Waardenburg Syndrome: The Contribution of Next-Generation Sequencing to the Identification of Novel Causative Variants-Reference-Cited by-同舟云学术

Waardenburg Syndrome: The Contribution of Next-Generation Sequencing to the Identification of Novel Causative Variants

Published:2023-12-21 Issue:1 Volume:14 Page:9-25
ISSN:2039-4349
Container-title:Audiology Research
language:en
Short-container-title:Audiology Research

Author:

Bertani-Torres William¹²^ORCID,Lezirovitz Karina³^ORCID,Alencar-Coutinho Danillo³^ORCID,Pardono Eliete⁴⁵,da Costa Silvia Souza¹,Antunes Larissa do Nascimento¹,de Oliveira Judite⁶,Otto Paulo Alberto¹,Pingault Véronique²⁶^ORCID,Mingroni-Netto Regina Célia¹

Affiliation:

1. Centro de Estudos sobre o Genoma Humano e Células Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo 05508-090, Brazil

2. Department of Embryology and Genetics of Malformations, INSERM (Institut National de la Santé et de la Recherche Médicale) UMR (Unité Mixte de Recherche) 1163, Université Paris-Cité and Institut Imagine, 75015 Paris, France

3. Otorhinolaryngology Lab-LIM 32, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246-000, Brazil

4. Instituto de Ciências da Saúde, Universidade Paulista UNIP, São Paulo 04026-002, Brazil

5. Colégio Miguel de Cervantes, São Paulo 05618-001, Brazil

6. Médecine Génomique des Maladies Rares, AP-HP, Hôpital Necker-Enfants Malades, 75015 Paris, France

Abstract

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.

Funder

Fundação de Amparo à Pesquisa do Estado de São Paulo

CNPq

Publisher

MDPI AG

Subject

Podiatry,Otorhinolaryngology

Link

https://www.mdpi.com/2039-4349/14/1/2/pdf

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