טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKurolap Alina
SubjectNew Pathophysiological Mechanisms Revealed by Discovery of
Disease-Causing Genes for Rare Monogenic
Phenotypes
DepartmentDepartment of Medicine
Supervisors Professor Tamar Ben-Yosef
Dr. Hagit Baris Feldman
Full Thesis textFull thesis text - English Version


Abstract

The study of human biology and physiology provides important insights into the underlying pathophysiology of rare and common diseases. Studying rare phenotypes can guide our knowledge on the molecular function of disease-causing genes, proteins and pathways. The advent of next-generation sequencing technologies has revolutionized the Medical Genetics field by promoting discovery of genes involved in numerous Mendelian disorders; nevertheless, over half of the documented rare disorders remain undiagnosed.

Our study aimed to uncover and investigate novel pathophysiological mechanisms by deciphering the genetic cause of rare monogenic phenotypes in families referred to the Genetics Institute at Rambam Health Care Campus. Whole exome sequencing and in-house bioinformatic analyses served as the basic model for gene discovery.

During this project, we recruited and studied 91 families with 95 rare disorders suspected to be monogenic. Diagnosis was reached in 59 cases (62.1%), implicating 20 novel genes and pathways in human disease (33.9% of all diagnosed cases), and expanding the phenotype of a known disorder in 17% of diagnosed cases. We selected three genetic discoveries of novel genes (SLC6A9, CD55 and GATC) and three phenotype establishments (PLVAP) or expansions (TUFM and CARMIL2) to be further evaluated by comprehensive clinical characterization and tailored functional assays; in the case of CD55-deficiency, our discovery even led to life-saving tailored treatment.

Understanding the genetic causes of rare phenotypes has immediate clinical implications for the patient and family by providing them with genetic counseling and family planning options, and directing population-screening programs once a founder effect is discovered. Broader scientific implications lie in discovery of novel gene roles and pathophysiological mechanisms, providing a target for the development of new therapies. Our study shows that exploring rare phenotypes across different medical specialties has significant yield and benefits in advancing medical science discoveries and innovations.