Clinical and molecular investigation of rare genetic overgrowth disorders

Foster, Alison Claire (2023). Clinical and molecular investigation of rare genetic overgrowth disorders. University of Birmingham. Ph.D.

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Abstract

Genetic overgrowth disorders are a group of rare conditions characterised by generalised and/or regional overgrowth. They are associated with a wide spectrum of clinical features including intellectual disability, developmental disorders, congenital anomalies, and other medical problems. In recent years several novel overgrowth genes have been identified but the clinical phenotypes and natural history of these emerging conditions are not yet fully understood.
The Phenotyping of Overgrowth Disorders (POD) study was established to investigate the clinical and molecular features of rare genetic overgrowth disorders. Comprehensive clinical phenotyping data was collected from 100 participants and entered in an electronic data capture system. Genomic testing was performed on a custom targeted next generation sequencing panel of overgrowth genes. Additional molecular investigation with whole exome sequencing was performed in selected participants and trios.
This work identified a molecular genetic diagnosis in over 40% of the study cohort, confirmed the genetic heterogeneity of overgrowth disorders, and identified phenotypic overlap between overgrowth disorders and other rare genetic disorders. Knowledge of the clinical phenotypes of rare genetic overgrowth disorders has been expanded, including the clinically significant discovery of vascular complications in PDGFRB-related disorders that may be amenable to targeted molecular therapy.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):