title: Whole-exome sequencing, without prior linkage, identifies a mutation in LAMB3 as a cause of dominant hypoplastic amelogenesis imperfecta.
abstract: The conventional approach to identifying the defective gene in a family with an inherited disease is to find the disease locus through family studies. However, the rapid development and decreasing cost of next generation sequencing facilitates a more direct approach. Here, we report the identification of a frameshift mutation in LAMB3 as a cause of dominant hypoplastic amelogenesis imperfecta (AI). Whole-exome sequencing of three affected family members and subsequent filtering of shared variants, without prior genetic linkage, sufficed to identify the pathogenic variant. Simultaneous analysis of multiple family members confirms segregation, enhancing the power to filter the genetic variation found and leading to rapid identification of the pathogenic variant. LAMB3 encodes a subunit of Laminin-5, one of a family of basement membrane proteins with essential functions in cell growth, movement and adhesion. Homozygous LAMB3 mutations cause junctional epidermolysis bullosa (JEB) and enamel defects are seen in JEB cases. However, to our knowledge, this is the first report of dominant AI due to a LAMB3 mutation in the absence of JEB.
authors: Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
authors: James A
authors: JA
authors: Poulter
authors: 1] Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK [2] Department of Oral Biology, Dental School, Suez Canal University, Ismailia, Egypt [3] Department of Oral Medicine, Leeds Dental Institute, University of Leeds, Leeds, UK.
authors: Walid
authors: W
authors: El-Sayed
authors: Department of Oral Biology, Leeds Dental Institute, University of Leeds, Leeds, UK.
authors: Roger C
authors: RC
authors: Shore
authors: Department of Oral Biology, Leeds Dental Institute, University of Leeds, Leeds, UK.
authors: Jennifer
authors: J
authors: Kirkham
authors: Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
authors: Chris F
authors: CF
authors: Inglehearn
authors: 1] Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK [2] Department of Oral Medicine, Leeds Dental Institute, University of Leeds, Leeds, UK.
authors: Alan J
authors: AJ
authors: Mighell
mesh_terms: D000567:Amelogenesis Imperfecta / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D016109:Epidermolysis Bullosa, Junctional / Q000235:genetics / Q000473:pathology; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D008040:Genetic Linkage; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D010375:Pedigree; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D000097794:Kalinin
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