High Prevalence ofPROP1Defects in Lithuania: Phenotypic Findings in an Ethnically Homogenous Cohort of Patients With Multiple Pituitary Hormone Deficiency

Abstract

High prevalence of PROP1 defects in Lithuania is due to 296delGA mutation, suggesting a founder effect.

Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations

“…The data used were the level of allelic association between variant alleles and surrounding markers obtained by haplotype analyses. The input parameters were the recombination rates derived from Rutgers Combined Map 20 , the estimated frequencies of the mutant alleles in the present populations (0.003 for c. [150delA] carriers derived from epidemiological studies 10,22 (see Supplementary Tables 3 and 4 for the values assumed in each population). We performed a joint maximumlikelihood estimation of the age of the studied variants as well as the population growth rates assuming neutrality.…”

“…The genetic diagnosis of CPHD, that is, detection of causal variants in the PROP1 gene in all patients was performed in several centers by either denaturing high-pressure liquid chromatography followed by direct Sanger sequencing if a DNA sequence alteration was suspected, 8 or by direct Sanger sequencing only, 9,10 or by DNA digestion with BcgI and Mnl, respectively and confirmation by direct Sanger sequencing. 11 To avoid inconsistencies, randomly selected samples from all participating centers were retested by direct Sanger sequencing in the Prague laboratory with the same results as obtained from the original laboratories.…”

“…4,[8][9][10][12][13][14] Participants gave written informed consent in their native language for genetic testing. This study was approved by the Institutional Ethics Committee of University Hospital Motol and 2nd Faculty of Medicine, Charles University, Prague, the Czech Republic.…”

“…[301_302delAG] variant carriers worldwide 10 , followed by variant occurrence in the neighboring or close-by countries including the Eastern part of Germany, Belarus, Poland, the Czech Republic and Russia.…”

“…The dramatic geographic clustering of the respective subjects in the selected parts of the world (Supplementary Table 1), illustrated by 70% prevalence of c.[301_302delAG] in Lithuanian patients with CPHD 10 and no patient with the PROP1 anomaly from Netherlands, 27 suggests a founder effect. On the other hand, the c.[301_302delAG] variant is located in three tandem GA repeats and such genetic regions are prone to polymerase slippage during DNA replication.…”