In-frame de novo mutation in BICD2 in two patients with muscular atrophy and arthrogryposis
- Daniel C. Koboldt1,2,
- Rama D. Kastury3,
- Megan A. Waldrop2,4,
- Benjamin J. Kelly1,
- Theresa Mihalic Mosher1,2,5,
- Heather McLaughlin6,
- Don Corsmeier1,
- Jonathan L. Slaughter2,7,
- Kevin M. Flanigan2,4,8,
- Kim L. McBride2,5,
- Lakshmi Mehta3,9,
- Richard K. Wilson1,2 and
- Peter White1,2
- 1Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA;
- 2Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA;
- 3Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 4Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio 43205, USA;
- 5Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA;
- 6GeneDx, Inc., Gaithersburg, Maryland 20877, USA;
- 7Center for Perinatal Research and Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio 43205, USA;
- 8Department of Neurology, The Ohio State University, Columbus, Ohio 43210, USA;
- 9Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Corresponding authors: daniel.koboldt{at}nationwidechildrens.org; peter.white{at}nationwidechildrens.org
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.
- 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
Footnotes
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[Supplemental material is available for this article.]
- Received May 10, 2018.
- Accepted July 23, 2018.
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