Diagnostic exome-based preconception carrier testing in consanguineous couples: results from the first 100 couples in clinical practice

Abstract

Purpose: Consanguineous couples are at increased risk of being heterozygous for the same autosomal recessive (AR) disorder(s), with a 25% risk of affected offspring as a consequence. Until recently, comprehensive preconception carrier testing (PCT) for AR disorders was unavailable in routine diagnostics. Here we developed and implemented such a test in routine clinical care.

Methods: We performed exome sequencing (ES) for 100 consanguineous couples. For each couple, rare variants that could give rise to biallelic variants in offspring were selected. These variants were subsequently filtered against a gene panel consisting of ~2,000 genes associated with known AR disorders (OMIM-based). Remaining variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, after which only likely pathogenic and pathogenic (class IV/V) variants, present in both partners, were reported.

Results: In 28 of 100 tested consanguineous couples (28%), likely pathogenic and pathogenic variants not previously known in the couple or their family were reported conferring 25% risk of affected offspring.

Conclusion: ES-based PCT provides a powerful diagnostic tool to identify AR disease carrier status in consanguineous couples. Outcomes provided significant reproductive choices for a higher proportion of these couples than previous tests.

Fig. 1. Preconception carrier test (PCT) results.

(a) In the cohort of 100 consanguineous couples. Green boxes: novel detected variants, red boxes: variants not initially detected with the current PCT test design. (b) In the subgroup of couples undergoing preimplantation genetic testing (PGT). AD autosomal dominant, CNV copy-number variant, HGMD Human Gene Mutation Database.

Fig. 2. Family pedigrees described in more detail in the paper.

For all pedigrees, see Supplementary Figure S1. *● homozygous for black variant, homozygous red variant, half filled symbols are heterozygous variants.

Fig. 3. Correlation between degree of consanguinity and the observed number of identical variants shared between partners.

Distant: all degrees of consanguinity farther removed than 2nd cousins. Novel findings: number of couples in which preconception carrier testing (PCT) detected at least one novel carriership. Crossbars: median with interquartile range. *Significant two-tailed p value (given) in Mann–Whitney t-test.