Comprehensive Identification of Pathogenic Gene Variants in Patients With Neuroendocrine Disorders

Abstract 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...

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Published in:	The journal of clinical endocrinology and metabolism Vol. 106; no. 7; pp. 1956 - 1976
Main Authors:	Vishnopolska, Sebastian Alexis, Mercogliano, Maria Florencia, Camilletti, Maria Andrea, Mortensen, Amanda Helen, Braslavsky, Debora, Keselman, Ana, Bergadá, Ignacio, Olivieri, Federico, Miranda, Lucas, Marino, Roxana, Ramírez, Pablo, Pérez Garrido, Natalia, Patiño Mejia, Helen, Ciaccio, Marta, Di Palma, Maria Isabel, Belgorosky, Alicia, Martí, Marcelo Adrian, Kitzman, Jacob Otto, Camper, Sally Ann, Pérez-Millán, Maria Ines
Format:	Journal Article
Language:	English
Published:	US Oxford University Press 01-07-2021
Subjects:	Adolescent Adult Argentina Birth defects Care and treatment Child Child, Preschool Children Clinical s Congenital defects DNA probes Endocrine System Diseases - genetics Female Fibroblast growth factor receptor 1 Genes Genetic aspects Genetic disorders Genetic Heterogeneity Genetic screening Genetic Testing - statistics & numerical data Health aspects Humans Hypopituitarism Hypopituitarism - genetics Infant LIM-Homeodomain Proteins - genetics Male Mutation Mutation - genetics Nucleic acids Otx2 protein Patients Pediatrics Phenotype Phenotypic variations Polymorphism, Single Nucleotide Thyroid transcription factor 1 Transcription Factors - genetics Young Adult Argentina congenital hypopituitarism single molecule molecular inversion probes genetic screening variants
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Summary:	Abstract 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-972X 1945-7197
DOI:	10.1210/clinem/dgab177