Whole-genome sequencing in Brazilian patients with neurofibromatosis type 1, including novel variants, incidental findings, and dual diagnoses.
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Angeloni Luise Longo, Jorente Josep, Oliveira Sobrinho Ruy Pires de, Gil-da-Silva-Lopes Vera Lúcia, Vidoti-Nascimento Carolina Gama, Guaragna Mara Sanches, Vieira Tarsis Paiva, Steiner Carlos Eduardo, Brazilian Rare Genomes Project Consortium, Teixeira Anne Caroline Barbosa, Coelho Antonio Victor Campos, Quaio Caio Robledo D' Angioli Costa, Moreno Carolina Araujo, Perrone Eduardo, Nascimento Junior Jose Bandeira do, Espolaor Jessica Grasiela Araujo, Prota Joana Rosa Marques, Oliveira Filho Joao Bosco de, Ceroni Jose Ricardo Magliocco, Chen Kelin, Ferreira Letícia Torres, Santana Lucas Santos de, Mofatto Luciana Souto, Virmond Luiza do Amaral, Silva Marina de Franca Basto, Migliavacca Michele Patricia, Minillo Renata Moldenhauer, Yamada Renata Yoshiko, Sitnik Roberta, Almeida Tatiana Ferreira de, Silva Thiago Yoshinaga Tonholo, Cintra Vivian Pedigone
Аннотация
METHODS: We conducted a retrospective study of 50 patients from 30 unrelated families, with features of Neurofibromatosis type 1, who underwent clinical evaluation and whole genome sequencing.
RESULTS: Patient ages ranged from 9 months to 62 years (mean 21.7 years). The most frequent manifestations were café-au-lait (100%), lentiginous macules (94%), Lisch nodules (62%), cutaneous (62%), and plexiform (38%) neurofibromas. Other findings included neurodevelopmental disorders (14%), congenital pseudarthrosis of the tibia (4%), optic pathway glioma (4%), and sphenoid wing dysplasia (2%). Eight individuals presented with tumors other than neurofibromas, including two with malignant peripheral nerve sheath tumors, two with breast cancer, and one each with a dysembryoplastic neuroepithelial tumor, cholangiocarcinoma, pilocytic astrocytoma, and basal cell carcinoma. All probands, except one, tested positive for pathogenic or likely pathogenic variants, of which three (11.1%) were novel (c.3372del, c.7299del, and c.7457_7457+2del), three were recurrent within this series (c.3826C>T, c.5902C>T, and c.6855C>A), and the others were private. Two families (6.6%) presented incidental findings, one in BRCA1 and the other in TMEM127. Three individuals (6.5%) had a second molecular diagnosis: one each with spinocerebellar ataxia type 19, primary ciliary dyskinesia type 3, and XYY syndrome.
CONCLUSION: This study presents the largest cohort of Brazilian individuals with neurofibromatosis type 1 to utilize whole-genome sequencing, identifying three novel germline NF1 variants and two previously unreported double diagnoses.