Characterizing the Genetic Bases of Autosomal Recessive Disorders

Nadia Awni Akawi


Autosomal recessive disorders have devastating effects on patients and their families. Elucidating the genetic bases of such disorders is essential to improve their clinical outcome and for implementing effective prevention programs. In this dissertation, the genetic bases of seven autosomal recessive disorders in consanguineous families were investigated using homozygosity mapping followed by candidate genes or whole-exome sequencing. Consequently, novel genomic loci and novel mutations have been revealed. The mutations underlying Silver-Russell syndrome in three families were found in OBSL1 and CUL7 genes, known to cause 3-M syndrome. In addition, the mutations identified in COL11A1 in two families were the first to link this gene with fibrochondrogenesis. Furthermore, the mutations detected in JAM3 in unrelated families confirmed the importance of this gene in maintaining blood vessels integrity. While, splicing defects in LINS and TTC23 genes provided evidence on the possible involvement of these genes in human cognition. Novel mutations in POMGNT1 and PRG4 have been found in families affected by congenital muscular dystrophy and camptodactyly-arthropathy-coxa-vara-pericarditis syndrome, respectively. Finally, a neonatal progeroid syndrome has been mapped to a novel single locus on chromosome19p13.3-13.2. These findings contributed significantly to our understanding of the studied disorders and their underlying molecular mechanisms.