Journal
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Volume 161, Issue 10, Pages 2519-2527Publisher
WILEY-BLACKWELL
DOI: 10.1002/ajmg.a.36128
Keywords
proteoglycans; growth disorder; Ehlers-Danlos syndrome; whole exome sequencing
Categories
Funding
- Harvard Catalyst, The Harvard Clinical and Translational Science Center [UL1 RR 025758]
- NIH [1K23HD073351-01]
- Genentech Center for Clinical Research in Endocrinology
- March of Dimes [6-FY09-507]
- Translational Research Program, Boston Children's Hospital
- Swedish Research Council [K2007-52X-20316-01-4, K2012-99X-21998-01-3]
- Stockholm County Council
- Swedish Society of Medicine
- Her Royal Highness Crown Princess Lovisa's Foundation for Pediatric Care
- Wera Ekstrom's Foundation for Pediatric Research
- Marta och Gunnar V Philipson's Foundation
- Sallskapet Barnavard
- Karolinska Institutet
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Proteoglycans are a component of the extracellular matrix and are critical for cellular and tissue function. Mutations in proteoglycan components and enzymes involved in proteoglycan synthesis have been implicated in several growth disorders, with common features including short stature and skeletal dysplasia. For example, mutations in B4GALT7, a gene whose protein product catalyzes proteoglycan synthesis, have been associated with the rare progeroid variant of Ehlers-Danlos syndrome. Here, we conducted exome sequencing in a patient with a previously undiagnosed growth disorder and identified compound heterozygous mutations in B4GALT7. This patient is just the fourth individual with genetically confirmed progeroid variant of Ehlers-Danlos syndrome. The mutations include a previously characterized c.808C>T p.Arg270Cys substitution, and a novel c.122T>C p.Leu41Pro substitution. We demonstrate that the novel mutation caused decreased levels of the enzyme, supporting the pathogenicity of the mutation. Our report identifies a novel mutation in B4GALT7 causing the progeroid variant of Ehlers-Danlos syndrome and contributes an extensive phenotypic characterization of a patient with the syndrome. We also reviewed the previous literature in addition to the present patient, and conclude that the key features associated with B4GALT7 deficiency are short stature, developmental anomalies of the forearm bones and elbow, and bowing of the extremities, in addition to the classic features of Ehlers-Danlos syndrome. This report helps define the phenotype of the progeroid variant of Ehlers-Danlos syndrome and furthers our understanding of the effect of proteoglycan defects in growth disorders. (c) 2013 Wiley Periodicals, Inc.
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