Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child

• Published in: European journal of human genetics : EJHG 2021-03, Vol.29 (3), p.455-462
• Main Authors: Mor-Shaked, Hagar, Rips, Jonathan, Gershon Naamat, Shiri, Reich, Avichai, Elpeleg, Orly, Meiner, Vardiella, Harel, Tamar
• Format: Article
• Language: English
• Subjects: Adult; Child; Classification; Consanguinity; Copy number; Couples; Diagnosis; Disease; Female; Gene Frequency; Genes; Genes, Recessive; Genetic Carrier Screening - standards; Genetic Carrier Screening - statistics & numerical data; Genetic counseling; Genetic disorders; Genetic screening; Genetics; Genomes; Hereditary diseases; Heterozygote; Humans; Inbreeding; Male; Models, Genetic; Pedigree; Phenotype; Population studies; Whole Exome Sequencing - statistics & numerical data
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/s41431-020-00756-y

Consanguinity, commonplace in many regions around the globe, is associated with an increased risk of autosomal recessive (AR) genetic disorders. Consequently, consanguineous couples undergoing preimplantation genetic diagnosis (PGD) for one Mendelian disorder may be at increased risk for a child with a second, unrelated AR genetic disorder. We examined the yield of exome analysis for carrier screening of additional AR disorders, beyond the primary diagnosis, amongst consanguineous vs. non-consanguineous populations. Parental samples from trio exomes of 102 consanguineous families and 105 non-consanguineous controls were evaluated for shared carrier status, after disregarding the primary molecular diagnosis. Results were sub-classified according to disease severity. Secondary shared carrier status for pathogenic and likely pathogenic variants leading to AR disorders of moderate to profound severity was identified in 10/102 (9.8%) consanguineous couples, as compared to 1/105 (0.95%) non-consanguineous couples (χ  = 8.0565, p value