TY - JOUR
T1 - Diagnostic exome-based preconception carrier testing in consanguineous couples
T2 - results from the first 100 couples in clinical practice
AU - Sallevelt, Suzanne C. E. H.
AU - Stegmann, Alexander P. A.
AU - de Koning, Bart
AU - Velter, Crool
AU - Steyls, Anja
AU - van Esch, Melanie
AU - Lakeman, Phillis
AU - Yntema, Helger
AU - Esteki, Masoud Zamani
AU - de Die-Smulders, Christine E. M.
AU - Gilissen, Christian
AU - van den Wijngaard, Arthur
AU - Brunner, Han G.
AU - Paulussen, Aimee D. C.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/6
Y1 - 2021/6
N2 - 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 similar to 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 chokes for a higher proportion of these couples than previous tests.
AB - 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 similar to 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 chokes for a higher proportion of these couples than previous tests.
U2 - 10.1038/s41436-021-01116-x
DO - 10.1038/s41436-021-01116-x
M3 - Article
C2 - 33742171
SN - 1098-3600
VL - 23
SP - 1125
EP - 1136
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 6
ER -