title: Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders.
abstract: The popliteal pterygia syndromes are a distinct subset of the hundreds of Mendelian orofacial clefting syndromes. Popliteal pterygia syndromes have considerable variability in severity and in the associated phenotypic features but are all characterized by cutaneous webbing across one or more major joints, cleft lip and/or palate, syndactyly, and genital malformations. Heterozygous mutations in IRF6 cause popliteal pterygium syndrome (PPS) while homozygous mutations in RIPK4 or CHUK (IKKA) cause the more severe Bartsocas-Papas syndrome (BPS) and Cocoon syndrome, respectively. In this study, we report mutations in six pedigrees with children affected with PPS or BPS. Using a combination of Sanger and exome sequencing, we report the first case of an autosomal recessive popliteal pterygium syndrome caused by homozygous mutation of IRF6 and the first case of uniparental disomy of chromosome 21 leading to a recessive disorder. We also demonstrate that mutations in RIPK4 can cause features with a range of severity along the PPS-BPS spectrum and that mutations in IKKA can cause a range of features along the BPS-Cocoon spectrum. Our findings have clinical implications for genetic counseling of families with pterygia syndromes and further implicate IRF6, RIPK4, and CHUK (IKKA) in potentially interconnected pathways governing epidermal and craniofacial development.
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Leslie
authors.forename: James
authors.initials: J
authors.lastname: O'Sullivan
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cunningham
authors.forename: Ankur
authors.initials: A
authors.lastname: Singh
authors.forename: Steven L
authors.initials: SL
authors.lastname: Goudy
authors.forename: Faroug
authors.initials: F
authors.lastname: Ababneh
authors.forename: Lamia
authors.initials: L
authors.lastname: Alsubaie
authors.forename: Gaik-Siew
authors.initials: GS
authors.lastname: Ch'ng
authors.forename: Ingrid M B H
authors.initials: IM
authors.lastname: van der Laar
authors.forename: A Jeannette M
authors.initials: AJ
authors.lastname: Hoogeboom
authors.forename: Martine
authors.initials: M
authors.lastname: Dunnwald
authors.forename: Seema
authors.initials: S
authors.lastname: Kapoor
authors.forename: Pawina
authors.initials: P
authors.lastname: Jiramongkolchai
authors.forename: Jennifer
authors.initials: J
authors.lastname: Standley
authors.forename: J Robert
authors.initials: JR
authors.lastname: Manak
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dixon
mesh_terms: D002971:Cleft Lip / Q000175:diagnosis* / Q000235:genetics*; D002972:Cleft Palate / Q000175:diagnosis* / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D059472:Exome; D005124:Eye Abnormalities / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005385:Fingers / Q000002:abnormalities*; D005808:Genes, Recessive; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D050835:Interferon Regulatory Factors / Q000235:genetics; D007717:Knee / Q000002:abnormalities; D007719:Knee Joint / Q000002:abnormalities*; D038061:Lower Extremity Deformities, Congenital / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D013576:Syndactyly / Q000175:diagnosis* / Q000235:genetics*; D014564:Urogenital Abnormalities / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; C417187:RIPK4 protein, human; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase
keywords: exome; orofacial cleft; popliteal pterygia; recessive; uniparental disomy