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.