title: Two novel disease-causing variants in BMPR1B are associated with brachydactyly type A1.
abstract: Brachydactyly type A1 is an autosomal dominant disorder primarily characterized by hypoplasia/aplasia of the middle phalanges of digits 2-5. Human and mouse genetic perturbations in the BMP-SMAD signaling pathway have been associated with many brachymesophalangies, including BDA1, as causative mutations in IHH and GDF5 have been previously identified. GDF5 interacts directly as the preferred ligand for the BMP type-1 receptor BMPR1B and is important for both chondrogenesis and digit formation. We report pathogenic variants in BMPR1B that are associated with complex BDA1. A c.975A>C (p.(Lys325Asn)) was identified in the first patient displaying absent middle phalanges and shortened distal phalanges of the toes in addition to the significant shortening of middle phalanges in digits 2, 3 and 5 of the hands. The second patient displayed a combination of brachydactyly and arachnodactyly. The sequencing of BMPR1B in this individual revealed a novel c.447-1G>A at a canonical acceptor splice site of exon 8, which is predicted to create a novel acceptor site, thus leading to a translational reading frameshift. Both mutations are most likely to act in a dominant-negative manner, similar to the effects observed in BMPR1B mutations that cause BDA2. These findings demonstrate that BMPR1B is another gene involved with the pathogenesis of BDA1 and illustrates the continuum of phenotypes between BDA1 and BDA2.
authors.affiliation: Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.|Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
authors.forename: Lemuel
authors.initials: L
authors.lastname: Racacho
authors.affiliation: Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.|Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Byrnes
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Heather
authors.identifier: http://orcid.org/0000-0001-9480-2677
authors.initials: H
authors.lastname: MacDonald
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Dranse
authors.affiliation: Faculty of Medicine, Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.|Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nikkel
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
authors.forename: Judith
authors.initials: J
authors.lastname: Allanson
authors.affiliation: Clinical Genetics Unit, Great Ormond Street Hospital for Children NHS Trust, London, UK.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rosser
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: T Michael
authors.initials: TM
authors.lastname: Underhill
authors.affiliation: Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.|Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.|Faculty of Medicine, Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
mesh_terms: D000818:Animals; D001483:Base Sequence; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D059327:Brachydactyly / Q000175:diagnosis / Q000235:genetics*; D002478:Cells, Cultured; D005091:Exons; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense
chemical_list: C498214:BMPR1B protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I