2. Academic Validation
  3. Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy

Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy

  • Am J Hum Genet. 2014 Aug 7;95(2):227-34. doi: 10.1016/j.ajhg.2014.07.007.
Kimberly A Aldinger 1,  Stephen J Mosca 2,  Martine Tétreault 3,  Jennifer C Dempsey 4,  Gisele E Ishak 5,  Taila Hartley 6,  Ian G Phelps 4,  Ryan E Lamont 2,  Diana R O'Day 4,  Donald Basel 7,  Karen W Gripp 8,  Laura Baker 8,  Mark J Stephan 9,  Francois P Bernier 2,  Kym M Boycott 6,  Jacek Majewski 10,  University of Washington Center for Mendelian Genomics,  Care4Rare Canada,  Jillian S Parboosingh 2,  A Micheil Innes 11,  Dan Doherty 12
Affiliations

Affiliations

  • 1 Department of Pediatrics, University of Washington, Seattle, WA 98105, USA; Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 2 Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T3B 6A8, Canada.
  • 3 McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 1A4, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
  • 4 Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
  • 5 Department of Radiology, Seattle Children's Hospital, Seattle, WA 98105, USA.
  • 6 Care4Rare, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
  • 7 Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53201, USA.
  • 8 Division of Medical Genetics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
  • 9 Department of Pediatrics, Madigan Army Medical Center, Tacoma, WA 98431, USA.
  • 10 Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
  • 11 Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T3B 6A8, Canada. Electronic address: micheil.innes@albertahealthservices.ca.
  • 12 Department of Pediatrics, University of Washington, Seattle, WA 98105, USA; Seattle Children's Research Institute, Seattle, WA 98101, USA. Electronic address: ddoher@uw.edu.
PMID: 25105227 DOI: 10.1016/j.ajhg.2014.07.007
Abstract

Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping and whole-exome Sequencing, we identified biallelic mutations in LAMA1 as the cause of CDC in seven affected individuals (from five families) independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Most of these individuals also have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. In one additional family, we identified two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts, indicating that cysts are not an obligate feature associated with loss of LAMA1 function. This work expands the phenotypic spectrum associated with the lamininopathy disorders and highlights the tissue-specific roles played by different laminin-encoding genes.

Figures