Body mass varies considerably between different mammals and this variation is
largely accounted for by a difference in total cell number rather than individual cell
size. Insights into mechanisms regulating growth can therefore be gained by
understanding what governs total cell number at any one point. In addition, control
of cell proliferation and programmed cell death is fundamental to other areas of
research such as cancer and stem cell research. Microcephalic Primordial Dwarfism
(MPD) is a group of rare Mendelian human disorders in which there is an extreme
global failure of growth with affected individuals often only reaching a height of
around one metre in adulthood. To date, all identified disease genes follow an
autosomal recessive mode of inheritance and encode key regulators of the cell cycle,
where mutations impact on overall cell number and result in a substantially reduced
body size. MPD therefore provides a valuable model for examining genetic and
cellular mechanisms that impact on growth. The overall aims of this thesis were to
identify novel disease causing genes, as well as provide further characterisation of
known disease causing genes, through the analysis of whole exome sequencing
(WES) within a large cohort of MPD patients. Following the design and
implementation of an analytical bioinformatics pipeline, deleterious mutations were
identified in multiple disease genes including LIG4 and XRCC4. Both genes encode
components of the non-homologous end joining machinery, a DNA repair
mechanism not previously implicated in MPD. Additionally, the pathogenicity of
novel mutations in subunits of a protein complex involved in chromosome
segregation was assessed using patient-derived cells. These findings demonstrate
WES can be successfully implemented to identify known and novel disease causing
genes within a large heterogeneous cohort of patients, expanding the phenotype of
known disorders and improving diagnosis as well as providing novel insights into
intrinsic cellular mechanisms critical to growth