title: Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short-rib polydactyly type I, Saldino-Noonan type.
abstract: The short-rib polydactyly syndromes (SRPS) are autosomal recessively inherited, genetically heterogeneous skeletal ciliopathies. SRPS phenotypes were historically categorized as types I-IV, with type I first delineated by Saldino and Noonan in 1972. Characteristic findings among all forms of SRP include short horizontal ribs, short limbs and polydactyly. The SRP type I phenotype is characterized by a very small thorax, extreme micromelia, very short, poorly mineralized long bones, and multiple organ system anomalies. To date, the molecular basis of this most severe type of SRP, also known as Saldino-Noonan syndrome, has not been determined. We identified three SRP cases that fit the original phenotypic description of SRP type I. In all three cases, exome sequence analysis revealed compound heterozygosity for mutations in DYNC2H1, which encodes the main component of the retrograde IFT A motor, cytoplasmic dynein 2 heavy chain 1. Thus SRP type I, II, III and asphyxiating thoracic dystrophy (ATD), which also result from DYNC2H1 mutations. Herein we describe the phenotypic features, radiographic findings, and molecular basis of SRP type I.
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Badiner
authors.affiliation: Department of Human Genetics, Los Angeles, CA, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Taylor
authors.affiliation: Department of Orthopaedic Surgery, Los Angeles, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Forlenza
authors.affiliation: International Skeletal Dysplasia Registry at UCLA, Los Angeles, CA, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Lachman
authors.affiliation: University of Washington Center for Mendelian Genomics, Seattle, WA, USA.
authors.affiliation: University of Washington Center for Mendelian Genomics, Seattle, WA, USA.|Department of Genome Sciences, Seattle, WA, USA.|Department of Pediatrics, University of Washington, Seattle, WA, USA.|Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bamshad
authors.affiliation: University of Washington Center for Mendelian Genomics, Seattle, WA, USA.|Department of Genome Sciences, Seattle, WA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Nickerson
authors.affiliation: Department of Orthopaedic Surgery, Los Angeles, CA, USA.|International Skeletal Dysplasia Registry at UCLA, Los Angeles, CA, USA.|Department of Developmental Cell and Molecular Biology, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Cohn
authors.affiliation: Department of Human Genetics, Los Angeles, CA, USA.|Department of Orthopaedic Surgery, Los Angeles, CA, USA.|International Skeletal Dysplasia Registry at UCLA, Los Angeles, CA, USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Krakow
mesh_terms: D056445:Cytoplasmic Dyneins / Q000235:genetics*; D004613:Ellis-Van Creveld Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005333:Fetus / Q000000981:diagnostic imaging / Q000503:physiopathology; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D011859:Radiography; D012779:Short Rib-Polydactyly Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D000073359:Exome Sequencing
chemical_list: C099883:DYNC2H1 protein, human; D056445:Cytoplasmic Dyneins
keywords: DYNC2H1; IFT-A; Saldino-Noonan syndrome; dynein cytoplasmic 2 heavy chain 1; intraflagellar transport A; short rib polydactyly syndrome; short rib polydactyly syndrome type I