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

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 <i>FBN1</i> and <i>TRPS1</i> were identified as causing two distinct autosomal dominant conditions, each with de novo inheritance. Fibrillin 1 (<i>FBN1)</i> mutations are associated with Marfan syndrome and a spectrum of similar phenotypes. <i>TRPS1</i> 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.