Voster, Elana2018-10-162018-10-162017https://hdl.handle.net/10539/25810A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in Medicine (MSc (Med)) Johannesburg, 23 June 2017Spinal muscular atrophy (SMA) is an autosomal recessive, neuromuscular disorder, characterised by muscle atrophy and impaired mobility. A homozygous deletion of exon 7 of the survival motor neuron 1 gene (SMN1) is the main cause of SMA in ~94% of patients worldwide but only accounts for 51% of South African (SA) black patients. SMN1 and its highly homologous pseudogene, SMN2, are located in a complex duplicated region on chromosome 5q13. Unusual copy number variations (CNVs) have been reported in black patients, suggesting the presence of complex pathogenic rearrangements. The aim of this project was to investigate the disease mechanism in the black SA population further. MLPA (multiplex ligation-dependent amplification) testing was performed on 172 unrelated black individuals referred for SMA testing. Of these, 50 had a homozygous deletion of SMN1, exon 7; 50 had a homozygous deletion of SMN2, exon 7 and 72 had no homozygous deletions, but a strong clinical suspicion of SMA. Furthermore, 122 black individuals negative for SMA were tested. For comparison, 68 white individuals (30 with a homozygous deletion of SMN1; 8 with a homozygous deletion of SMN2, exon 7 and 30 negative for SMA) were tested. No clear pathogenic CNV pattern was identified in black patients. Only 8.3% (6/72) of patients with a strong clinical suspicion had a heterozygous deletion of SMN1, exon 7 which is lower than previous SA reports of 69.5%. Multiple (>2) copies of SMN1, exon 7 were observed in 50.8% (62/122) of black negative controls which could mask the presence of silent carriers and potential pathogenic CNVs. This study re-emphasises the hypervariability and the limited understanding of CNVs of the SMN region in black populations. While MLPA has been shown to be an appropriate technique to identify SMA carriers in the white population, it has limited clinical utility in the black SA population.enMuscular Atrophy, SpinalNeuromuscular DiseasesThesis