Gene Hunting Approaches through the Combination of Linkage Analysis with Whole-Exome Sequencing in Mendelian Diseases: From Darwin to the Present Day

Abstract

<b><i>Background:</i></b> In the context of medical genetics, gene hunting is the process of identifying and functionally characterizing genes or genetic variations that contribute to disease phenotypes. In this review, we would like to summarize gene hunting process in terms of historical aspects from Darwin to now. For this purpose, different approaches and recent developments will be detailed. <b><i>Summary:</i></b> Linkage analysis and association studies are the most common methods in use for explaining the genetic background of hereditary diseases and disorders. Although linkage analysis is a relatively old approach, it is still a powerful method to detect disease-causing rare variants using family-based data, particularly for consanguineous marriages. As is known that, consanguineous marriages or endogamy poses a social problem in developing countries, however, this same condition also provides a unique opportunity for scientists to identify and characterize pathogenic variants. The rapid advancements in sequencing technologies and their parallel implementation together with linkage analyses now allow us to identify the candidate variants related to diseases in a relatively short time. Furthermore, we can now go one step further and functionally characterize the causative variant through in vitro and in vivo studies and unveil the variant-phenotype relationships on a molecular level more robustly. <b><i>Key Messages:</i></b> Herein, we suggest that the combined analysis of linkage and exome analysis is a powerful and precise tool to diagnose clinically rare and recessively inherited conditions.

An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients

“…The combination of NGS data with linkage analysis to perform deep sequencing of linkage regions has already been employed for several mendelian diseases, leading to an increase in the identification of genes involved in their pathogenesis [41,42]. More recently, the same strategy has also been applied to complex diseases, including MS. For example, in a recent study [13], a large MS Dutch family with 11 affected individuals was analyzed by coupling linkage analysis with WES, leading to the identification of a rare missense variant located in the FKBP prolyl isomerase family member 6 (FKBP6) gene, segregating with the disease.…”

Current state of the art in hypoplastic left heart syndrome

“…Linkage analysis is a powerful tool that identifies the chromosomal location of genes that are responsible for a particular disease ( 17 ). This technique has been used in the case of HLHS and several examples are presented here.…”