Neurology
To summarize DES (diagnostic exome sequencing) findings in individuals with intellectual disability and/or developmental delay (ID/DD).
As part of a comprehensive evaluation for individuals with ID, the AAN, ACMG, and AAP recommend genetic testing. Due to genetic heterogeneity in ID, first-tier genetic tests are often uninformative. Since 2011, DES has become an effective diagnostic tool in cases with unknown etiologies.
Retrospective analysis was performed on the first unselected 1200 samples submitted for DES at our laboratory. Analysis scheme and results categories were previously described (Farwell, 2014).
67% of patients (806/1200) had syndromic ID/DD. Diagnostic yield in individuals with ID/DD was 30% in characterized genes (243/806) and 7% in novel genes (52/806), compared to 23% (91/394) and 4% (14/394), respectively, in individuals without ID/DD (chi square p-value = 6e-4). Uncertain findings in characterized genes and negative results were reported in 79 (10%) and 432 (54%) individuals with ID/DD, respectively, compared to 36 (9%) and 253 (64.2%) individuals without ID/DD. Among individuals with ID/DD, positive/likely positive findings were identified in 24.5% (13/53), 28.5% (40/141), and 31% (189/601) of individuals with strong (≥1 relative with similar phenotype), mild (≥1 relative with ID/DD), and no family history, respectively. Novel genetic etiology detection in individuals with ID/DD and strong family histories (7/53, 13%) was more than double that in those with mild family history (3%) (p-value =1.0e-2) and absent/unknown family history (7%) (p-value=9e-2)]. The de novo rate among individuals with positive findings and strong family histories was 2%, as the majority (52/53) were inherited in an autosomal recessive or X-linked fashion.
These data highlight the utility of DES in providing a molecular diagnosis given the heterogeneity of ID/DD and demonstrate that strong family history of ID/DD is a positive predictor of informative DES results and increased novel genetic etiology detection.