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Cold Spring Harb Mol Case Stud. 2018 Oct 1;4(5). pii: a003160. doi: 10.1101/mcs.a003160. Print 2018 Oct.

In-frame de novo mutation in BICD2 in two patients with muscular atrophy and arthrogryposis.

Author information

1
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
2
Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA.
3
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
4
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
5
Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
6
GeneDx, Inc., Gaithersburg, Maryland 20877, USA.
7
Center for Perinatal Research and Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
8
Department of Neurology, The Ohio State University, Columbus, Ohio 43210, USA.
9
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

Abstract

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

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