Abstract
BackgroundCongenital Hypopituitarism is caused by genetic and environmental factors. Over 30 genes have been implicated in isolated and/or combined pituitary hormone deficiency. The etiology remains unknown for up to 80% of the patients, but most cases have been analyzed by limited candidate gene screening. Mutations in the PROP1 gene are the most common known cause, and the frequency of mutations in this gene varies greatly by ethnicity. We designed a custom array to assess the frequency of mutations in known hypopituitarism genes and new candidates, using single molecule molecular inversion probes sequencing (smMIPS).MethodsWe used this panel for the first systematic screening for causes of hypopituitarism in children. Molecular inversion probes were designed to capture 693 coding exons of 30 known genes and 37 candidate genes. We captured genomic DNA from 51 pediatric patients with CPHD (n = 43) or isolated GH deficiency (IGHD) (n = 8) and their parents and conducted next generation sequencing.ResultsWe obtained deep coverage over targeted regions and demonstrated accurate variant detection by comparison to whole‐genome sequencing in a control individual. We found a dominant mutation GH1, p.R209H, in a three‐generation pedigree with IGHD.ConclusionssmMIPS is an efficient and inexpensive method to detect mutations in patients with hypopituitarism, drastically limiting the need for screening individual genes by Sanger sequencing.
Highlights
Pituitary dysfunction is an important human health problem that is caused primarily by congenital birth defects and pituitary adenomas
Whole blood was collected from 51 Argentinean patients belonging to 44 unrelated families diagnosed with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency (CPHD) at the Hospital de Ni~nos Ricardo Gutierrez, Buenos Aires, Argentina
We developed a refined version of the single-molecule molecular inversion probe capture assay (Hiatt et al, 2013)
Summary
Pituitary dysfunction is an important human health problem that is caused primarily by congenital birth defects and pituitary adenomas. Prop is necessary to activate expression of Pou1f1 (*173110) (Sornson et al, 1996), and POU1F1 is mutated in individuals with CPHD or IGHD (Radovick et al, 1992; Sobrier et al, 2016; Tatsumi et al, 1992; Turton, Reynaud, et al, 2005; Turton, Strom, Langham, Dattani, & Le Tissier, 2012) and no other clinical features From these examples, it is clear that CPHD is part of a spectrum disorder that spans from severe abnormalities including holoprosencephaly (HPE) and septo-optic dysplasia (SOD) to milder cases with hypogonadotropic hypogonadism or IGHD (Fang et al, 2016; Raivio et al, 2012). Identifying these potential variants will make it feasible to predict clinical outcomes from genetic data, which is necessary for patient diagnosis and prognosis, and for assessing the risk of future affected individuals
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