Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.

2nd Department of Pediatrics Medical Faculty Comenius University and Children's University Hospital Bratislava Slovakia

2nd Department of Pediatrics Semmelweis University Budapest Hungary

CICS UBI Health Sciences Research Centre Faculty of Health Sciences University of Beira Interior Covilha Portugal

Department of Endocrinology and Diabetology The Children's Memorial Heath Institute Warsaw Poland

Department of Endocrinology State Center for Medical Rehabilitation Minsk Belarus

Department of Pediatric Endocrinology Diabetes and Metabolic Diseases University Medical Center Ljubljana and University Children's Hospital Ljubljana Slovenia

Department of Pediatrics 2nd Faculty of Medicine Charles University Prague and University Hospital Motol Prague Czech Republic

Department of Pediatrics Endocrinology and Diabetes Medical University of Silesia Upper Silesian Centre for Child's Health Katowice Poland

Developmental Endocrinology Unit Laboratory of Hormones and Molecular Genetics Faculty of Medicine Department of Endocrinology University of Sao Paulo Sao Paulo Brazil

Division of Pediatric Endocrinology and Diabetes Department of Pediatrics Emory University School of Medicine Atlanta GA USA

Division of Pediatric Endocrinology Department of Pediatrics University of Leipzig Leipzig Germany

Institute of Endocrinology Medical Academy Lithuanian University of Health Sciencies Kaunas Lithuania

Laboratory of Eco Anthropology and Ethnobiology National Museum of Natural History National Centre for Scientific Research University Paris Diderot Paris France

Unit of Pediatric Endocrinology and Diabetology Department of Pediatrics University Hospital Center Sestre Milosrdnice Zagreb Croatia

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Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion: Frequencies, phenotypes and growth outcomes

Combined pituitary hormone deficiency due to gross deletions in the POU1F1 (PIT-1) and PROP1 genes