title: Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes.
abstract: We report on a father and his two daughters diagnosed with Klippel-Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS.
authors.affiliation: University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Philip F
authors.initials: PF
authors.lastname: Giampietro
authors.forename: Linlea
authors.initials: L
authors.lastname: Armstrong
authors.forename: Alex
authors.initials: A
authors.lastname: Stoddard
authors.forename: Robert D
authors.initials: RD
authors.lastname: Blank
authors.forename: Janet
authors.initials: J
authors.lastname: Livingston
authors.forename: Cathy L
authors.initials: CL
authors.lastname: Raggio
authors.forename: Kristen
authors.initials: K
authors.lastname: Rasmussen
authors.forename: Michael
authors.initials: M
authors.lastname: Pickart
authors.forename: Rachel
authors.initials: R
authors.lastname: Lorier
authors.forename: Amy
authors.initials: A
authors.lastname: Turner
authors.forename: Sarah
authors.initials: S
authors.lastname: Sund
authors.forename: Nara
authors.initials: N
authors.lastname: Sobrera
authors.forename: Enid
authors.initials: E
authors.lastname: Neptune
authors.forename: David
authors.initials: D
authors.lastname: Sweetser
authors.forename: Alberto
authors.initials: A
authors.lastname: Santiago-Cornier
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
mesh_terms: D002648:Child; D020090:Chromosome Segregation / Q000235:genetics*; D019295:Computational Biology; D004252:DNA Mutational Analysis; D012321:DNA-Directed RNA Polymerases / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005190:Family; D005220:Fathers; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007231:Infant, Newborn; D007714:Klippel-Feil Syndrome / Q000150:complications / Q000235:genetics*; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000150:complications / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009679:Nuclear Family; D010375:Pedigree
chemical_list: D012321:DNA-Directed RNA Polymerases; C569282:POLR1D protein, human
keywords: Klippel-Feil; Treacher Collins syndrome; autosomal dominant