Exome sequencing identifies de novo pathogenic variants in FBN1 and TRPS1 in a patient with a complex connective tissue phenotype

Cold Spring Harb Mol Case Stud. 2017 Jan;3(1):a001388. doi: 10.1101/mcs.a001388.


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 in FBN1 and TRPS1 were 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. TRPS1 mutations 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.

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.