Molecular Genetic Causes of Selected Rare Diseases in Childhood

Rare diseases are a heterogeneous group of more than 6,000 diseases that are rare in the population. Most rare diseases are genetic in origin and affect mainly children. Accurate and timely diagnosis, together with possible treatment and genetic counselling, is therefore based on the identification of a genetic cause. Nevertheless, many patients remain undiagnosed for a long time. This study focuses on the identification of the genetic cause of rare diseases, especially in paediatric patients and their families, by using modern methods of DNA, RNA, and protein analysis. In particular, it involves the application of next-generation sequencing methods in combination with other appropriate molecular genetics and bioinformatics methods chosen according to the needs of the individual patient. Using targeted long-read sequencing on the PacBio platform, we identified a causal deletion of the AVPR2 gene in a patient with X-linked nephrogenic diabetes insipidus. Furthermore, we combined exome sequencing with other methods to identify causal variants for various rare diseases with a diagnostic yield of 24%. We detected causal sequence variants in the UBR1, L1CAM, KDM5C, POLG, and SPTBN2 genes, as well as two large deletions and two large duplications. In another 7%, we detected two candidate sequence...