Key diagnostic markers for Autoimmune Lymphoproliferative Syndrome with molecular genetic diagnosis.

Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunodeficiency caused by mutations in genes affecting the extrinsic apoptotic pathway (FAS, FASL, CASP10). This study evaluated the clinical manifestations, laboratory findings and molecular genetic results of 215 patients referred as possible ALPS. Double negative T-cell (DNT) percentage and in vitro apoptosis functional tests were evaluated by FACS; interleukin 10 and 18 (IL-10, -18) and soluble FAS ligand (sFASL) were measured by ELISA. Genetic analysis was performed by next generation sequencing. Clinical background data were collected from patients' records. Patients were categorised into definite, suspected and unlikely ALPS, and laboratory parameters were compared among these groups. From 215 patients, 38 met the criteria for definite ALPS and 17 for suspected ALPS. The definite and suspected ALPS patient population showed higher DNT than unlikely ALPS and had higher rates of lymphoproliferation. Definite ALPS patients had a significantly more abnormal in vitro apoptosis function with lower annexin than patients with suspected ALPS (P=0.002) and patients not meeting the ALPS criteria (P<0.001). The combination of elevated DNT and an abnormal in vitro apoptosis functional test was the most useful to identify all types of ALPS patients; the combination of abnormal in vitro apoptosis functional test and elevated sFASL was a predictive marker for ALPS-FAS group identification. Lymphoproliferation, apoptosis functional test and DNT are the most sensitive markers; elevated IL-10 and IL-18 are additional indicators for ALPS. The combination of elevated sFASL and an abnormal apoptosis function was the most valuable prognosticator for patients with FAS mutations.