Rare Disease Diagnostics: A Single-center Experience and Lessons Learnt.

Area of Science:

• Medical Genetics
• Genomic Medicine
• Rare Disease Research

Background:

• Next-generation sequencing (NGS) has transformed medical genetics, enabling the discovery of genes responsible for Mendelian disorders.
• Despite advancements, a significant number of rare disease cases remain undiagnosed.
• Whole-exome sequencing (WES) is a powerful tool for investigating complex genetic conditions.

Purpose of the Study:

• To evaluate the diagnostic utility of WES in identifying causative genes for rare genetic disorders.
• To report the experience of the Genetics Institute at Rambam Health Care Campus in rare disease diagnostics.
• To assess the rate of novel gene discovery in undiagnosed rare disease cases.

Main Methods:

• Phenotypic characterization of patients in collaboration with referring physicians.
• Application of WES analysis for families with suspected rare genetic disorders.
• In-house bioinformatic analysis utilizing the Genoox platform.

Main Results:

• A total of 34 families were studied between 2014 and 2017.
• A definitive molecular diagnosis was achieved in 62% of cases (21 families).
• Novel causative genes were identified in 19% of diagnosed cases, with further candidate gene discoveries.

Conclusions:

• Accurate molecular diagnosis via WES significantly improves patient care and facilitates the development of tailored treatments.
• The study demonstrated high diagnostic yield and novel gene discovery rates, potentially influenced by the unique genetic landscape of Northern Israel.
• Close collaboration between analysts, geneticists, and clinicians enhances diagnostic success in rare disease investigations.