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
Instituto de Biociencias, Biotecnología y Biología Traslacional (IB3), Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Ciudad de Buenos Aires, Argentina.
Instituto de Química Biología en Exactas y Naturales (IQUIBICEN-CONICET), Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Ciudad de Buenos Aires, Argentina.
J Clin Endocrinol Metab. 2021 Jun 16;106(7):1956-1976. doi: 10.1210/clinem/dgab177.
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.
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.
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).
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.
先天性垂体功能减退症（CH）可单独出现或伴有其他出生缺陷。多个基因的突变可导致CH，使用基因筛查面板可确定该疾病已知基因和候选基因中突变的发生率。这也可能增加接受基因诊断的患者比例。
我们使用单分子分子倒位探针测序进行靶向基因筛查面板，以评估阿根廷已知垂体功能减退症基因和新候选基因中突变的频率。我们从170例单独或伴有其他异常的CH儿科患者中获取基因组脱氧核糖核酸。我们进行启动子激活试验以测试患者LHX3和LHX4变体的功能效应。
我们在15.3%的病例中发现了分类为致病性、可能致病性或意义不确定的变体。这些变体在已知的CH致病基因（LHX3、LHX4、GLI2、OTX2、HESX1）、较少报道的基因（FOXA2、BMP4、FGFR1、PROKR2、PNPLA6）和新的候选基因（BMP2、HMGA2、HNF1A、NKX2-1）中被鉴定出来。
在这项工作中，我们报告了阿根廷已知CH基因中突变的发生率，并为新的候选基因提供了证据。我们表明CH是一种具有高表型变异和不完全外显率的遗传异质性疾病，我们的结果支持对CH进行进一步基因发现的必要性。识别特定人群的致病变体将提高遗传数据预测最终临床结果的能力。
