Next-generation phenotyping contributing to the identification of a non-coding deletion in KANSL1 causing Koolen-de Vries syndrome

Next-generation phenotyping (NGP) is the application of advanced methods of computer vision on medical imaging data such as portrait photos of individuals with rare disorders. NGP on portraits results in gestalt scores that can be used for the selection of appropriate genetic tests, and for the interpretation of the molecular data. Here, we report on an exceptional case of a young girl that was presented at the age of eight and fifteen and enrolled in NGP diagnostics at the latter occasion. The girl had clinical features associated with Koolen-de Vries syndrome and a suggestive facial gestalt. However, chromosomal micro array (CMA), Sanger sequencing, multiplex ligation-dependent probe analysis (MLPA), and trio exome sequencing remained inconclusive. Based on the highly indicative gestalt score for Koolen-de Vries, the decision was made to perform genome sequencing to also evaluate non-coding variants. This analysis revealed a 4.7 kb deletion at the end of intron 6 of the KANSL1 gene, which is the smallest reported structural variant to date for this phenotype. The case illustrates how NGP can be integrated into the iterative diagnostic process of test selection and interpretation of sequencing results.