Deep familial phenotyping and genotyping to resolve phenotypic variability of inherited pathogenic genetic variants

The high burden of de novo pathogenic genetic variants in sporadic patients with rare developmental disorders (DD) has led to a de novo paradigm in genetic research and diagnostics. Genetic variants inherited from an unaffected parent are typically disregarded in variant interpretation pipelines. However, we are confronted with a growing list of rare inherited variants, that are enriched in patient versus control cohorts. Mechanisms underlying reduced penetrance of these variants are poorly understood. Whole genome sequencing (WGS) is particularly suited to explore genetic modifiers underlying this phenotypic variability, given its ability to detect both coding and non-coding variants. We aim to bridge the knowledge gap of phenotypic variability by combining deep phenotyping, genotyping and hi-C sequencing in affected and unaffected relatives of patients with inherited pathogenic copy number variants for DD. This will be crucial for improved diagnosis and counseling of genetic risk variants in DD.

Keywords:phenotypic variability, deep familial phenotyping, whole genome sequencing, multi-omics, inherited genetic variants

Disciplines:Genome structure and regulation