Assessing the digenic model in rare disorders using population sequencing data

• Published in: European journal of human genetics : EJHG Vol. 30; no. 12; pp. 1439 - 1443
• Main Authors: Moreno-Ruiz, Nerea, Lao, Oscar, Aróstegui, Juan Ignacio, Laayouni, Hafid, Casals, Ferran
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-12-2022; Springer International Publishing
• Subjects: Brief Communication; Exome; Exome Sequencing; Genes; Genetic analysis; Genetic counseling; Genomic analysis; Genomics; Genotype & phenotype; Heredity; Humans; Life sciences; Multifactorial Inheritance; Rare Diseases - genetics; Sample size; Sequence Analysis, DNA; Simulation; Statistical power; Whole genome sequencing
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/s41431-022-01191-x

An important fraction of patients with rare disorders remains with no clear genetic diagnostic, even after whole-exome or whole-genome sequencing, posing a difficulty in giving adequate treatment and genetic counseling. The analysis of genomic data in rare disorders mostly considers the presence of single gene variants in coding regions that follow a concrete monogenic mode of inheritance. A digenic inheritance, with variants in two functionally-related genes in the same individual, is a plausible alternative that might explain the genetic basis of the disease in some cases. In this case, digenic disease combinations should be absent or underrepresented in healthy individuals. We develop a framework to evaluate the significance of digenic combinations and test its statistical power in different scenarios. We suggest that this approach will be relevant with the advent of new sequencing efforts including hundreds of thousands of samples.