Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma

Classic Kaposi sarcoma (KS) is exceedingly rare in children from the Mediterranean Basin, despite the high prevalence of human herpesvirus-8 (HHV-8) infection in this region. We hypothesized that rare single-gene inborn errors of immunity to HHV-8 may underlie classic KS in childhood. We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age. Whole-exome sequencing in the patient revealed a homozygous splice-site mutation in STIM1, the gene encoding stromal interaction molecule 1, which regulates store-operated Ca²⁺ entry. STIM1 mRNA splicing, protein production, and Ca²⁺ influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1. Based on the previous discovery of STIM1 deficiency in a single family with a severe T cell immunodeficiency and the much higher risk of KS in individuals with acquired T cell deficiencies, we conclude that STIM1 T cell deficiency precipitated the development of lethal KS in this child upon infection with HHV-8. Our report provides the first evidence that isolated classic KS in childhood may result from single-gene defects and provides proof-of-principle that whole-exome sequencing in single patients can decipher the genetic basis of rare inborn errors.Kaposi sarcoma (KS) is an angiogenic, inflammatory neoplasm first described by Moritz Kaposi (1872). The etiology of KS was unknown until Chang et al. (1994) isolated KS-associated herpesvirus, also known as human herpesvirus (HHV)-8, from KS lesions. Cells of endothelial origin are the principal targets of HHV-8 infection and the major components proliferating in KS lesions (Ganem, 2010). It has been clearly established that all forms of KS are associated with HHV-8 (Dupin et al., 1995; Moore and Chang, 1995; Schalling et al., 1995; Chang et al., 1996). Infection with HHV-8 is necessary but not sufficient for the development of KS. Despite the high seroprevalence of HHV-8, at up to 30% in the Mediterranean Basin (classic KS) and 70% in sub-Saharan Africa (endemic KS), the incidence of KS is very low (Boshoff and Weiss, 2001). Individuals with acquired immunodeficiency caused by HIV infection (epidemic KS; Martellotta et al., 2009) or immunosuppression after organ transplantation (iatrogenic KS; Lebbé et al., 2008) are at a much higher risk of developing KS than the general population. Host factors in other patients are therefore likely to play a critical role in determining the outcome of HHV-8 infection, including the development of KS in particular.As a first approach to testing the hypothesis that KS may result from inborn errors of immunity to HHV-8 in some patients (Casanova and Abel, 2007), we focused on classic KS in childhood. Classic KS is exceedingly rare in children, with only 30 cases reported since 1960, and follows a disseminated and often lethal course (Dutz and Stout, 1960; Bisceglia et al., 1988; Akman et al., 1989; Zurrida et al., 1994; Erdem et al., 1999; Landau et al., 2001; Ferrari et al., 2002; Hussein, 2008). We previously reported two children from the Mediterranean Basin with KS caused by an underlying primary immunodeficiency, one with autosomal recessive complete IFN-γR-1 deficiency (Camcioglu et al., 2004) and the other with X-linked recessive Wiskott-Aldrich syndrome (Picard et al., 2006). These children had several other clinical phenotypes, including mycobacterial disease in the IFN-γR1–deficient child and EBV-driven lymphoma in the child with Wiskott-Aldrich syndrome. These two cases provided the first evidence that classic KS in childhood may result from inborn errors of immunity, at least in children with multiple infectious and tumoral phenotypes, including KS.More recently, we described three unrelated Turkish children with classic KS in the absence of any other infectious or tumoral phenotype, each born to consanguineous parents (Sahin et al., 2010). This suggested that classic KS in children with no overt signs of immunodeficiency might also result from single-gene defects impairing HHV-8 immunity. Because the age of onset, clinical features, and outcome of KS reported in previous studies differ from child to child (Dutz and Stout, 1960; Bisceglia et al., 1988; Akman et al., 1989; Zurrida et al., 1994; Erdem et al., 1999; Landau et al., 2001; Ferrari et al., 2002; Picard et al., 2006; Camcioglu et al., 2004; Hussein, 2008; Sahin et al., 2010), we further hypothesized that the single-gene inborn errors of immunity underlying classic KS in children are heterogeneous. Using the recently developed whole-exome sequencing approach, which has been used to determine the genetic basis of other rare Mendelian disorders in small numbers of affected individuals (Choi et al., 2009; Hoischen et al., 2010; Lalonde et al., 2010; Ng et al., 2010; Walsh et al., 2010), we focused our investigation on a single Turkish child with early-onset disseminated KS that eventually ran a lethal course.