Dissertation

Clinical and molecular genetics of the multiple pterygium syndromes

Vogt, Julie

2017

Overview

The multiple pterygium syndromes are a heterogeneous group of conditions in which arthrogryposis (joint contractures), pterygia (webbing) and a variety of other developmental anomalies are present. It is caused by lack of fetal movement in the womb. Mutations in CHRNG, the embryonic subunit of the acetylcholine receptor (AChR), cause some of the cases. CHRNG mutation analysis was undertaken in a large patient cohort of 100 families and the mutations identified were included in a new Locus Specific Database. Genotype phenotype analysis showed that pterygia were almost invariably present in the CHRNG mutation positive patients. It was hypothesised that mutations in other genes necessary for fetal AChR function may cause fetal akinesia. Using a candidate gene approach a homozygous frameshift mutation in RAPSN was identified in one family and a homozygous splice site DOK7 mutation in second family. Mild mutations in both RAPSN and DOK7 have been previously identified in the congenital myasthenic syndromes (CMS). Thus, mild mutations in RAPSN and DOK7 cause CMS whereas severe mutations cause fetal akinesia. Finally, work was done to identify a novel cause of fetal akinesia in a consanguineous family using an autozygosity mapping approach. A region of homozygosity was located and candidate genes sequenced.

• Publisher: ProQuest Dissertations & Theses
• Subject: Akinesia