[Clinical features of JAK1 gain-of-function variants and perspectives on ‍monogenic disorders in allergic diseases]

The prevalence of allergic diseases is increasing worldwide, with approximately one in two individuals in Japan affected by some form of allergic condition, making it a common disease. While most allergic diseases are multifactorial, involving a complex interplay between genetic predispositions and environmental factors, a subset of cases is attributed to monogenic disorders, which have been increasingly reported in recent years. This article focuses on JAK1 gain-of-function (GOF) variants, highlighting their clinical features, therapeutic potential, and the future prospects of research on monogenic disorders in allergic diseases. JAK1-GOF variants are characterized by early onset and severe atopic dermatitis that does not respond to conventional therapies. They are also frequently associated with other allergic diseases, such as food allergies and asthma, as well as autoimmune diseases and growth impairments. JAK inhibitors represent a promising therapeutic option for JAK1-GOF mutations, with previous reports suggesting their efficacy. Predicting drug efficacy through in vitro studies could enable the selection of tailored treatments for individual patients, potentially leading to significant clinical improvements. It is hypothesized that undiagnosed patients with such monogenic disorders may exist. Accurate diagnosis of these patients could facilitate effective treatments. Moreover, research on monogenic disorders has the potential to lead to the development of novel molecular-targeted therapies through the elucidation of disease pathophysiology, benefiting not only patients with rare genetic disorders but ultimately a broader population.