Variant interpretation in action: a case study

One of the first diagnostic variants identified from the Deciphering Developmental Disorder in Africa (DDD-Africa) study was a variant linked with Takenouchi-Kosaki syndrome in this patient, which to our knowledge is the first reported case in Africa.

This patient was initially referred to a genetics clinic in South Africa, at the age of 6 months for an assessment, based on her cardiac disease and associated dysmorphic features. A diagnostic microarray test was negative. The patient’s clinical features didn’t point to a suspected disorder, and several other targeted investigations failed to yield a diagnosis. Tests that are targeted to diagnose a specific disorder are often not useful in cases like this, but in a resource-constrained setting (such as South Africa) it might be the only diagnostic option available to a patient. Agnostic tests like exome sequencing are more useful in diagnosing these kinds of rare disorders.

At 10 years of age the patient was enrolled in the DDD-Africa exome sequencing study. A de-novo missense variant in the CDC42 gene, was classified as likely pathogenic (class IV). This was on the basis that it was absent in population databases (PM2), had two pathogenic submissions in ClinVar (PP5), and there was evidence from existing functional studies (PS3) showing this variant had a deleterious effect. The location of the variant in a functional domain suggests the application of the PM1 criterion. Tools that predict the deleterious effect of missense variants indicated a strong likelihood of pathogenicity for this variant (PP3). Finally, by comparing sequencing data from both parents, the variant was confirmed as de novo (PM6).

This case study illustrates how next-generation sequencing combined with a thorough variant interpretation process can lead to the end of a patient’s long wait for an answer to the cause of the disease they are living with.

You can use the knowledge you have gained over these past weeks to review this variant and the ACMG variant interpretation codes that were applied in this case.