Methods and Systems for Universal Carrier Screening

摘要

Provided herein are methods, systems, and devices for genetic screening. The genetic screening of two or more individuals can be utilized to predict the phenotype of a child from the group of individuals. Also disclosed is prediction of a phenotype of a child from a subset of biological relatives, such as a potential mother and father, before conception. In many instances, the methods, systems and devices herein are utilized to predict the probability of a child developing a rare genetic disease.

主权项

1. A method comprising:
a) obtaining sequence information from a DNA or RNA sample from a prospective parent in a multiplexed genetic test by sequencing or hybridization to provide sequence data that estimates:
(i) the probability of the presence or absence of at least one causal genetic variant (CGV) corresponding to at least one Mendelian genetic disease having a frequency of less than 1% in humans, and(ii) the presence or absence of at least one ancestry informative marker (AIM), wherein the at least one AIM is different from the causal genetic variant, is located in the region of the genome comprising the CGV, and distinguishes between populations for which the causal genetic variant exhibits a difference in incidence; b) obtaining information/data of prior probabilities of genotype frequencies of the at least one AIM; c) inferring ancestry for the region of the chromosome comprising the CGV from the presence or absence of the at least one AIM obtained in step (a)(ii), and the genotype frequencies of the at least one AIM obtained in step (b); d) correcting the estimation of the probability of presence of the CGV obtained step (a)(i) as a function of the ancestry local to the region of the genome comprising the CGV based on the estimation of the at least one AIM located in/near the region of the genome containing the CGV obtained in step (a)(ii), e) using the corrected estimation obtained in step (c), obtaining a posterior probability of the prospective parent being a carrier of the at least one Mendelian disease; f) using the CGV and AIM information collected in steps (a) and (c)-(e), performing a fully probabilistic analysis to calculate a probability of a phenotype of a potential child of the prospective parent with respect to the at least one Mendelian genetic disease; and g) informing the prospective parent of the carrier status of the prospective parent for the at least one Mendelian disease determined in step e) and/or the chances that the individual's future offspring will develop Mendelian disease determined in step f);
wherein said analysis is performed with the aid of a computer processor.