Perinatal genetic diagnostic yield in a population of fetuses with the phenotype arthrogryposis multiplex congenita: a cohort study 2007-2021.

Abstract

Arthrogryposis multiplex congenita (AMC) presents challenges for prenatal detection due to its heterogeneous etiology, onset, and phenotypical manifestations. This study aims to describe the genetic diagnostic yield in a population of fetuses with detailed phenotypic description over a 15-year period (2007-2021) at the Fetal Medicine Unit of Amsterdam UMC, the Netherlands. The fetal and neonatal phenotypes were classified into three clinical AMC Groups, with the exception that Groups 1 and 2 were combined in the prenatal classification. Group 1 involves limb involvement primarily, Group 2 includes musculoskeletal involvement plus other system anomalies, and Group 3 involves musculoskeletal involvement with central nervous system disability, lethality, fetal akinesia deformation sequence, and/or intellectual disability. The cohort consisted of 64 consecutive cases, 13 in Groups 1 + 2 and 51 in Group 3. Perinatal genetic testing occurred in all cases: prenatally in 56 of the 64 (88%), postnatally in 36 of the 64 (56%), and combined testing in 28 of the 64 cases (44%). The overall genetic diagnostic yield was 28% (18/64), and it increased over the 5-year period from 14% to 50%. Whole exome sequencing had the highest yield (41.7%). The yield per phenotype was 30.8% (4/13) for AMC Group 1 + 2 and 27.4% (14/51) for AMC Group 3. Detailed fetal phenotyping and perinatal genetic testing in all cases showed improved diagnostic yield over time, likely due to the introduction of Next-generation sequencing-based tests. The availability of stored DNA will be beneficial for future investigations since further improvements in genetic testing possibilities are expected.