3.2 Diagnostic yield of the undiagnosed GDD/ID cohort
In this cohort, pathogenic variants were identified in 23 families with
GS. Highly suspicious variants (i.e., variants reported in the
literature but lack a well-established disease-causing relationship)
were found in four families (Table 2 ). The identified
pathogenic variations included small variants, CNVs and one LOH causing
Angelman syndrome. No mitochondrial variants or abnormal expanded
repeats were found in the study. The diagnostic yield of GS in CMA only
cases was high (64.3%, 9/14), while in ES only families and CMA + ES
families (12.9%, 8/62 and 25.0%, 6/24, respectively) the diagnostic
yield of GS was significantly lower (p=0.000194, chi-square (degrees of
freedom=2) = 17.0975).
We examined the pathogenic variants found by GS and compared them to the
data from previous CMA/ES tests. Nine different scenarios were
identified as plausible explanations for missed CMA/ES diagnoses
(Figure 2b ): 1.
Patients
received CMA only and the causative variants were too small to be
detected (n=9); 2. The disease-causing genes were reported after study
enrollment (n=5); 3. ES failed to detect pathogenic CNVs (n=4); 4. LOH
was not called in ES reanalysis (n=1); 5. Improper annotation (n=1); 6.
Patient did not manifest the clinical features when the previous tests
were performed (n=1); 7. Mutant allele dropped out in ES (n=1,Figure 3a ); 8. The complex variant was not captured well by ES
(n=1, Figure 3b ); and 9. A 3’ untranslated region (3’UTR)
deletion was not captured by ES (n=1).
Of the 23 positive cases, seven could have been solved by reanalyzing
data from prior tests (30.4%): three had previous ES testing, and four
were previously tested with both ES and CMA. Updates to analysis
pipelines, annotation databases, and clinical follow-up were reasons for
reanalysis success (Figure 2b ). Reanalyzed data from CMA only
cases provided no additional diagnoses.