A Novel MPIG6B Gene Variant Identified in a Patient with Congenital Thrombocytopenia from Turkey

To the Editor, Congenital thrombocytopenia associated with MPIG6B mutations is a rare autosomal recessive disorder characterized by defective megakaryopoiesis and variable clinical manifestations [1].MPIG6B encodes the inhibitory receptor G6b-B, expressed on megakaryocytes and platelets.G6b-B suppresses intracellular signaling through SHP-1 and SHP-2 phosphatases.Loss of receptor function disrupts megakaryocyte maturation, resulting in macrothrombocytopenia and progressive myelofibrosis [2].Clinical manifestations include thrombocytopenia, anemia, leukocytosis, splenomegaly, and bone marrow fibrosis [3].We report a patient with congenital thrombocytopenia carrying a novel homozygous MPIG6B variant associated with marked intrafamilial phenotypic variability.A 9-year-old boy presented with congenital thrombocytopenia diagnosed on the third day of life (platelet count 60,000/mm³).Platelet counts remained persistently low, while mean platelet volume was normal (8-9 fL), and peripheral smear findings were consistent with automated counts.Hemoglobin and leukocyte counts were initially normal, and no bleeding episodes occurred.Growth and development were appropriate.His parents were first-degree cousins, and thrombocytopenia was present in his sister and cousin.At four years of age, he developed microcytic anemia (Hb 7-8 g/dL, MCV 70 fL) and splenomegaly (8 cm below the costal margin).Peripheral smear demonstrated teardrop cells, spherocytes, microcytosis, and circulating immature myeloid and erythroid cells(Figure 1).Iron studies and diepoxybutane testing were normal.Bone marrow examination revealed erythroid and myeloid hyperplasia, increased atypical hypolobulated megakaryocytes, and grade 2-3 reticulin fibrosis.Cytogenetics, FISH, and testing for JAK2, MPL, and CALR mutations were negative.Whole-exome sequencing identified a novel homozygous MPIG6B variant (NM_001282584.3.103T>C;p.Cys35Arg)(Table 1).Variant interpretation was performed according to the American College of Medical Genetics and Genomics(ACMG) guidelines using the GRCh38 (hg38) reference genome.According to ACMG/AMP criteria, the variant was classified as a variant of uncertain significance (PM2).Segregation analysis demonstrated heterozygosity in both parents and one sibling, whereas the affected sister and cousin were homozygous.Despite carrying the same homozygous variant, these relatives exhibited isolated thrombocytopenia (20,000-80,000/mm³) without anemia, splenomegaly, or fibrosis, indicating marked intrafamilial phenotypic variability.Because of progressive myelofibrosis and severe thrombocytopenia (<20,000/mm³), hematopoietic stem cell transplantation was considered but deferred owing to the absence of a suitable donor and the patient's stable clinical status without bleeding.Ruxolitinib (5 mg twice daily) was initiated to reduce splenomegaly.After three months, spleen size decreased from 8 cm to 4 cm, hemoglobin improved to 9-10 g/dL, and platelet counts u n c o r r e c t e d p r o o f fluctuated between 20,000 and 90,000/mm³.The patient has remained on treatment for more than one year without adverse effects although post-treatment marrow evaluation has not yet been performed.Approximately 20 patients with MPIG6B deficiency have been reported, most of Arab origin [4,5].Our case expands the mutational spectrum by describing a novel homozygous variant in a consanguineous Kurdish family and illustrates striking intrafamilial phenotypic heterogeneity.Although functional studies are required to establish pathogenicity, the clinical findings strongly support disease association.While HSCT remains the only curative treatment, ruxolitinib provided clinically meaningful improvement in splenomegaly and hematologic parameters.Additional studies are needed to determine its long-term efficacy and safety in MPIG6B-associated disease.