title: Exome sequencing identifies de novo pathogenic variants inFBN1andTRPS1in a patient with a complex connective tissue phenotype.
abstract: Here we describe a patient who presented with a history of congenital diaphragmatic hernia, inguinal hernia, and recurrent umbilical hernia. She also has joint laxity, hypotonia, and dysmorphic features. A unifying diagnosis was not identified based on her clinical phenotype. As part of her evaluation through the Undiagnosed Diseases Network, trio whole-exome sequencing was performed. Pathogenic variants inFBN1andTRPS1were identified as causing two distinct autosomal dominant conditions, each with de novo inheritance. Fibrillin 1 (FBN1)mutations are associated with Marfan syndrome and a spectrum of similar phenotypes.TRPS1mutations are associated with trichorhinophalangeal syndrome types I and III. Features of both conditions are evident in the patient reported here. Discrepant features of the conditions (e.g., stature) and the young age of the patient may have made a clinical diagnosis more difficult in the absence of exome-wide genetic testing.
authors.affiliation: Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California 94305, USA.|Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Diane B
authors.initials: DB
authors.lastname: Zastrow
authors.affiliation: Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California 94305, USA.|Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Zornio
authors.affiliation: Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California 94305, USA.|Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Annika
authors.initials: A
authors.lastname: Dries
authors.affiliation: Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California 94305, USA.|Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Jennefer
authors.initials: J
authors.lastname: Kohler
authors.affiliation: Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California 94305, USA.|Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Liliana
authors.initials: L
authors.lastname: Fernandez
authors.affiliation: Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California 94305, USA.|Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Daryl
authors.initials: D
authors.lastname: Waggott
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, Texas 77021-2024, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Walkiewicz
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, Texas 77021-2024, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.affiliation: Department of Pathology, Stanford School of Medicine, Stanford, California 94305, USA.|Department of Pediatrics, Stanford School of Medicine, Stanford, California 94305, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Manning
authors.affiliation: Lucille Packard Children's Hospital Stanford, Palo Alto, California 94304, USA.
authors.forename: Ellyn
authors.initials: E
authors.lastname: Farrelly
authors.affiliation: Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California 94305, USA.|Department of Pediatrics, Stanford School of Medicine, Stanford, California 94305, USA.|Department of Neurology, Stanford School of Medicine, Stanford, California 94304, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Fisher
authors.affiliation: Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California 94305, USA.|Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.|Department of Genetics, Stanford School of Medicine, Stanford, California 94305, USA.
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
authors.affiliation: Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California 94305, USA.|Department of Pediatrics, Stanford School of Medicine, Stanford, California 94305, USA.|Lucille Packard Children's Hospital Stanford, Palo Alto, California 94304, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.affiliation: Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California 94305, USA.|Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Matthew T
authors.identifier: http://orcid.org/0000-0001-8721-3022
authors.initials: MT
authors.lastname: Wheeler
keywords: central hypotonia; congenital diaphragmatic hernia; fourth toe clinodactyly; hammertoe; inguinal hernia; joint laxity; long philtrum; malar flattening; pes planus; protruding ear; smooth philtrum; sparse anterior scalp hair; sparse lateral eyebrow; superior pectus carinatum; thin nail; thin upper lip vermilion; thoracic scoliosis; umbilical hernia