Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 95, Issue 2, Pages 227-234Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2014.07.007
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Funding
- Genome Canada
- Canadian Institutes of Health Research
- Ontario Genomics Institute
- Ontario Research Fund
- Genome Quebec
- Children's Hospital of Eastern Ontario Foundation
- Alberta Children's Hospital Research Institute
- Alberta Innovates Health Solutions
- University of Washington Center for Mendelian Genomics (National Human Genome Research Institute) [U54HG006493]
- Alberta Children's Hospital Foundation
- University of Washington School of Medicine Department of Pediatrics
- NIH National Institute for Neurological Disorders and Stroke [R01NS050375]
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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 LAM41 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.
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