Identification of Novel Disease-Causing Gene Mutations Detected by Whole-Exome Sequencing and Whole-Genome Sequencing in Palestinian Families with Rare Diseases رسالة ماجستير

Abstract

Presence of isolated populations and communities in Palestine contributes to the rise of rare genetic diseases with founder pathogenic variants. These founder variants were found to be not common in the Palestinians genomic data or international controls. Therefore, it’s essential to study the genetic makeup of such communities and build a map for the founder variants in a national screening theme. In this study, we used whole-exome and whole-genome sequencing approaches in order to decipher and segregate the molecular causes of rare genetic disorders among three Palestinian families living in Palestinian villages. Our study included a complex form of hereditary spastic paraplegia (cHSP), cystic fibrosis (CF), microcephaly primordial dwarfism (MPD), and Rett syndrome (RTT). The segregation analysis showed the presence of the two recessive disorders, cHSP and CF, in several genotypes in the same family. cHSP was found to be associated with novel biallelic PTPN23 variant, p. (P1572T fs*12)], confirming that PTPN23 is a causal gene for hereditary spastic paraplegia. MPD was found to be caused by a novel frameshift-deletion biallelic TOP3A variant, [p.(Trp950Glyfs*58)]. Our sequencing results confirmed that the variants are inherited in an autosomal recessive manner. Furthermore, our segregation analysis supported the presence of a de novo inframe deletion variant in the MECP2 gene, [p.(Ser411del)], that may have caused RTT in one identified case. Our study showed the genomic power to deliver a diagnosis and inform management plans in large highly consanguineous and isolated communities that have been without a diagnosis for several years. It also revealed the presence of different modes of inheritance for the rare diseases that can arise in these consanguineous settings and not exclusively the expected autosomal recessive mode.