Worth the Effort: Lessons for Discovery and Care From an Unusual Case of Gorlin Syndrome

Gorlin-Goltz Syndrome (GGS) is a rare autosomal dominant genetic disorder encompassing a diverse range of clinical manifestations, including congenital anomalies and predisposition to cancer. Pathogenic variants in PTCH1 and SUFU account for up to 79% and 6% of cases, respectively. Currently, an estimated 15%-27% of individuals with a clinical diagnosis of GGS do not have a pathogenic variant identified in either gene. We report on a 17-year-old female referred to the Undiagnosed Disease Network with a clinical diagnosis of GGS that manifested as both classic and unusual findings, including isolated hypogonadotropic hypogonadism and anosmia (Kallmann syndrome), orofacial cleft, and abnormal semicircular canals (SCC). Prior genetic testing, including a targeted gene panel, genomic microarray, exome sequencing, and genome sequencing, was non-diagnostic, although these studies identified a variant of uncertain significance in CHD7, which may have contributed to elements of the phenotype (e.g., abnormal SCC). Reanalysis of genome sequencing data using research analytic methods, together with karyotyping, FISH, and Sanger sequencing, identified a novel de novo paracentric inversion that truncated PTCH1. These findings underscore the value of in-depth phenotype-guided genomic analysis, including chromosomal structural variants, as well as the occurrence of possible dual genetic diagnoses in the same individuals. Moreover, the definitive diagnosis provided the patient and family with a firmer basis for management and counseling.