Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth

Preterm birth is the leading cause of infant mortality, and prematurity is further associated with serious morbidities in later life. Genetic and environmental risk factors play a role in the susceptibility to preterm birth. Despite numerous studies, the genetic basis for preterm birth remains poorly defined. We investigated the presence of rare, possibly risk associated nucleotide variants in mothers with spontaneous preterm births (SPTB). The first set of mothers with family history of recurrent preterm births was of northern Finnish origin. An additional set of mothers (sister pairs, both giving birth preterm) of European origin was also studied. Whole exome sequencing identified multiple rare, likely damaging HSPA1L variants in several families affected by SPTB, and this gene was associated with the glucocorticoid receptor signaling pathway. Potential involvement of one of the HSPA1L variants in SPTB was further supported by large GWAS dataset. In addition, this variant alters protein post-translational modification potential, and thus may affect protein stability and its function as a chaperone.