The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN-associatedAMCas a type of viable fetal akinesia deformation sequence

Recessive variants in theGLDNgene, which encodes the gliomedin protein and is involved in nervous system development, have recently been associated with Arthrogryposis Multiplex Congenita (AMC), a heterogenous condition characterized by congenital contractures of more than one joint. Two cohorts of patients withGLDN-associated AMC have previously been described, evolving the understanding of the condition from lethal to survivable with the provision of significant neonatal support. Here, we describe one additional patient currently living with the syndrome, having one novel variant, p.Leu365Phe, for which we provide functional data supporting its pathogenicity. We additionally provide experimental data for four other previously reported variants lacking functional evidence, including p.Arg393Lys, the second variant present in our patient. We discuss unique and defining clinical features, adding calcium-related findings which appear to be recurrent in theGLDNcohort. Finally, we compare all previously reported patients and draw new conclusions about scope of illness, with emphasis on the finding of pulmonary hypoplasia, suggesting that AMC secondary toGLDNvariants may be best fitted under the umbrella of fetal akinesia deformation sequence (FADS).