Confirming variant-phenotype association and diagnosis
DECIPHER provides an assessment interface (Fig. 5D) which is designed to be used in a multidisciplinary team meeting to evaluate whether one or more variants explain the clinical features seen in a patient, and record if a diagnosis has been made (or excluded). Depositors can report evidence from several evidence lines, such as the age at presentation or additional clinical investigation, to weigh evidence for or against a genotype-phenotype relationship. An OMIM gene-disease pair and assertion is recorded, for example ‘genetic diagnosis confirmed’, ‘uncertain genetic diagnosis’, or ‘non-penetrant (or pre-symptomatic) for a dominant genetic disorder’. The output of the assessment is a date-stamped report providing the patient’s variants and phenotypes, in addition to the diagnosis and evidence on which that diagnosis was made.
There are many published examples of patients having compound phenotypes due to pathogenic variants in more than one gene, for example, in Ferreret al ., 2019, the patient had three independent rare disease diagnoses due to pathogenic variants in SIN3A (Witteveen–Kolk syndrome), FLG (dermatitis), and EDAR (ectodermal dysplasia). A recent study has suggested that multiple molecular diagnoses occur in approximately 5% of cases (Posey et al ., 2017). The assessment interface allows multiple assessments to be created for a patient, allowing the genetic basis of compound phenotypes to be recorded and shared.