Genetic screening of regulatory regions of pituitary transcription factors in patients with idiopathic pituitary hormone deficiencies.
PURPOSE
Mutation frequencies of PROP1, POU1F1 and HESX1 in patients with combined pituitary hormone deficiencies (CPHD) vary substantially between populations. They are low in sporadic CPHD patients in Western Europe. However, most clinicians still routinely send DNA of their CPHD patients for genetic screening of these pituitary transcription factors. Before we can recommend against screening of PROP1, POU1F1 and HESX1 as part of routine work-up for Western-European sporadic CPHD patients, it is crucial to rule out possible defects in regulatory regions of these genes, which could also disturb the complex process of pituitary organogenesis.


METHODS
The regulatory regions of PROP1, POU1F1 and HESX1 are not covered by Whole Exome Sequencing as they are largely located outside the coding regions. Therefore, we manually sequenced the regulatory regions, previously defined in the literature, of PROP1, POU1F1 and HESX1 among 88 Dutch patients with CPHD. We studied promoter SNPs in relation to phenotypic data.


RESULTS
We found six known SNPs in the PROP1 promoter. In the POU1F1 promoter, we found one new variant and two known SNPs. We did not find any variant in the HESX1 promoter.


CONCLUSION
Although the new POU1F1 variant might explain the phenotype of one patient, the general conclusion of this study is that variants in regulatory regions of PROP1, POU1F1 and HESX1 are rare in patients with sporadic CPHD in the Netherlands. We recommend that genetic screening of these pituitary transcription factors should no longer be part of routine work-up for Western-European, and especially Dutch, sporadic CPHD patients.
['Elizabeth|Melitza|M|', 'Hokken-Koelega|Anita C S|ACS|', 'Schuilwerve|Joyce|J|', 'Peeters|Robin P|RP|', 'Visser|Theo J|TJ|', 'de Graaff|Laura C G|LCG|http://orcid.org/0000-0003-3530-7865']
D005260:Female D056726:Genetic Association Studies D005819:Genetic Markers D020022:Genetic Predisposition to Disease D005820:Genetic Testing D018398:Homeodomain Proteins D006801:Humans D007018:Hypopituitarism D008297:Male D009426:Netherlands D010641:Phenotype D020641:Polymorphism, Single Nucleotide D011237:Predictive Value of Tests D011401:Promoter Regions, Genetic D050817:Transcription Factor Pit-1 D019564:Unnecessary Procedures D000073359:Whole Exome Sequencing
Genetic screening Regulatory region Pituitary Transcription factor Growth Hypopituitarism