Comprehensive Identification of Pathogenic Gene Variants in Patients With Neuroendocrine Disorders.

VISHNOPOLSKA SA; MERCOGLIANO MF; CAMILLETTI MA; MORTENSEN AH,; BRASLAVSKY D,; KESELMAN A; BERGADA I; MARINO , ROXANA; BELGOROSKY A; MARTI MA; PEREZ-MILLAN MI

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Año: 2021 vol. 106 p. 1956 - 1976

0021-972X

Purpose: Congenital hypopituitarism (CH) can present in isolation or with other birthdefects. Mutations in multiple genes can cause CH, and the use of a genetic screeningpanel could establish the prevalence of mutations in known and candidate genes for thisdisorder. It could also increase the proportion of patients that receive a genetic diagnosis.Methods: We conducted target panel genetic screening using single-moleculemolecular inversion probes sequencing to assess the frequency of mutations inknown hypopituitarism genes and new candidates in Argentina. We captured genomicdeoxyribonucleic acid from 170 pediatric patients with CH, either alone or with other abnormalities. We performed promoter activation assays to test the functional effects ofpatient variants in LHX3 and LHX4.Results: We found variants classified as pathogenic, likely pathogenic, or with uncertainsignificance in 15.3% of cases. These variants were identified in known CH causativegenes (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 inArgentina and provide evidence for new candidate genes. We show that CH is a geneticallyheterogeneous disease with high phenotypic variation and incomplete penetrance, andour results support the need for further gene discovery for CH. Identifying populationspecific pathogenic variants will improve the capacity of genetic data to predict eventualclinical outcomes.