Variable penetrance of COL6A1 null mutations: Implications for prenatal diagnosis and genetic counselling in Ullrich congenital muscular dystrophy families

Peat, Rachel A.; Baker, Naomi L.; Jones, Kristi J.; North, Kathryn N.; Lamandé, Shireen R.

doi:10.1016/j.nmd.2007.03.017

« Previous Next »Neuromuscular Disorders
Volume 17, Issue 7 , Pages 547-557, July 2007

Variable penetrance of COL6A1 null mutations: Implications for prenatal diagnosis and genetic counselling in Ullrich congenital muscular dystrophy families

Rachel A. Peat
- The Neurogenetics Research Unit, Children’s Hospital at Westmead and the Discipline of Paediatrics and Child Health, University of Sydney, Australia
- These authors contributed equally to this work.
Naomi L. Baker
- Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Parkville, 3052 Vic., Australia
- These authors contributed equally to this work.
Kristi J. Jones
- The Neurogenetics Research Unit, Children’s Hospital at Westmead and the Discipline of Paediatrics and Child Health, University of Sydney, Australia
- Western Sydney Genetics Programme, Children’s Hospital at Westmead, Sydney, Australia
Kathryn N. North
- The Neurogenetics Research Unit, Children’s Hospital at Westmead and the Discipline of Paediatrics and Child Health, University of Sydney, Australia
Shireen R. Lamandé
- Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Parkville, 3052 Vic., Australia
- Corresponding author. Tel.: +61 3 9345 6650; fax: +61 3 9345 7997.

Received 23 November 2006; received in revised form 16 March 2007; accepted 27 March 2007.

Abstract

Collagen VI mutations cause mild Bethlem myopathy and severe, progressive Ullrich congenital muscular dystrophy (UCMD). We identified a novel homozygous COL6A1 premature termination mutation in a UCMD patient that causes nonsense-mediated mRNA decay. Collagen VI microfibrils cannot be detected in muscle or fibroblasts. The parents are heterozygous carriers of the mutation and their fibroblasts produce reduced amounts of collagen VI. The molecular findings in the parents are analogous to those reported for a heterozygous COL6A1 premature termination mutation that causes Bethlem myopathy. However, the parents of our UCMD proband are clinically normal. The proband’s brother, also a carrier, has clinical features consistent with a mild collagen VI phenotype. Following a request for prenatal diagnosis in a subsequent pregnancy we found the fetus was a heterozygous carrier indicating that it would not be affected with severe UCMD. COL6A1 premature termination mutations exhibit variable penetrance necessitating a cautious approach to genetic counselling.

Keywords: Collagen VI, Ullrich congenital muscular dystrophy, Bethlem myopathy, Prenatal diagnosis