Intrafamilial Variability of the R694C Variant in BICD2 Presenting with Lethal Severe Arthrogryposis

Abstract

Arthrogryposis multiplex congenita (AMC) is a heterogeneous condition comprising congenital multiple joint contractures, and it is secondary to decreased fetal mobility following environmental/genetic abnormalities. BICD2 pathogenic variants have been associated with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). We report the case of a newborn with decreased fetal movements and ventriculomegaly diagnosed in utero, born with severe AMC, multiple bone fractures, congenital hip dislocation, and respiratory insufficiency that led to neonatal death. His mother had AMC diagnosis without established etiology. Her phenotype characterization was key to guide the genetic investigation. A BICD 2 heterozygous variant (NM_001003800.1; c.2080C > T; p. [Arg694Cys]) was detected both in the mother and the newborn. This variant had previously been reported in 3 cases, all having de novo severe SMALED-type 2B (MIM#618291) phenotype. This is the first report of this variant (p. [Arg694Cys]) presenting with an inherited, severe, and lethal phenotype associated to intrafamilial variability, suggesting a more complex phenotype-genotype correlation than previously stated.