Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.

TitleExpanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.
Publication TypeJournal Article
Year of Publication2018
AuthorsZhang, W, S Taylor, P, Ennis, HA, Forlenza, KN, Duran, I, Li, B, Sanchez, JAOrtiz, Nevarez, L, Nickerson, DA, Bamshad, M, Lachman, RS, Krakow, D, Cohn, DH
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalHum Mutat
Date Published2018 01
KeywordsCiliopathies, Cytoplasmic Dyneins, Genetic Association Studies, Genetic Markers, Genetic Variation, Genotype, Humans, Mutation, Phenotype, Proteins, Radiography, Skeleton, Whole Exome Sequencing

Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.

Alternate JournalHum. Mutat.
PubMed ID29068549
PubMed Central IDPMC6198324
Grant ListR01 DE019567 / DE / NIDCR NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 AR066124 / AR / NIAMS NIH HHS / United States
R01 AR062651 / AR / NIAMS NIH HHS / United States