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Case Reports
. 2018 Oct 1;4(5):a003160.
doi: 10.1101/mcs.a003160. Print 2018 Oct.

In-frame De Novo Mutation in BICD2 in Two Patients With Muscular Atrophy and Arthrogryposis

Free PMC article
Case Reports

In-frame De Novo Mutation in BICD2 in Two Patients With Muscular Atrophy and Arthrogryposis

Daniel C Koboldt et al. Cold Spring Harb Mol Case Stud. .
Free PMC article


We describe two unrelated patients, a 12-yr-old female and a 6-yr-old male, with congenital contractures and severe congenital muscular atrophy. Exome and genome sequencing of the probands and their unaffected parents revealed that they have the same de novo deletion in BICD2 (c.1636_1638delAAT). The variant, which has never been reported, results in an in-frame 3-bp deletion and is predicted to cause loss of an evolutionarily conserved asparagine residue at position 546 in the protein. Missense mutations in BICD2 cause autosomal dominant spinal muscular atrophy, lower-extremity predominant 2 (SMALED2), a disease characterized by muscle weakness and arthrogryposis of early onset and slow progression. The p.Asn546del clusters with four pathogenic missense variants in a region that likely binds molecular motor KIF5A. Protein modeling suggests that removing the highly conserved asparagine residue alters BICD2 protein structure. Our findings support a broader phenotypic spectrum of BICD2 mutations that may include severe manifestations such as cerebral atrophy, seizures, dysmorphic facial features, and profound muscular atrophy.

Keywords: absent speech; arthrogryposis multiplex congenita; decreased muscle mass; flexion contracture; fractures of the long bones; frontal bossing; generalized cerebral atrophy/hypoplasia; generalized muscle weakness; infantile spasms; prominent ear helix; relative macrocephaly; severe muscular hypotonia; skeletal myopathy; thick eyebrow.


Figure 1.
Figure 1.
Location and conservation of the p.Asn546del variant. (A) Pathogenic and likely pathogenic variants reported in the ClinVar database as of July 3, 2018. Blue dots represent missense variants. The p.Asn542del variant is shown in red. BICD2 protein structure, coiled-coil domains (gold), and KIF5 interaction region (red bar) were taken from UniProtKB entry Q8TD16. (B) UCSC Genome Browser screenshot for the region harboring the p.Asn542del variant.

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