Autoimmune lymphoproliferative syndrome (ALPS) is a chronic non-malignant lymphoproliferative disorder caused by mutations in the genes involved in programmed cell death. It is inherited as an autosomal dominant pattern with variable penetrance. Here we present first Macedonian case of ALPS, caused by a novel heterozygous mutation in FAS gene.
Genetic analysis included a targeted resequencing in the proband on MiSeq personal sequencer using Illumina TruSight One kit. Direct DNA sequencing of FASexon 9 was performed for the proband, her parents and her grandparents.
Here, we report a 14 months old Macedonian girl whowas referred to our departmentfor the examination of hepatosplenomegaly. Family history provided data forsplenomegaly and subsequent splenectomy in patients’ mother at the age of 17, as well as suspicion of spherocytosis. Genetic analysis showed no pathogenic variants in the genes associated with spherocytosis. However, a novel pathogenicvariant c.913dupA, p.Thr305AsnfsTer16 in exon 9 of FASgene was revealed. The same mutation was present in the patient’s mother, but not in her parents (proband’s grandparents). Thus, the pathogenic FASvariant has arisen as a de novoevent in the proband’s mother. Additional clinical and laboratory investigations confirmed the presence of specific biomarkers for ALPS.
A first-line NGS analysis allows identification of genetic defect and initiation of appropriate clinical examinations to promptly reach the clinical diagnosis in patients with rare diseases. Reverse phenotyping in our case provided prompt and accurate diagnosis and early initiation of specific therapy.