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A novel PAX3 mutation in a Japanese boy with Waardenburg syndrome type 1.

ABSTRACT: Waardenburg syndrome type 1 (WS1) is a rare autosomal dominant disorder characterized by hair hypopigmentation, abnormal iris pigmentation, and congenital hearing loss. WS1 is caused by mutations in paired box gene 3 (PAX3). We identified a novel PAX3 mutation (c.1107 C>G, p.Ser369Arg) in a Japanese WS1 patient showing abnormal right iris pigmentation, right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism.

SUBMITTER: Yoshida Y

PROVIDER: S-EPMC4775770 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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A novel PAX3 mutation in a Japanese boy with Waardenburg syndrome type 1.

Yoshida Yu Y Doi Rieko R Adachi Kaori K Nanba Eiji E Kodani Isamu I Ryoke Kazuo K

Human genome variation 20160303

Waardenburg syndrome type 1 (WS1) is a rare autosomal dominant disorder characterized by hair hypopigmentation, abnormal iris pigmentation, and congenital hearing loss. WS1 is caused by mutations in paired box gene 3 (PAX3). We identified a novel PAX3 mutation (c.1107 C>G, p.Ser369Arg) in a Japanese WS1 patient showing abnormal right iris pigmentation, right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism. ...[more]

PMID: 27081571

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A novel mutation of the PAX3 gene in a Chinese family with Waardenburg syndrome type I.

Project description:BackgroundTo analyze the clinical phenotypes and genetic variants of a Chinese family with Waardenburg syndrome (WS) and to explore the possible molecular pathogenesis of WS.MethodsThe clinical data from a patient and his family were collected. The genomic DNA of the patient and his family was purified from their peripheral blood. All exons and flanking sequences of the MITF, PAX3, SOX10, SNAI2, END3, and EDNRB genes were investigated through high-throughput sequencing. Based on the results of high-throughput sequencing, genetic variants in the patient and his family were verified and analyzed by Sanger sequencing.ResultsThe patient was diagnosed with typical WS1 that manifested in hearing impairment, inner canthus ectopia and heterochromic iris. Sanger sequencing revealed the pathogenic heterozygous c.420-424de1CGCGGinsTTAC mutation in the PAX3 gene in the proband, which is a frameshift mutation that changed the amino acid sequence of the PAX3 protein from AVCDRNTVPSV to YSVIETPCRQ* (* refers to a stop codon) from amino acids 141-151. The stop codon induced by this mutation resulted in the truncation of the PAX3 protein. The same mutation sites were also found in the mother and younger sister of the proband. No previous report of this mutation was found in the Human Gene Mutation Database.ConclusionThe novel heterozygous c.420-424de1CGCGGinsTTAC mutation is the molecular pathological cause for WS1 in our patient. The clinical and genetic characterization of this family with WS1 elucidated the genetic heterogeneity of PAX3 in WS1. Moreover, the mutation detected in this case has expanded the database of PAX3 mutations.

| S-EPMC6625151 | biostudies-literature

PAX3 mutations and clinical characteristics in Chinese patients with Waardenburg syndrome type 1.

Project description:To detect paired box gene 3 (PAX3) mutations and associated phenotypes in Chinese patients with Waardenburg syndrome type 1 (WS1).Five unrelated families with suspected WS1 were selected from our Genomic DNA Repository for Hereditary Eye Diseases. The coding and adjacent intronic regions of PAX3 were amplified by polymerase chain reaction and the amplicons were then analyzed by cycle sequencing. Variations detected were further evaluated in available family members as well as one hundred controls with heteroduplex-single strand conformational polymorphism (heteroduplex-SSCP) analysis and/or clone sequencing.Three novel and two known mutations in PAX3 were detected in five patients, respectively: c.567_586+17del (p.Asp189_Gln505delinsGluGlyGlyAlaLeuAlaGly), c.456_459dupTTCC (p.Ile154PhefsX162), c.795_800delCTGGTT (p.Trp266_Phe267del), c.799T>A (p.Phe267Ile), and c.667C>T (p.Arg223X). Two novel mutations proved to be de novo as their parents did not carry the mutations. All five patients with PAX3 mutations had dystopia canthorum and different iris color and fundi between their two eyes. However, none had white forelock, skin hypopigmentation, and deafness.Our findings expand the frequency and spectrum of PAX3 mutations and ethnic-related phenotypes in Chinese patients with WS1. De novo mutations in PAX3 have not been reported before.

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A novel PAX3 mutation in a Korean patient with Waardenburg syndrome type 1 and unilateral branch retinal vein and artery occlusion: a case report.

Project description:BACKGROUND:Waardenburg syndrome (WS) is a very rare genetic disorder affecting the neural crest cells. Coexistence of branch retinal vein occlusion (BRVO) and branch retinal artery occlusion (BRAO) in the same eye is also a rare finding. Here we report a case of WS type 1 that was confirmed by a novel mutation with the finding of unilateral BRVO and BRAO. CASE PRESENTATION:A 36-year-old, white-haired Korean man presented with a complaint of loss of vision in the inferior visual field of his right eye and hearing loss. He had telecanthus with a medial eyebrow and a hypochromic left iris. Funduscopy showed an ischemic change at the posterior pole in the right eye with sparing of the foveal center as well as retinal hemorrhages and white patches along the superotemporal arcade. Fundus angiography revealed the presence of both BRVO and BRAO, and optical coherence tomography showed thickening and opacification of the retinal layers corresponding to the ischemic area. A blood workup revealed hyperhomocysteinemia and the presence of antiphospholipid antibodies; both are suggestive as the cause of the BRVO and BRAO. Single nucleotide polymorphism analysis confirmed a novel PAX3 mutation at 2q35 (c.91-95 ACTCC deletion causing a frameshift). These findings confirmed a diagnosis of WS type 1. CONCLUSIONS:WS is a heterogeneous inherited disorder of the neural crest cells that causes pigment abnormalities and sensorineural hearing loss. This is the first report of unilateral BRVO and BRAO in a patient with WS. Furthermore, the PAX3 mutation identified in this patient has not been reported previously.

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A novel SOX10 variant in a Japanese girl with Waardenburg syndrome type 4C and Kallmann syndrome.

Project description:We report the first case of Waardenburg syndrome type 4C and Kallmann syndrome in the same person. The patient, a Japanese girl, presented with bilateral iris depigmentation, bilateral sensorineural hearing loss, Hirschsprung disease, hypogonadotropic hypogonadism, and anosmia. We identified a novel SOX10 variant, c.124delC, p.Leu42Cysfs*67.

| S-EPMC7522263 | biostudies-literature

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

Project description:BackgroundThe 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.MethodsPAX3 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.ResultsThe 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.ConclusionWe 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.

| S-EPMC7216796 | biostudies-literature

A Novel Spontaneous Mutation of the SOX10 Gene Associated with Waardenburg Syndrome Type II.

Project description:Waardenburg syndrome (WS), also known as auditory-pigmentary syndrome, is the most common cause of syndromic hearing loss. It is responsible for 2-5% of congenital deafness. WS is classified into four types depending on the clinical phenotypes. Currently, pathogenic mutation of PAX3, MITF, EDNRB, EDN3, SNAI2, or SOX10 can cause corresponding types of WS. Among them, SOX10 mutation is responsible for approximately 15% of type II WS or 50% of type IV WS. We report the case of a proband in a Chinese family who was diagnosed with WS type II. Whole exome sequencing (WES) of the proband detected a novel heterozygous spontaneous mutation: SOX10 c.246delC. According to analysis based on nucleic acid and amino acid sequences, this mutation may produce a truncated protein, with loss of the HMG structure domain. Therefore, this truncated protein may fail to activate the expression of the MITF gene, which regulates melanocytic development and plays a key role in WS. Our finding expands the database of SOX10 mutations associated with WS and provides more information regarding the molecular mechanism of WS.

| S-EPMC7474791 | biostudies-literature

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

Project description: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.

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Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I).

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| S-EPMC1682157 | biostudies-other

A frameshift mutation in the gene for PAX3 in a girl with spina bifida and mild signs of Waardenburg syndrome.

Project description:Neural tube defects (NTD) are among the most prevalent congenital malformations in man. Based on the molecular defect of Splotch, an established mouse model for NTD, and on the clinical association between NTD and Waardenburg syndrome (WS), mutations in the PAX3 gene can be expected to act as factors predisposing to human NTD. To test this hypothesis, 39 patients with familial NTD were screened by SSC analysis for mutations in exons 2 to 6 of the human PAX3 gene. One patient with lumbosacral meningomyelocele was identified with a 5 bp deletion in exon 5 approximately 55 bp upstream of the conserved homeodomain. The deletion causes a frameshift with a stop codon almost immediately after the mutated site. Clinical investigation of the index patient indicated mild signs of WS type I. Varying signs of this syndrome were found to cosegregate with the mutation in the family. Our results support the hypothesis that mutations in the gene for PAX3 can predispose to NTD, but also show that, in general, mutations within or near the conserved domains of the PAX3 protein are only very infrequently involved in familial NTD.

| S-EPMC1050180 | biostudies-other

The heterozygous EDNRB mutation in a Chinese family with Waardenburg syndrome type I.

Project description:The genovariation of endothelin receptor type B (EDNRB) was identified in a Chinese family with Waardenburg syndrome type I (WS1) in the present study. WS1 was diagnosed in a 19-year-old young man, his older sister and aunt according to WS consortium criteria. After extracting genomic DNA from the peripheral blood samples, the coding exons and intronic regions of EDNRB were sequenced. A missense heterozygous mutation was found in the coding region of exon 2 in the EDNRB gene on chormosome 13q22.3 of the proband. The same mutation was detected in the proband's afflicted paternal aunt and first older sister. Subsequent polyphen analysis and three-dimensional modeling confirmed that the c.469A>G heterozygous mutation in EDNRB was possibly pathogenic. This is the first report of EDNRB mutation as a potential disease-causing mutation in Chinese patients with WS1.

| S-EPMC6739585 | biostudies-literature

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