title: Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy.
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.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98105, USA; Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Aldinger
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T3B 6A8, Canada.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Mosca
authors.affiliation: McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 1A4, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Tétreault
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Dempsey
authors.affiliation: Department of Radiology, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Gisele E
authors.initials: GE
authors.lastname: Ishak
authors.affiliation: Care4Rare, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Taila
authors.initials: T
authors.lastname: Hartley
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Phelps
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T3B 6A8, Canada.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Lamont
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
authors.forename: Diana R
authors.initials: DR
authors.lastname: O'Day
authors.affiliation: Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53201, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Basel
authors.affiliation: Division of Medical Genetics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Gripp
authors.affiliation: Division of Medical Genetics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Baker
authors.affiliation: Department of Pediatrics, Madigan Army Medical Center, Tacoma, WA 98431, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Stephan
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T3B 6A8, Canada.
authors.forename: Francois P
authors.initials: FP
authors.lastname: Bernier
authors.affiliation: Care4Rare, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T3B 6A8, Canada.
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.affiliation: 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.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98105, USA; Seattle Children's Research Institute, Seattle, WA 98101, USA. Electronic address: ddoher@uw.edu.
authors.forename: Dan
authors.initials: D
authors.lastname: Doherty
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D002525:Cerebellar Cortex / Q000002:abnormalities*; D002526:Cerebellar Diseases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003560:Cysts / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007797:Laminin / Q000235:genetics*; D008297:Male; D009136:Muscular Dystrophies / Q000235:genetics; D058499:Retinal Dystrophies / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D007797:Laminin; C084098:laminin A
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