- Title
- The genetics of overgrowth syndromes
- Creator
- Kamien, Benjamin
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Overgrowth syndromes are a group of Mendelian conditions that cause large stature and intellectual disability. This thesis focuses on the generalised overgrowth syndromes hypothesised to have a Mendelian genetic basis rather than the localised or segmental overgrowth conditions considered to have a mosaic genetic aetiology. Clinical geneticists aim to provide diagnoses to patients and their consulting families and classifying a generalised overgrowth condition offers the starting point to make a diagnosis. At the time of commencing this PhD, a clinical audit revealed that diagnostic detection rates were low in this group of patients and I set out to improve this situation by developing a next-generation sequencing panel to apply to a cohort of undiagnosed patients. The clinical audit found that traditional clinical genetics practice could make a diagnosis in approximately 35% of patients. Moving to a next-generation sequencing panel did not improve diagnostic detection rates significantly but resulted in the finding of genetic variants of uncertain significance. There are several possible reasons for the low additional diagnostic rate within this cohort. First, comprehensive clinical phenotyping and single-gene analysis provided a diagnosis before the introduction of gene panels. Second, patients with an overgrowth phenotype may have an intellectual disability with familial tall-stature as opposed to true overgrowth; and third, there could be a number of overgrowth genes that still need to be characterised. There are many reported overgrowth syndromes in the medical literature, and most of the syndromes are very rare. This study had the advantage of examining all overgrowth patients from one clinical genetics unit, and it indicates that using overgrowth as a clinical diagnostic sign has a low diagnostic yield. Compared to the diagnosis rate using an overgrowth panel, newer approaches, such as exome sequencing, demonstrated more success. Genome-wide methylation analysis also is a promising tool to aid in patient diagnostics, particularly to resolve genetic variants of uncertain significance. The insights gained in studying overgrowth syndromes extend to understanding molecular mechanisms of cell growth, and cancer predisposition seen in overgrowth patients.
- Subject
- overgrowth syndrome; large stature; macrocephaly; tall stature; clinical genetics
- Identifier
- http://hdl.handle.net/1959.13/1507405
- Identifier
- uon:56017
- Rights
- Copyright 2021 Benjamin Kamien
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 18 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 126 KB | Adobe Acrobat PDF | View Details Download |