info:eu-repo/semantics/article
Comprehensive identification of pathogenic gene variants in patients with neuroendocrine disorders
Fecha
2021-03Registro en:
Vishnopolska, Sebastián Alexis; Mercogliano, María Florencia; Camilletti, María Andrea; Mortensen, Amanda Helen; Braslavsky, Debora Giselle; et al.; Comprehensive identification of pathogenic gene variants in patients with neuroendocrine disorders; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 106; 7; 3-2021; 1956-1976
0021-972X
CONICET Digital
CONICET
Autor
Vishnopolska, Sebastián Alexis
Mercogliano, María Florencia
Camilletti, María Andrea
Mortensen, Amanda Helen
Braslavsky, Debora Giselle
Keselman, Ana Claudia
Bergadá, Ignacio
Olivieri, Federico Alberto
Miranda, Lucas
Marino, Roxana Marcela
Ramírez, Pablo
Pérez Garrido, Nora
Patiño Mejia, Helena
Ciaccio, Marta Graciela Cristina
Di Palma, María Isabel
Belgorosky, Alicia
Marti, Marcelo Adrian
Kitzman, Jacob Otto
Camper, Sally Ann
Pérez Millán, María Inés
Resumen
Purpose: Congenital hypopituitarism (CH) can present in isolation or with other birth defects. Mutations in multiple genes can cause CH, and the use of a genetic screening panel could establish the prevalence of mutations in known and candidate genes for this disorder. It could also increase the proportion of patients that receive a genetic diagnosis. Methods: We conducted target panel genetic screening using single-molecule molecular inversion probes sequencing to assess the frequency of mutations in known hypopituitarism genes and new candidates in Argentina. We captured genomic deoxyribonucleic acid from 170 pediatric patients with CH, either alone or with other abnormalities. We performed promoter activation assays to test the functional effects of patient variants in LHX3 and LHX4. Results: We found variants classified as pathogenic, likely pathogenic, or with uncertain significance in 15.3% of cases. These variants were identified in known CH causative genes (LHX3, LHX4, GLI2, OTX2, HESX1), in less frequently reported genes (FOXA2, BMP4, FGFR1, PROKR2, PNPLA6) and in new candidate genes (BMP2, HMGA2, HNF1A, NKX2-1). Conclusion: In this work, we report the prevalence of mutations in known CH genes in Argentina and provide evidence for new candidate genes. We show that CH is a genetically heterogeneous disease with high phenotypic variation and incomplete penetrance, and our results support the need for further gene discovery for CH. Identifying population-specific pathogenic variants will improve the capacity of genetic data to predict eventual clinical outcomes.