View article

Recent evidence supports the involvement of rare variants (population allele frequency< 1%) in the aetiology of common diseases [1],[2]. It is possible that much of the genetic control of common diseases is due to rare and pathogenic variants with a major effect on the phenotype. The detection of these rare genomic variants harboured in coding regions has shown to be achievable using extreme phenotypes (those exhibiting an unexpected and extreme accumulation of signs and/or symptoms than those expected by the disease’s natural history) and pedigrees segregating exceptional phenotypes [1],[2].

Polyautoimmunity is defined as the presence of more than one autoimmune disease (AD) in a single patient [3]. When three or more ADs coexist, the condition is called multiple autoimmune syndrome (MAS), which characterises the best example of polyautoimmunity, and probably the most conspicuous extreme autoimmune phenotype [4] i. e.,(i) MAS amalgamates signs and symptoms that are present in several ADs,(ii) the MAS signs and symptoms clustering is not random but it outlines the presence of subtypes,(iii) in many occurrences, it clusters in families, and (iv) major gene effects and the potential location of these MAS major loci have been established [4],[5]. Consequently, it is fair to consider that MAS, as an extreme phenotype of autoimmunity, would be critical for dissecting genes of major effect conferring susceptibility to autoimmunity [5],[6]. Sjogrens syndrome (SS), an autoimmune exocrinopathy, is frequently observed in MAS patients [7].