RVsharing

RVsharing tests cosegregation of rare variants with disease in family-based studies by calculating exact or simulated probabilities that affected relatives share a variant.

Key Features:

• Exact Sharing Probability Calculation: Extends closed-form expressions to compute probabilities that a rare variant observed in a family is shared by all affected relatives, supporting pedigrees with more than two relatives.
• Kinship-Adjusted and Simulation-Based Estimation: Approximates sharing probabilities using empirical kinship estimates from genome-wide marker data for related founders and applies Monte Carlo simulations for general pedigree structures.

Scientific Applications:

• Rare Disease Variant Cosegregation Analysis: Identifies disease-associated rare variants in multiplex families, including whole exome sequencing studies detecting variants such as rs149253049 in ADAMTS9 in non-syndromic oral clefts.

Methodology:

RVsharing computes variant-sharing probabilities under the null hypothesis of no linkage or association using generalized closed-form expressions, incorporates genome-wide marker–based kinship estimates for related founders, and employs Monte Carlo simulations to estimate probabilities across diverse family structures.