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.