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

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.