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

Autor(es)

Bertani-Torres, William ; Lezirovitz, Karina ; Alencar-Coutinho, Danillo ; Pardono, Eliete ; da Costa, Silvia Souza ; Antunes, Larissa do Nascimento ; de Oliveira, Judite ; Otto, Paulo Alberto ; Pingault, Veronique ; Mingroni-Netto, Regina Celia

• Tipo de documento: Artigo Científico
• Fonte: AUDIOLOGY RESEARCH; v. 14, n. 1, p. 17-pg., 2024-02-01.

Resumo

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. (AU)

• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 18/03433-9 - Utilização de células IPS e modelos animais para elucidação da fisiopatologia de perda auditiva sensorioneural pós-lingual de etiologia genética
• Beneficiário: Karina Lezirovitz Mandelbaum
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/13071-6 - Identificação de novos genes e estudos funcionais na surdez não-sindrômica
• Beneficiário: Karina Lezirovitz Mandelbaum
• Modalidade de apoio: Auxílio à Pesquisa - Regular