Spadoni, E.; (2011) An investigation of genetic variation in complex disorders of the pituitary gland. Masters thesis , UCL (University College London).

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Abstract

Congenital hypopituitarism can be triggered by environmental insults, such as viral infections, vascular or degenerative damage and exposure to alcohol and drugs. Genetic mutations have been identified in genes responsible for pituitary development and function, however, only up to 10% of patients affected by hypopituitarism have recognised mutations in known genes. Clinical phenotypes may arise from gene dosage imbalance, but routine cytogenetic and molecular techniques can be insufficiently sensitive to detect chromosome rearrangements that are either submicroscopic in size or limited to a specific genomic locus or both. In the present study, ten patients with a complex pathology of the pituitary gland of unknown aetiology were clinically pre-selected according to a criteria checklist, to undergo a genome-wide screening of copy number changes with high-resolution 250K SNP array. Genomic sequencing of three candidate genes, BARX2, OTX2 and BMP4, was carried out in larger cohorts of selected patients. Three pathogenic genomic imbalances, chromosome 6q terminal duplication, chromosome 11q terminal deletion, and an interstitial deletion of chromosome 22q were detected in two patients, and the breakpoints were defined at high resolution. A submicroscopic rearrangement in the chromosome region 1p36.33 was found in a patient presenting with the association of hypopituitarism and tetralogy of Fallot. Two CNVs were found at the location of the breakpoints of a cytogenetically visible translocation between chromosomes 11q and 22q in one patient. One region of genomic imbalance, identified in one patient, contained the whole length of the ENG gene. A novel amino acid change was identified in BARX2 in a patient with isolated hypopituitarism. A novel nonsense mutation was found in OTX2 in a patient with pathology of the pituitary gland associated wth severe eye defects. These findings contribute to the understanding of the genetic bases of congenital hypopituitarism.

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