Identification of recurrent genetic patterns from targeted sequencing panels with advanced data science: a case-study on sporadic and genetic neurodegenerative diseases

BACKGROUND: Targeted Next Generation Sequencing is a common and powerful approach used in both clinical and research settings. However, at present, a large fraction of the acquired genetic information is not used since pathogenicity cannot be assessed for most variants. Further complicating this scenario is the increasingly frequent description of a poli/oligogenic pattern of inheritance showing the contribution of multiple variants in increasing disease risk. We present an approach in which the entire genetic information provided by target sequencing is transformed into binary data on which we performed statistical, machine learning, and network analyses to extract all valuable information from the entire genetic profile. To test this approach and unbiasedly explore the presence of recurrent genetic patterns, we studied a cohort of 112 patients affected either by genetic Creutzfeldt–Jakob (CJD) disease caused by two mutations in the PRNP gene (p.E200K and p.V210I) with different penetrance or by sporadic Alzheimer disease (sAD). RESULTS: Unsupervised methods can identify functionally relevant sources of variation in the data, like haplogroups and polymorphisms that do not follow Hardy–Weinberg equilibrium, such as the NOTCH3 rs11670823 (c.3837 + 21 T > A). Supervised classifiers can recognize clinical phenotypes with high accuracy based on the mutational profile of patients. In addition, we found a similar alteration of allele frequencies compared the European population in sporadic patients and in V210I-CJD, a poorly penetrant PRNP mutation, and sAD, suggesting shared oligogenic patterns in different types of dementia. Pathway enrichment and protein–protein interaction network revealed different altered pathways between the two PRNP mutations. CONCLUSIONS: We propose this workflow as a possible approach to gain deeper insights into the genetic information derived from target sequencing, to identify recurrent genetic patterns and improve the understanding of complex diseases. This work could also represent a possible starting point of a predictive tool for personalized medicine and advanced diagnostic applications. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12920-022-01173-4.