title: Fryns Syndrome Associated with Recessive Mutations in PIGN in two Separate Families.
abstract: Fryns syndrome is an autosomal recessive condition characterized by congenital diaphragmatic hernia (CDH), dysmorphic facial features, distal digital hypoplasia, and other associated malformations, and is the most common syndromic form of CDH. No gene has been associated with this condition. Whole-exome sequence data from two siblings and three unrelated individuals with Fryns syndrome were filtered for rare, good quality, coding mutations fitting a recessive inheritance model. Compound heterozygous mutations in PIGN were identified in the siblings, with appropriate parental segregation: a novel STOP mutation (c.1966C>T: p.Glu656X) and a rare (minor allele frequency <0.001) donor splice site mutation (c.1674+1G>C) causing skipping of exon 18 and utilization of a cryptic acceptor site in exon 19. A further novel homozygous STOP mutation in PIGN (c.694A>T: p.Lys232X) was detected in one unrelated case. All three variants affected highly conserved bases. The two remaining cases were negative for PIGN mutations. Mutations in PIGN have been reported in cases with multiple congenital anomalies, including one case with syndromic CDH. Fryns syndrome can be caused by recessive mutations in PIGN. Whether PIGN affects other syndromic and non-syndromic forms of CDH warrants investigation.
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.|Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Brisbane, QLD, Australia.
authors.forename: Aideen M
authors.initials: AM
authors.lastname: McInerney-Leo
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.|Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Brisbane, QLD, Australia.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Harris
authors.affiliation: Brisbane Genetics, Wesley Medical Centre, Auchenflower, QLD, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Gattas
authors.affiliation: Specialized Obstetric and Gynaecological Imaging, South Bank, QLD, Australia.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Peach
authors.affiliation: Specialized Obstetric and Gynaecological Imaging, South Bank, QLD, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Sinnott
authors.affiliation: Hunter Genetics, NSW Genetics of Learning Disability (GOLD) Service and GrowUpWell Priority Research Centre, The University of Newcastle, NSW, Australia.
authors.forename: Tracy
authors.initials: T
authors.lastname: Dudding-Byth
authors.affiliation: Department of Clinical Genetics, Liverpool Hospital, Liverpool BC, NSW, Australia.
authors.forename: Sulekha
authors.initials: S
authors.lastname: Rajagopalan
authors.affiliation: Paediatric and Reproductive Genetics Unit, Women's and Children's Hospital/SA Pathology, North Adelaide, South Australia.|School of Medicine, University of Adelaide, North Adelaide, SA, Australia.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Barnett
authors.affiliation: Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Brisbane, QLD, Australia.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Anderson
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.|Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Brisbane, QLD, Australia.
authors.forename: Lawrie
authors.initials: L
authors.lastname: Wheeler
authors.affiliation: Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Brisbane, QLD, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.|Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Brisbane, QLD, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.
authors.forename: Carol
authors.initials: C
authors.lastname: Wicking
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.|Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Brisbane, QLD, Australia.|School of Medicine, Faculty of Medicine and Biomedical Sciences, University of Queensland, Australia.|Department of Endocrinology, James Mayne Building, Royal Brisbane and Women's Hospital, Butterfield Street, Herston, QLD, Australia.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
mesh_terms: D059472:Exome; D019066:Facies; D006548:Hernia, Diaphragmatic / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010770:Phosphotransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites; D017422:Sequence Analysis, DNA
chemical_list: D022821:RNA Splice Sites; C561296:PIGN protein, human; D010770:Phosphotransferases
keywords: Fryns syndrome; PIGN; Phosphatidylinositol Glycan Anchor Biosynthesis Class N; diaphragmatic hernia; multiple congenital anomalies hypotonia seizures