On the origin of pontocerebellar hypoplasia: Finding genes for a rare disease

Pontocerebellar hypoplasia (PCH) is a recessive neurodegenerative disease with, in most cases, a prenatal onset. The patients suffer from severe intellectual and motor impairments. The majority of patients dies in childhood.
This thesis describes novel genes and genotype-phenotype correlations in PCH. In chapter 2 we confirm the presence of PCH and disorders of sex development as an isolated disease (PCH subtype 7). Chapter 3 focuses on genotype-phenotype correlations in EXOSC3-related PCH. We describe a cohort of twelve families and show that specific mutations can predict disease progression. Chapter 4 describes CLP1 as a novel PCH-causing gene and investigates the function of CLP1 in brain development using a zebrafish model. Chapter 5 discusses (t)RNA processing deficiencies as possible underlying disease mechanism in PCH.