Non-Isolated Dandy-Walker Malformation: Exome Sequencing Efficacy and Phenotypic Expansions.

Genetic heterogeneity; clinical exome superior to targeted panels

Clinical exome sequencing applied to 91 DWM+ patients achieved a 35.2% diagnostic rate. Commercially available brain malformation panels would have detected only 24–55% of exome-established diagnoses. Nine phenotypic expansions involving DWM were identified for genes including ANKRD11, COL4A1, KMT2D, KRAS, OPHN1, and SHOC2. These findings support that clinical exome should be offered to all DWM+ patients without an established molecular diagnosis.

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With a 35% yield, exome markedly outperforms targeted panels in this context. The 9 phenotypic expansions represent potential pitfalls for panels. The recommendation against additional genetic workup in ANKRD11, COL4A1, or KMT2D syndrome patients is practically very useful.

Clinical impact: 2/3 · Evidence quality: 2/3 · Novelty: 1/2 · Sample size: 1/1 · Journal quality: 0/1 → Total: 6/10