Dataset Information

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

ABSTRACT: Pituitary development depends on a complex cascade of interacting transcription factors and signaling molecules. Lesions in this cascade lead to isolated or combined pituitary hormone deficiency (CPHD). The aim of this study was to identify copy number variants (CNVs) in genes known to cause CPHD and to determine their structure. We analyzed 70 CPHD patients from 64 families. Deletions were found in three Turkish families and one family from northern Iraq. In one family we identified a 4.96?kb deletion that comprises the first two exons of POU1F1. In three families a homozygous 15.9?kb deletion including complete PROP1 was discovered. Breakpoints map within highly homologous AluY sequences. Haplotype analysis revealed a shared haplotype of 350?kb among PROP1 deletion carriers. For the first time we were able to assign the boundaries of a previously reported PROP1 deletion. This gross deletion shows strong evidence to originate from a common ancestor in patients with Kurdish descent. No CNVs within LHX3, LHX4, HESX1, GH1 and GHRHR were found. Our data prove multiplex ligation-dependent probe amplification to be a valuable tool for the detection of CNVs as cause of pituitary insufficiencies and should be considered as an analytical method particularly in Kurdish patients.

SUBMITTER: Bertko E

PROVIDER: S-EPMC5537413 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Bertko Eleonore E Klammt Jürgen J Dusatkova Petra P Bahceci Mithat M Gonc Nazli N Ten Have Louise L Kandemir Nurgun N Mansmann Georg G Obermannova Barbora B Oostdijk Wilma W Pfäffle Heike H Rockstroh-Lippold Denise D Schlicke Marina M Tuzcu Alpaslan Kemal AK Pfäffle Roland R

Journal of human genetics 20170330 8

Pituitary development depends on a complex cascade of interacting transcription factors and signaling molecules. Lesions in this cascade lead to isolated or combined pituitary hormone deficiency (CPHD). The aim of this study was to identify copy number variants (CNVs) in genes known to cause CPHD and to determine their structure. We analyzed 70 CPHD patients from 64 families. Deletions were found in three Turkish families and one family from northern Iraq. In one family we identified a 4.96 kb d ...[more]

PMID: 28356564

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Project description:Pathogenic variants within the gene encoding the pituitary-specific transcription factor, POU class 1 homeobox 1 (POU1F1), are associated with combined pituitary hormone deficiency (CPHD), including growth hormone, prolactin, and thyrotropin stimulating hormone deficiencies. The aim of the study was to identify genetic aetiology in 10 subjects with CPHD from four consanguineous Sudanese families. Medical history, as well as hormonal and radiological information, was obtained from participants' medical records. Targeted genetic analysis of the POU1F1 gene was performed in two pedigrees with a typical combination of pituitary deficiencies, using Sanger sequencing, and whole-exome sequencing was performed in the other two pedigrees, where hypocortisolism and additional neurologic phenotypes were also initially diagnosed. In POU1F1 gene (NM_001122757.2) a novel homozygous splice-site deletion-namely, c.744-5_749del-was identified in all 10 tested affected family members as a cause of CPHD. Apart from typical pituitary hormonal deficiencies, most patients had delayed but spontaneous puberty; however, one female had precocious puberty. Severe post-meningitis neurologic impairment was observed in three patients, of whom two siblings had Dyke-Davidoff-Masson syndrome, and an additional distantly related patient suffered from cerebral infarction. Our report adds to the previously reported POU1F1 gene variants causing CPHD and emphasises the importance of genetic testing in countries with high rates of consanguineous marriage such as Sudan. Genetic diagnostics elucidated that the aetiologies of hypopituitarism and brain abnormalities, identified in a subset of affected members, were separate. Additionally, as central hypocortisolism is not characteristic of POU1F1 deficiency, hydrocortisone replacement therapy could be discontinued. Elucidation of a genetic cause, therefore, contributed to the more rational clinical management of hypopituitarism in affected family members.

Dataset Information

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

Publications

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

Similar Datasets

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