NADİR KONJENİTAL NÖTROPENİLERDE SOMATİK VE KALITSAL GENETİK NEDENLERİN ARAŞTIRILMASI

Abstract

Erkan, D.D., Investigation of Somatic and Hereditary Genetic Causes in Rare Congenital Neutropenias, Hacettepe University Faculty of Medicine, Department of Medical Genetics, Specialization Thesis, Ankara, 2025. Congenital neutropenia (CN) is a rare disorder characterized by reduced neutrophil counts and recurrent infections. The most common genetic causes of CN are ELANE, SBDS, HAX1, SLC37A4 and TAFAZZIN. Neutropenia can be isolated or appear as a component of a syndrome. In this thesis, a cohort of 23 affected individuals from different families where the most common causes are excluded was studied to elucidate the rare or yet unknown etiology of CN. Initially, clinical exome sequencing data was analyed comprehensively and SBDS gene was sequenced. Afterwards, whole exome sequencing and microarray analysis were performed to evaluate hereditary and somatic variants. As a result, 47% (11/23) of individuals were diagnosed with variants which are autosomal recessively, dominantly or mitochondrially inherited. In 3 of 23 affected individuals, the homozygous rs2814778 polymorphism was identified leading to ACKR1/Duffy associated neutropenia. Additionally, 6 of 10 individuals with extra clinical features unrelated to neutropenia were diagnosed with more than one genetic variant explaining the phenotype. In 5 of the 6 individuals, parents were consangineous with high rate of homozygosity regions. This study highlights the complicated rare genetic etiology of CN in a population with high consanguinity. Additional phenotypic features in individuals with consanguineous parents is a good indicator of multiple disease-causing genes. This emphasizes the need for comprehensive evaluation of genetic studies to fully explain the clinical phenotype.