Patients Cohort and Diagnostic yield
A total of 85 out of 162 patients received a definitive genetic diagnosis, including 9 of 85 cases with a previously negative array-CGH, (Table 1), demonstrating an overall diagnostic yield of 52.5%. Specifically, 40 patients (24.6%) received a definitive diagnosis based on the identification of highly scored known variants in phenotype-relevant genes. In 62 cases where family segregation studies were performed, WES findings were confirmed and mode of inheritance supported a definitive diagnosis in 45 more patients. Two cases (1.2%) with VUS remained unresolved as parents refused DNA analysis. In the remaining 58 (35.9%) cases no candidate causative variant was identified. From amongst the 77 unresolved cases, 75 were advised to proceed to clinical and bioinformatics re-evaluation after 1-2 years (Bruel et al., 2019; Ewans et al., 2018; Jalkh et al., 2019).
The majority of patients resolved (58/85 68%) concerned an autosomal dominant disease, followed by 20 (24%) patients with an autosomal recessive disease and 7 (8%) with X-linked diseases. The highest diagnostic yield (83%) was achieved among the sub-cohort of patients referred with dermatological abnormalities (epidermolysis bullosa, ichthyosis etc.) and neuromuscular diseases (muscular dystrophies, myopathies etc.). Furthermore, >60% of cases with multiple congenital anomalies/syndromic (Noonan syndrome, Kabuki syndrome, Sotos syndrome etc.) and skeletal/connective tissue abnormalities (Marfan syndrome, Ehlers-Danlos syndrome, skeletal dysplasia etc), were resolved. The lowest diagnostic yield (22%) was observed in cases with cardio and/or vascular abnormalities (Fig. 3). In 77 (47.53%) of cases no relevant variant could be identified, even following variant filtering and analysis with all combinations described (Figure 2). In four patients with complex clinical presentations, additional variants in likely phenotype-relevant genes were identified alongside the primary disease-associated genotype, as summarized in Table 2 and described in Discussion.