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2.
Mol Genet Genomic Med ; 12(3): e2296, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38419387

RESUMO

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. CONCLUSION: 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.


Assuntos
Mutação da Fase de Leitura , Síndrome de Waardenburg , Humanos , Feminino , Síndrome de Waardenburg/genética , Síndrome de Waardenburg/patologia , China , Linhagem , DNA , Fatores de Transcrição SOXE/genética
3.
Biochem Biophys Res Commun ; 698: 149510, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38278051

RESUMO

Waardenburg syndrome type 1 (WS1) is a hereditary disease mainly characterized by sensorineural hearing loss, dystopia canthorum, and pigmentary defects. To elucidate molecular mechanisms underlying PAX3-associated hearing loss, we developed inner ear organoids model using induced pluripotent stem cells (iPSCs) derived from WS1 patient and healthy individual. Our results revealed a significant reduction in the size of inner ear organoids, accompanied by an increased level of apoptosis in organoids derived from WS1 patient-iPSCs carrying PAX3 c.214A > G. Transcriptome profiling analysis by RNA-seq indicated that inner ear organoids from WS1 patients were associated with suppression of inner ear development and WNT signaling pathway. Furthermore, the upregulation of the WNT1/ß-catenin pathway which was achieved through the correction of PAX3 isogenic mutant iPSCs using CRISPR/Cas9, contributed to an increased size of inner ear organoids and a reduction in apoptosis. Together, our results provide insight into the underlying mechanisms of hearing loss in WS.


Assuntos
Surdez , Orelha Interna , Células-Tronco Pluripotentes Induzidas , Síndrome de Waardenburg , Humanos , Síndrome de Waardenburg/genética , Fator de Transcrição PAX3/genética , beta Catenina/genética , Mutação , Via de Sinalização Wnt , Organoides , Apoptose , Proliferação de Células
4.
Sci Rep ; 14(1): 2210, 2024 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-38278860

RESUMO

Cochlear melanocytes are intermediate cells in the stria vascularis that generate endocochlear potentials required for auditory function. Human PAX3 mutations cause Waardenburg syndrome and abnormalities of skin and retinal melanocytes, manifested as congenital hearing loss (~ 70%) and hypopigmentation of skin, hair and eyes. However, the underlying mechanism of hearing loss remains unclear. Cochlear melanocytes in the stria vascularis originated from Pax3-traced melanoblasts and Plp1-traced Schwann cell precursors, both of which derive from neural crest cells. Here, using a Pax3-Cre knock-in mouse that allows lineage tracing of Pax3-expressing cells and disruption of Pax3, we found that Pax3 deficiency causes foreshortened cochlea, malformed vestibular apparatus, and neural tube defects. Lineage tracing and in situ hybridization show that Pax3+ derivatives contribute to S100+, Kir4.1+ and Dct+ melanocytes (intermediate cells) in the developing stria vascularis, all of which are significantly diminished in Pax3 mutant animals. Taken together, these results suggest that Pax3 is required for the development of neural crest cell-derived cochlear melanocytes, whose absence may contribute to congenital hearing loss of Waardenburg syndrome in humans.


Assuntos
Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Síndrome de Waardenburg , Camundongos , Animais , Humanos , Síndrome de Waardenburg/genética , Cóclea , Estria Vascular , Perda Auditiva Neurossensorial/genética , Melanócitos , Fator de Transcrição PAX3/genética
5.
Pigment Cell Melanoma Res ; 37(1): 21-35, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37559350

RESUMO

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.


Assuntos
Transtornos da Pigmentação , Síndrome de Waardenburg , Animais , Humanos , Transtornos da Pigmentação/genética , Transtornos da Pigmentação/metabolismo , Síndrome de Waardenburg/genética , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Mutação/genética , Melanócitos/metabolismo
6.
Nat Rev Dis Primers ; 9(1): 54, 2023 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-37828049

RESUMO

Hirschsprung disease (HSCR) is a rare congenital intestinal disease that occurs in 1 in 5,000 live births. HSCR is characterized by the absence of ganglion cells in the myenteric and submucosal plexuses of the intestine. Most patients present during the neonatal period with the first meconium passage delayed beyond 24 h, abdominal distension and vomiting. Syndromes associated with HSCR include trisomy 21, Mowat-Wilson syndrome, congenital central hypoventilation syndrome, Shah-Waardenburg syndrome and cartilage-hair hypoplasia. Multiple putative genes are involved in familial and isolated HSCR, of which the most common are the RET proto-oncogene and EDNRB. Diagnosis consists of visualization of a transition zone on contrast enema and confirmation via rectal biopsy. HSCR is typically managed by surgical removal of the aganglionic bowel and reconstruction of the intestinal tract by connecting the normally innervated bowel down to the anus while preserving normal sphincter function. Several procedures, namely Swenson, Soave and Duhamel procedures, can be undertaken and may include a laparoscopically assisted approach. Short-term and long-term comorbidities include persistent obstructive symptoms, enterocolitis and soiling. Continued research and innovation to better understand disease mechanisms holds promise for developing novel techniques for diagnosis and therapy, and improving outcomes in patients.


Assuntos
Síndrome de Down , Doença de Hirschsprung , Deficiência Intelectual , Síndrome de Waardenburg , Recém-Nascido , Humanos , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/genética , Doença de Hirschsprung/patologia , Síndrome de Down/complicações , Síndrome de Waardenburg/complicações , Canal Anal , Deficiência Intelectual/complicações
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 40(11): 1367-1372, 2023 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-37906143

RESUMO

OBJECTIVE: To explore the genetic basis for a Chinese pedigree featuring congenital profound syndromic deafness and chronic constipation, and provide prenatal diagnosis for a high-risk fetus. METHODS: Whole-exome sequencing was carried out to analyze the sequences of genes associated with hereditary deafness, and multiplex ligation-dependent probe amplification (MLPA) was used to verify the candidate variant in the proband's parents and the fetus. RESULTS: The proband was found to have harbored a heterozygous deletion of SOX10, a pathogenic gene associated with Waardenburg syndrome type 4C (WS4C). The same deletion was found in her mother (with profound syndromic deafness and chronic constipation) and the fetus, but not in her father with normal hearing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the SOX10 gene deletion was predicted to be a pathogenic variant (PVS1+PM2_Supporting+PP1+PP4). CONCLUSION: The pedigree was diagnosed with WS4C, which has conformed to an autosomal dominant inheritance. Deletion of the entire SOX10 gene, as a loss-of-function variant, probably underlay its pathogenesis. Above finding has facilitated genetic counseling and prenatal diagnosis for this family.


Assuntos
Surdez , Perda Auditiva Neurossensorial , Síndrome de Waardenburg , Humanos , Feminino , Gravidez , Linhagem , Síndrome de Waardenburg/diagnóstico , Síndrome de Waardenburg/genética , População do Leste Asiático , Testes Genéticos , Diagnóstico Pré-Natal , Perda Auditiva Neurossensorial/genética , Surdez/genética , Mães , Constipação Intestinal/genética , Mutação , Fatores de Transcrição SOXE/genética
8.
Int J Pediatr Otorhinolaryngol ; 175: 111738, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37847940

RESUMO

OBJECTIVE: Waardenburg syndrome (WS) is a genetic condition associated with moderate to profound sensorineural hearing loss. The aim of this review is to characterize cochlear implant (CI) outcomes in patients with a confirmed clinical diagnosis of WS. DATA SOURCES: MEDLINE, Ovid EMBASE, and Cochrane Library. REVIEW METHODS: All reports describing defined sets of patients with WS who underwent CI and subsequent evaluation of clinical outcomes were included. To harmonize outcome data between studies that used different measures, a binary variable Favored CI was developed to capture success of procedures (1 = favored, 0 = unfavored) based on original authors' description, commentary, discussion, and conclusions. Expert reviewers independently reviewed and selected articles, extracted data and scored Favored CI values. Synthetic and analytic meta-analyses were implemented using standard analytic techniques. RESULTS: Twenty articles meeting inclusion criteria provided data on 192 WS patients and 210 CIs. The mean age at CI was 3.8 years (95% confidence interval [95%CI]; 3.1-4.5 years), and the mean duration of follow up was 5.2 years (95% CI; 3.4-7.0 years). Surgical complications were rare (11/210 implants, 5.2%) where gusher was the most common complication. CIs yielded favorable hearing outcomes in 90% (95% CI; 84-94%) of cases, and appear successful for those with temporal bone anomalies (p = 0.04). CONCLUSIONS: Quantitative synthesis of the study data demonstrates that in the majority of patients with WS, CI yield favorable hearing outcomes and low rates of surgical complications. CI has shown to provide clinical benefits in patients with WS.


Assuntos
Implante Coclear , Implantes Cocleares , Perda Auditiva Neurossensorial , Síndrome de Waardenburg , Humanos , Pré-Escolar , Síndrome de Waardenburg/complicações , Síndrome de Waardenburg/cirurgia , Resultado do Tratamento , Perda Auditiva Neurossensorial/cirurgia , Perda Auditiva Neurossensorial/reabilitação
9.
BMJ Case Rep ; 16(9)2023 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-37678941

RESUMO

Waardenburg syndrome is a rare genetic condition with an incidence of 1 in 212 000. The condition is classically associated with distinctive facial features, congenital hearing loss and pigmentary changes of the hair, iris and skin. There is a paucity of literature about the association of neurodevelopmental conditions with this syndrome. We present a toddler with Waardenburg syndrome type 1 who was referred to our service for developmental delay concerns. The child was diagnosed with the condition at birth, had distinctive facial features, but the hearing was normal. The child's father also shares a similar mutation. Following a multidisciplinary assessment, the child was diagnosed to have autism spectrum disorder with possible regression. We acknowledge that there may not be a causal relationship between autism spectrum and Waardenburg syndrome. However, this highlights the need for developmental surveillance among children diagnosed with Waardenburg syndrome and to consider its association with neurodevelopmental conditions.


Assuntos
Transtorno do Espectro Autista , Síndrome de Waardenburg , Recém-Nascido , Pré-Escolar , Humanos , Síndrome de Waardenburg/complicações , Síndrome de Waardenburg/diagnóstico , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico , Pele , Cabelo , Iris , Doenças Raras
11.
Am J Med Genet A ; 191(12): 2813-2818, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37533297

RESUMO

Waardenburg syndrome (WS) is characterized by the association of sensorineural hearing loss and pigmentation abnormalities. Among the four types, WS Type 2 (WS2) is the only one without a remarkable distinguishing feature. Here, we report a patient initially diagnosed with WS2 who exhibits a 446 kb mosaic duplication in chromosome 22q13.1, encompassing SOX10, and detected using whole genome sequencing in a trio. The patient, a 46,XY boy, presents with profound bilateral sensorineural hearing loss, right heterochromia iridium, left bright blue iris, and skin-depigmented areas in the abdomen and limbs. Vestibular and imaging tests are normal, without inner ear or olfactory bulb malformations. Bilateral cochlear implantation did not prevent language and speech delays. Moderate congenital chronic constipation and neurodevelopmental difficulties were also present. Given the few genes included in this duplicated region (only one OMIM gene with dominant inheritance), this report provides further delineation of the phenotype related to duplications encompassing the entire SOX10 gene.


Assuntos
Perda Auditiva Neurossensorial , Vestíbulo do Labirinto , Síndrome de Waardenburg , Masculino , Humanos , Mosaicismo , Fenótipo , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Síndrome de Waardenburg/diagnóstico , Síndrome de Waardenburg/genética , Fatores de Transcrição SOXE/genética , Mutação
12.
J Int Adv Otol ; 19(3): 255-259, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37272645

RESUMO

Waardenburg syndrome is an autosomal dominant inherited syndromic hereditary hearing loss characterized by varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. The aim of this study was to analyze the clinical phenotypes and genetic variants of a Chinese boy with Waardenburg syndrome type 2 and to explore the possible molecular pathogenesis of Waardenburg syndrome type 2. Clinical, audiological, and ophthalmologic evaluations were performed on the proband. Clinical data from the principal members in the proband's family were collected through questionnaires. Genetic analysis was conducted, including targeted next-generation sequencing of 144 known deafness genes, Sanger sequencing, and bioinformatic analysis. Waardenburg syndrome type 2was diagnosed in a 4-year-old boy according to the Waardenburg Syndrome Consortium Criteria. The novel missense mutation c.426G>T (p.Trp142Cys) was identified in SOX10 in the proband but was absent in his parents and the controls. A de novo missense mutation in SOX10 was the genetic cause of Waardenburg syndrome type 2 in the proband, which was useful for the molecular diagnosis of Waardenburg syndrome type 2.


Assuntos
Perda Auditiva Neurossensorial , Fatores de Transcrição SOXE , Síndrome de Waardenburg , Humanos , População do Leste Asiático , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Mutação , Fenótipo , Fatores de Transcrição SOXE/genética , Síndrome de Waardenburg/diagnóstico , Síndrome de Waardenburg/genética , Masculino , Pré-Escolar
13.
BMC Med Genomics ; 16(1): 147, 2023 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-37365589

RESUMO

BACKGROUND: Waardenburg syndrome (WS) is a rare genetic disorder characterized by varying degrees of sensorineural hearing loss and accumulated pigmentation in the skin, hair and iris. The syndrome is classified into four types (WS1, WS2, WS3, and WS4), each with different clinical phenotypes and underlying genetic causes. The aim of this study was to identify the pathogenic variant in a Chinese family with Waardenburg syndrome type IV. METHODS: The patient and his parents underwent a thorough medical examination. We applied whole exome sequencing to identify the causal variant on the patient and other family members. RESULTS: The patient presented with iris pigmentary abnormality, congenital megacolon and sensorineural hearing loss. The clinical diagnosis of the patient was WS4. The whole exome sequencing (WES) revealed a novel variant (c.452_456dup) in the SOX10 gene, which could be responsible for the observed pathogenic of WS4 in this patient. Our analysis suggests that this variant produces a truncated protein that contributes to the development of the disease. The genetic test confirmed the diagnosis of WS4 in the patient from the studied pedigree. CONCLUSIONS: This present study demonstrated that genetic test based on WES, an effective alternative to regular clinical examinations, helps diagnose WS4. The newly identified SOX10 gene variant can expand the understanding of WS4.


Assuntos
Perda Auditiva Neurossensorial , Síndrome de Waardenburg , Humanos , Síndrome de Waardenburg/genética , Síndrome de Waardenburg/diagnóstico , Testes Genéticos , Fenótipo , Linhagem , Perda Auditiva Neurossensorial/genética , Mutação , Fatores de Transcrição SOXE/genética
14.
Twin Res Hum Genet ; 26(2): 195-198, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37170787

RESUMO

Waardenburg's syndrome involves deafness accompanied by various visual difficulties. The role of twins in identifying this disorder and advancing understanding of its origins and symptoms is described, beginning in 1916 and continuing to the present. This overview is followed by current research on monozygotic (MZ) twins' different dermatoglyphic features, twins with sagittal suture crainosynostosis, blood pressure in female twins, and MZ twins' education and political knowledge. The final section presents media reports describing controversies surrounding twins created by reciprocal in vitro fertilization, reared-apart triplets' limited TV series, abducted twin infants, the Winkelvoss twins' charges by the Securities and Exchange Commission, and going from 'Me' to 'We'.


Assuntos
Síndrome de Waardenburg , Feminino , Humanos , Lactente , Pressão Sanguínea , Dermatoglifia , Fertilização In Vitro , Suturas , Gêmeos Dizigóticos , Gêmeos Monozigóticos/genética , Estudos em Gêmeos como Assunto
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 40(6): 661-667, 2023 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-37211999

RESUMO

OBJECTIVE: To explore the genetic basis for four Chinese pedigrees affected with Waardenburg syndrome (WS). METHODS: Four WS probands and their pedigree members who had presented at the First Affiliated Hospital of Zhengzhou University between July 2021 and March 2022 were selected as the study subjects. Proband 1, a 2-year-and-11-month female, had blurred speech for over 2 years. Proband 2, a 10-year-old female, had bilateral hearing loss for 8 years. Proband 3, a 28-year-old male, had right side hearing loss for over 10 years. Proband 4, a 2-year-old male, had left side hearing loss for one year. Clinical data of the four probands and their pedigree members were collected, and auxiliary examinations were carried out. Genomic DNA was extracted from peripheral blood samples and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: Proband 1, with profound bilateral sensorineural hearing loss, blue iris and dystopia canthorum, was found to have harbored a heterozygous c.667C>T (p.Arg223Ter) nonsense variant of the PAX3 gene, which was inherited from her father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PVS1+PM2_Supporting+PP4), and the proband was diagnosed with WS type I. Proband 2, with moderate sensorineural hearing loss on the right side and severe sensorineural hearing loss on the left side, has harbored a heterozygous frameshifting c.1018_1022del (p.Val340SerfsTer60) variant of the SOX10 gene. Neither of her parents has harbored the same variant. Based on the ACMG guidelines, it was classified as pathogenic (PVS1+PM2_Supporting+PP4+PM6), and the proband was diagnosed with WS type II. Proband 3, with profound sensorineural hearing loss on the right side, has harbored a heterozygous c.23delC (p.Ser8TrpfsTer5) frameshifting variant of the SOX10 gene. Based on the ACMG guidelines, it was classified as pathogenic (PVS1+PM2_Supporting+PP4), and the proband was diagnosed with WS type II. Proband 4, with profound sensorineural hearing loss on the left side, has harbored a heterozygous c.7G>T (p.Glu3Ter) nonsense variant of the MITF gene which was inherited from his mother. Based on the ACMG guidelines, the variant was classified as pathogenic (PVS1+PM2_Supporting+PP4), and the proband was diagnosed with WS type II. CONCLUSION: By genetic testing, the four probands were all diagnosed with WS. Above finding has facilitated molecular diagnosis and genetic counseling for their pedigrees.


Assuntos
Surdez , Perda Auditiva Neurossensorial , Síndrome de Waardenburg , Feminino , Humanos , Masculino , População do Leste Asiático , Perda Auditiva Neurossensorial/genética , Mutação , Linhagem , Fenótipo , Síndrome de Waardenburg/genética , Síndrome de Waardenburg/diagnóstico
16.
Anim Genet ; 54(4): 549-552, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37062854

RESUMO

A white calf, with minimal pigmented markings, was born to two registered Black Angus parents. Given the possibility of an unknown recessive or de novo dominant mutation, whole-genome sequencing was conducted on the trio of individuals. A 3-bp in-frame deletion in MITF was identified; this mutation was unique to the calf but identical to the delR217 variant reported in both humans and murine models of Waardenburg syndrome type 2A and Tietz syndrome. Given the coat color phenotype and identity of the mutation, our data support that this calf represents the first instance of this recurring MITF mutation in cattle.


Assuntos
Doenças dos Bovinos , Fator de Transcrição Associado à Microftalmia , Animais , Bovinos/genética , Humanos , Camundongos , Doenças dos Bovinos/genética , Surdez/genética , Surdez/veterinária , Fator de Transcrição Associado à Microftalmia/genética , Mutação , Fenótipo , Deleção de Sequência , Síndrome de Waardenburg/genética , Síndrome de Waardenburg/veterinária
17.
Stem Cell Res ; 69: 103074, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36989619

RESUMO

Waardenburg syndrome type 1 (WS1), a rare genetic disease characterized by pigmentation defects and mild craniofacial anomalies often associated with congenital deafness is caused by heterozygous mutations in the PAX3 gene (2q36.1). We have generated two induced pluripotent stem cell lines (PCli029-A and PCli031-A) from two patients from the same family both carrying the same heterozygous deletion in PAX3 exon 1 (c.-70_85 + 366del). These cells are pluripotent as they can differentiate into ectoderm, mesoderm and endoderm. They also can activate the early neural crest marker SNAI2. These cells will be useful for studying the human neural crest-derived pigment cells.


Assuntos
Células-Tronco Pluripotentes Induzidas , Síndrome de Waardenburg , Humanos , Síndrome de Waardenburg/genética , Crista Neural , Fator de Transcrição PAX3/genética , Mutação
18.
Artigo em Chinês | MEDLINE | ID: mdl-36756824

RESUMO

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.


Assuntos
Surdez , Perda Auditiva Neurossensorial , Síndrome de Waardenburg , Feminino , Humanos , Surdez/genética , Perda Auditiva Neurossensorial/genética , Biologia Molecular , Mutação , Linhagem , Fenótipo , Síndrome de Waardenburg/genética , Criança
20.
Hum Genet ; 142(3): 419-430, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36576601

RESUMO

Waardenburg syndrome (WS) is a rare inherited autosomal dominant disorder caused by SOX10, PAX3, MITF, EDNRB, EDN3, and SNAI2. A large burden of pathogenic de novo variants is present in patients with WS, which may be derived from parental mosaicism. Previously, we retrospectively analyzed 90 WS probands with family information. And the frequency of de novo events and parental mosaicism was preliminary investigated in our previous study. In this study, we further explored the occurrence of low-level parental mosaicism in 33 WS families with de novo variants and introduced our procedure of quantifying low-level mosaicism. Mosaic single nucleotide polymorphisms (SNPs) were validated by amplicon-based next-generation sequencing (NGS); copy-number variants (CNVs) were validated by droplet-digital polymerase chain reaction (ddPCR). Molecular validation of low-level mosaicism of WS-causing variants was performed in four families (12.1%, 4/33). These four mosaic variants, comprising three SNVs and one CNV, were identified in SOX10. The rate of parental mosaicism was 25% (4/16) in WS families with de novo SOX10 variants. The lowest allele ratio of a mosaic variant was 2.0% in parental saliva. These de novo WS cases were explained by parental mosaicism conferring an elevated recurrence risk in subsequent pregnancies of parents. Considering its importance in genetic counseling, low-level parental mosaicism should be systematically investigated by personalized sensitive testing. Amplicon-based NGS and ddPCR are recommended to detect and precisely quantify the mosaicism for SNPs and CNVs.


Assuntos
Mosaicismo , Síndrome de Waardenburg , Humanos , Síndrome de Waardenburg/diagnóstico , Síndrome de Waardenburg/genética , Estudos Retrospectivos , Pais , Éxons , Mutação
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