type â caused 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.

Establishment of an iPSC line (CSUXHi004-A) from a patient with Waardenburg syndrome type I caused by a PAX3 splice mutation.

Waardenburg Syndrome (WS) is a common autosomal dominant syndrome associated with hearing loss. Its clinical manifestations include hearing impairment and pigmentation anomalies. In this study, we generated an induced pluripotent stem cell (iPSC) line from the Epstein-Barr virus-immortalized B lymphocytes of a 6-year-old boy affected with WS type I, caused by a heterozygous splice site mutation in the PAIRED BOX GENE 3 (PAX3) (NM_181457.3: c.452-2A > G). The patient-specific iPSC line (CSUXHi004-A) carrying the same PAX3 mutation showed a normal karyotype, expressed pluripotent markers, and presented differentiation capacity in vitro. This method may be a useful tool for the in vitro modeling of WS.

Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[Analysis of genetic characteristics in two Chinese children of type â ¡ Waardenburg syndrome].

Objective: To screen and analyze the mutations of MITF gene in two children of type Ⅱ Waardenburg syndrome (WS2) from different families in Yunnan,China,and to explore the possible molecular pathogenesis. Methods: With informed consent, medical history collection, physical examinations, audiological evaluation, and high resolution computer tomography (HRCT) scan of temporal bone were performed on the two WS2 probands and their family members. Genomic DNA was extracted from peripheral blood of all individuals. The coding regions including all exons, part of introns and promoters of MITF, PAX3, SOX10, SNAI2, END3, ENDRB, and KITLG genes were sequenced by high-throughput sequencing. According to the results of high-throughput sequencing, pathogenic mutations detected in the probands and their parents were verified by Sanger sequencing. Results: The proband 1 carried c.641_643delGAA mutation in the 7th exon of MITF gene, which was a frame-shift mutation resulting in an amino acid change of p.214delR. It was a de novo mutation as the parents of proband 1 showed no variation on this site. The proband 2 carried heterozygous loss of the large fragment ranging from exon 1 to exon 9 of MITF gene, which defected the function of MITF protein. Conclusion: Genetic examinations provide important evidence for diagnosis of Waardenburg syndrome. Heterozygous mutation c.641_643delGAA and heterozygous loss of the large fragment ranging from exon 1 to exon 9 of MITF gene might be the molecular pathogenesis of the two WS2 probands in this study.

Identification and functional analysis of a novel missense mutation of PAX3 associated with Waardenburg syndrome type I.

PURPOSE: Waardenburg syndrome type 1 (WS1) is a rare genetic disorder characterized by dystopia canthorum, abnormal iris pigmentation, and congenital hearing loss with variable penetrance.WS1 is caused by mutations in paired box gene 3 (PAX3). The current study aimed to investigate the genetic cause of hearing loss in a four-generation Chinese WS1 family. METHODS: The phenotype of the study family was characterized using clinical evaluation and pedigree analysis. Target region high-throughput sequencing system was designed to screen the all coding exons and flanking intronic sequences of the six WS-associated genes. Sanger sequencing was used to identify the causative nucleotide changes and perform the co-segregating analysis. The expression, subcellular distribution, and transcriptional activity of the mutant PAX3 protein were analysis to reveal the functional consequences of the mutation. RESULTS: Based on diagnostic criteria, the proband of this pedigree classified as WS1. We identified a novel missense mutation (c.117 C > A, p. Asn39Lys) in exon 2 of the PAX3 gene. In vitro, the Asn39Lys PAX3 retained nuclear distribution ability. However, it failed to activate the melanocyte inducing transcription factor (MITF) promoter and impaired the function of WT PAX3. CONCLUSIONS: Our study reports a novel missense PAX3 mutation in a Chinese family and shows haploinsufficiency may be the underlying mechanism for the WS1 phenotype.

SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FINDINGS IN WAARDENBURG SYNDROME.

PURPOSE: Waardenburg syndrome (WS) is a rare condition characterized by six main features. It has been previously observed that WS is also associated with hypopigmentation of the choroid through multimodal imaging. To our knowledge, this is the first report of using swept-source optical coherence tomography angiography (OCTA) on a patient with known WS. METHODS: Report of a single case. The swept-source OCT images were captured using Topcon DRI OCT Triton (Topcon, Inc, Tokyo, Japan), whereas swept-source OCTA images were captured by Optovue AngioVue (Optovue, Inc, Fremont, CA) using DualTrack Motion Correction Technology. RESULTS: In this case, OCTA demonstrated evidence of normal vasculature of all layers (superficial, deep, and choricocapillaris), a normal foveal avascular zone measuring 0.267 mm2 in the right eye and 0.307 mm2 in the left eye, and a normal capillary density measuring 49.8% in the right eye and 52.6% in the left eye. CONCLUSION: There are many conditions that may mimic the hypopigmentation of the choroid associated with WS; it has been documented that these similar conditions such as choroidal nevus, choroidal melanoma, and Vogt-Koyanagi-Harada syndrome all demonstrated abnormal OCTA findings. Unlike these conditions, our patient with WS had unremarkable OCTA findings.

Novel variants in EDNRB gene in Waardenburg syndrome type II and SOX10 gene in PCWH syndrome.

Waardenburg syndrome (WS) is a clinically and genetically heterogeneous group of inherited disorders manifesting with sensorineural hearing loss and pigmentary anomalies. Here we present two Caucasian families with novel variants in EDNRB and SOX10 representing both sides of phenotype spectrum in WS. The c.521G>A variant in EDNRB identified in Family 1 leads to disruption of the cysteine disulfide bridge between extracellular segments of endothelin receptor type B and causes relatively mild phenotype of WS type II with low penetrance. The novel nonsense variant c.900C>A in SOX10 detected in Family 2 leads to PCWH syndrome and was found to be lethal.

[Identification of a novel mutation of SOX10 gene and analysis of the phenotype].

Objective: To explore the clinical features and pathogenic mechanisms of a special syndrome with congenital sensorineural hearing loss, albinism, heterochromia iridis, nystagmus and myelin dysplasia. Methods: Detailed medical history, systematic audiology tests, ophthalmic and neurological examinations were carried out to analyze the clinical features of the child, and further molecular genetic tests including chromosome karyotype analysis, and deafness gene screening were conducted. Results: A new de novo heterozygous mutation (c.336G>T/p.Met112Ile) was detected in the child, while both his parents were demonstrated to be wild-type and symptom free. The analysis of clinical features indicated the diagnosis of PCW syndrome. Conclusion: This study identified a new mutation of SOX10 gene, which enriched the mutation spectrum of this gene. And the analysis of clinical characteristics of this patient also expanded the phenotype of this gene. This study provided a reference for clinical diagnosis and genetic diagnosis of PCW syndrome.

Triple diagnosis of Wiedemann-Steiner, Waardenburg and DLG3-related intellectual disability association found by WES: A case report.

BACKGROUND: The development of whole-exome sequencing (WES) and whole-genome sequencing (WGS) for clinical purposes now allows the identification of multiple pathogenic variants in patients with a rare disease. This occurs even when a single causative gene was initially suspected. We report the case of an 8-year-old patient with global developmental delays and dysmorphic features, with a possibly pathogenic variant in three distinct genes. METHODS: Trio-based exome sequencing was performed by IntegraGen SA (Evry, France), on an Illumina HiSeq4000 (Illumina, San Diego, CA, USA). Sanger sequencing was performed to confirm the variants that were found. RESULTS: WES showed the presence of three possibly deleterious variants: KMT2A: c.9068delA;p.Gln3023Argfs*3 de novo, PAX3: c.530C>G;p.Ala177Gly de novo and DLG3: c.127delG;p.Asp43Metfs*22 hemizygous inherited from the mother. KMT2A pathogenic variants are involved in Wiedemann-Steiner syndrome, and PAX3 is the gene responsible for Waardenburg syndrome. DLG3 variants have been described in a non-syndromic X-related intellectual disability. CONCLUSIONS: Considering the dysmorphic features and intellectual disability presented by this patient, these three variants were imputed as pathogenic and their association was considered responsible for his phenotype. Dual molecular diagnoses have already been found by WES in several cohorts with an average of diagnostic yield of 7%. This case demonstrates and reminds us of the importance of analyzing exomes rigorously and exhaustively because, in some cases (< 10%), it can explain superimposed traits or blended phenotypes.

Two novel mutations of PAX3 and SOX10 were characterized as genetic causes of Waardenburg Syndrome.

BACKGROUND: The objective of this study was to investigate the genetic causes of two probands diagnosed as Waardenburg syndrome (WS type I and IV) from two unrelated Chinese families. METHODS: PAX3 and SOX10 were the main pathogenic genes for WS type I (WS I) and IV (WS IV), respectively; all coding exons of these genes were sequenced on the two probands and their family members. Luciferase reporter assay and co-immunoprecipitation (CO-IP) were conducted to verify potential functional outcomes of the novel mutations. RESULTS: The first proband is a 9 years old girl diagnosed with WS I. A novel PAX3 heterozygous mutation of c.372-373delGA (p.N125fs) was identified, which results in a frameshift and truncation of PAX3 protein. In family II, a 2 years old girl was diagnosed with WS IV, and Sanger sequencing revealed a de novo SOX10 mutation of c.1114insTGGGGCCCCCACACTACACCGAC (p.Q372fs), a frameshift mutation that extends the amino acid chain of SOX10 protein. Functional studies indicated that the novel mutation of SOX10 had no effects on the interaction of SOX10 and PAX3, but reduced transactivate capacity of melanocyte inducing transcription factor (MITF) promoter. Both PAX3 and SOX10 mutation-induced defects of MITF transcription might contribute to the WS pathogenesis. CONCLUSION: We revealed a novel mutation in PAX3 and a de novo mutation in SOX10, which might account for the underlying pathogenesis of WS. This study expands the database of both PAX10 and PAX3 mutations and improves our understanding of the causes of WS.

Kallmann Syndrome Due to Heterozygous Mutation in SOX10 Coexisting With Waardenburg Syndrome Type II: Case Report and Review of Literature.

Introduction: Kallmann syndrome (KS) is idiopathic hypogonadotropic hypogonadism with olfactory loss or decline. Waardenburg syndrome type II (WS2) is a clinically and genetically heterogeneous disease, characterized by congenital sensorineural deafness and abnormal pigmentation of the iris, hair, and skin. Recently, mutations in the well-known WS pathogenic gene SOX10 have been found in some KS patients with deafness, but whether SOX10 is a co-pathogenic gene of KS and WS remains uncertain. Here, we report a rare case of KS and WS2 co-occurrence due to SOX10 mutations. Methods: Detailed histories were collected through questionnaires and physical examination. Blood samples of the patient and his family members were collected after obtaining informed consents. Suspected mutations were amplified and verified by Sanger sequencing after the next generation sequencing of related genes. The raw sequence data were compared to the known gene sequence data in publicly available sequence data bases using Burrows-Wheeler Aligner software (BWA, 0.7.12-r1039). Results: A 28-year-old male patient sought treatment for hypogonadism and the absence of secondary sexual characteristics. In addition, he showed signs of obesity, hyposmia, sensorineural hearing loss, and blue iris. Magnetic resonance imaging (MRI) of the olfactory bulb showed small bilateral olfactory bulbs and tracts and diaphragma cerebri. MRI of the pituitary gland revealed a flat pituitary gland in the sella. Laboratory examination demonstrated hypogonadotropic hypogonadism, pituitary hypothyroidism, subclinical hypothyroidism, and the presence of insulin resistance with normal blood glucose levels. Sequencing of the SOX10 gene showed a 20 bp insertion in between coding bases 1,179 and 1,180 (c.1179_1180insACTATGGCTCAGCCTTCCCC). This results in a frame-shifting mutation of the 394th amino acid serine in exon4 with the resulting the amino acid sequence of the protein predicted to be TMAQPSP PSPAPSLTTL TISPQDPIMA TRARPLASTR PSPIWGPRSG PSTRPSLTPA PQGPSPTAPH TGSSQYIRHC PGPKGGPVAT TPRPAPAPSL CALFLAHLRP GGGSGGG*. Conclusion: SOX10 plays an important role in some critical stages of neural crest cell development and SOX10 mutation may be a common pathogenic factor for both KS and WS. Therefore, SOX10 mutation analysis should be considered for KS patients with combined WS clinical manifestations, especially deafness.

Hereditary Hearing Impairment with Cutaneous Abnormalities.

Syndromic hereditary hearing impairment (HHI) is a clinically and etiologically diverse condition that has a profound influence on affected individuals and their families. As cutaneous findings are more apparent than hearing-related symptoms to clinicians and, more importantly, to caregivers of affected infants and young individuals, establishing a correlation map of skin manifestations and their underlying genetic causes is key to early identification and diagnosis of syndromic HHI. In this article, we performed a comprehensive PubMed database search on syndromic HHI with cutaneous abnormalities, and reviewed a total of 260 relevant publications. Our in-depth analyses revealed that the cutaneous manifestations associated with HHI could be classified into three categories: pigment, hyperkeratosis/nail, and connective tissue disorders, with each category involving distinct molecular pathogenesis mechanisms. This outline could help clinicians and researchers build a clear atlas regarding the phenotypic features and pathogenetic mechanisms of syndromic HHI with cutaneous abnormalities, and facilitate clinical and molecular diagnoses of these conditions.