Traditional molecular testing methods greatly relied on Sanger sequencing technology ( Sanger et al., 1977). Other tests such as chromosomal microarray and metabolic testing may be inadequate ( Engbers et al., 2008 Miller et al., 2010). This approach requires prior understanding of the diseases’ etiology and is therefore only useful whenever such information is available. Additional information such as phenotype segregation within families or sets of families under examination may be required to narrow down the region of interest and for validation of putative causative genes ( Dawn Teare and Barrett, 2005). In most cases, large genomic regions containing multiple genes are identified limiting the likelihood of pinpointing the causative genes. Molecular tests identify candidate gene regions which are subjected to linkage analysis using multiple polymorphic markers within families and individuals that show variation in the trait of interest for positional mapping of the genes ( Leal and Speer, 2000). The absence of reliable diagnostic procedures further impedes progress in the development of effective preventative and therapeutic interventions.Ĭonventional diagnostic testing methods involve clinical assessment followed by laboratory testing. Although Mendelian diseases and complex genetic diseases are individually rare, collectively they affect millions of individuals and families causing negative socioeconomic implications ( Angelis et al., 2015 Stoller, 2018). Consequently, affected individuals remain without diagnosis and can therefore not be provided with treatment, proper prognosis, beneficial information and appropriate clinical guidance ( Stoller et al., 2005). Conventional diagnostic testing methods in most cases return inconclusive results with only less than half of cases receiving a genetic diagnosis ( Shashi et al., 2013). Many Mendelian and complex genetic diseases remain unknown despite extensive diagnostic efforts ( Shashi et al., 2013). Additionally, we also highlight the analytical, ethical and regulatory challenges associated with analyzing personal genomes which constitute the data used for family genetic inheritance.
In this review, we discuss next generation and third generation sequencing platforms, bioinformatic tools and genetic resources commonly used to analyze family based genomic data with a focus on identifying inherited or novel disease-causing mutations. Analysis of family genetic inheritance using whole genomes, whole exomes or a panel of genes has been shown to be effective in identifying disease-causing mutations. Regardless, some diseases are still without diagnosis as most tests rely on SNP genotyping panels developed from population based genetic analyses. Significant advances have been made in identifying novel diseases associated mutations especially with the introduction of next generation and third generation sequencing. Mendelian diseases are caused by genetic mutations in a singular gene while complex trait diseases are caused by the accumulation of mutations in either linked or unlinked genomic regions. The lack of effective tests has hampered diagnosis thus, the affected lack proper prognosis. Mendelian and complex genetic trait diseases continue to burden and affect society both socially and economically. Kwazulu-Natal Research and Innovation Sequencing Platform (KRISP), School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.Kanzi *, James Emmanuel San, Benjamin Chimukangara, Eduan Wilkinson, Maryam Fish, Veron Ramsuran and Tulio de Oliveira
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