Brain white matter disorders or leukodystrophies are rare genetic conditions that are usually incurable, severe disabling diseases leading to death in infancy in most cases. The genetic causes of are widespread, with over 100 causal genes identified to date. Classic approaches targeting the most prevalent culprits achieve a molecular diagnosis in only half of all patients. The rest remains undiagnosed, with families searching for answers in “Diagnostic Odysseys” of 10 years or longer. To help these patients’ communities, we developed a computational algorithm that explores the genomic sequences of each case (obtained by whole-exome or genome sequencing), combined with its clinical features, to build interactome networks with knowledge obtained from public available databases. The pipeline ranks the rare variants found in each patient using a metric derived from an interactome of known genes causing similar disorders, which is expanded to novel genes that associate with the first network.
We applied the algorithm to our cohort of 126 undiagnosed patients from 11 tertiary hospitals across Spain, and solved an unprecedented 72% of cases, improving by 30% the average international diagnostic rate for these diseases.Thanks to the algorithm, we discovered 9 novel genes not previously known to cause leukodystrophies, providing answers to hundreds of families and clinicians worldwide. At the same time, these findings allowed to gain fundamental scientific progress on mechanisms that are pivotal for brain development and maintenance, like in the cases of the novel recessive syndromes caused by malfunction of DEGS1, PI4KA or SLC35B2.
Importantly, our strategy enables the highest diagnostic yield with the lowest cost in time and resources for the health care system, and can be extended to other genetic disorders. A precise diagnosis is the first step for families to access optimal genetic counselling and clinical management, which leads in some cases to timely approved or experimental treatments, or provides an open avenue for searching a cure.
Work broadcasted in “El Cazador de Cerebros: Enfermedades Raras” TV2, May 9th 2022 and national press