Key result
AMC cases show ~68% autosomal recessive inheritance alongside frequent de novo variants, highlighting genetic heterogeneity.
Why the study?
Despite advances in genomic approaches, disease-gene identification has been achieved in fewer than half of arthrogryposis multiplex congenita cases, where accurate genetic diagnosis is critical for tailored management.
AMC exhibits marked genetic heterogeneity, with autosomal recessive inheritance being the most common, though de novo variants play a prominent role in dominant or X-linked forms.
May inform genetic counseling in AMC; leaves open causative gene identification in most cases.
Arthrogryposis multiplex congenita (AMC) is characterized by congenital joint contractures in two or more body areas resulting from reduced or absent fetal movements. AMC exhibits marked phenotypic and genetic heterogeneity, as it is a symptom rather than a disease and may be part of a large number of unrelated conditions. Despite advances in genomic approaches and the increasing number of newly identified genes, disease-gene identification was achieved in fewer than half of cases in several reports, including in a French cohort of 367 AMC patients. The most frequent cause of AMC in these reports was a primary involvement of skeletal muscle. In the French cohort, the most frequent mode of inheritance was autosomal recessive (68.3%); in autosomal dominant or X-linked form, a high proportion of de novo variants (24%) was observed, indicating that this mechanism plays a prominent part in this developmental condition. Accurate genetic diagnosis is critical for more tailored management of AMC and possibly other organ involvement.
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Judith Melki (2026) studied this question. In a French AMC cohort, 68.3% had autosomal recessive inheritance; 24% of autosomal dominant/X-linked cases had de novo variants, highlighting genetic heterogeneity.
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