FIGURES
Figure 1 | AutoCaSc workflow and
categories
a) Schematic of the proposed workflow embedding AutoCaSc into a
genetic pipeline for identification of pathogenic variants in
individuals with NDD. When trio exome sequencing does not lead to a
diagnosis, AutoCaSc is intended to prioritize variants and thus focus on
the most promising candidates. b) Composition of the CaSc with
the four categories, as well as the maximum achievable points: Variant
attributes (max. 6 points), Gene plausibility (max. 6 points),
Inheritance (max. 3 points), Gene constraint (max. 1 point). The maximum
number of points for inheritance is awarded for autosomal recessive
variants where the variant occurs in at least one other affected
sibling. Gene constraint metrics, however, are only awarded for
autosomal dominant inherited variants, which is why both categories
together score a maximum of 3 points. c) Depiction of the
AutoCaSc tools front-ends. Schematic illustration of vcfAutoCaSc, which
is intended for when whole VCFs or cohorts are to be screened (left
side). Screenshot of the results page of webAutoCaSc, which is intended
to evaluate single or small groups of variants quickly and without
installation (right side).
Figure 2 | Simulated and real trio
scoring
a) Achieved CaSc of the inserted variants, subdivided according
to the affected novel NDD gene. The color of the circles encodes the
mode of inheritance. The red dashed line represents a possible cutoff of
6. b) ROC curve relating the false positive rate and true
positive rate for the simulation experiment. optimal cutoff at CaSc 6
marked in red. c) Scoring results for the 78/93 (83.9%)
in-house trio exomes with at >0 candidate variants scored.
In the left part of the figure, the trios are plotted on the x-axis in
descending order of the highest candidate score (CaSc), the y-axis shows
the CaSc. The dots represent candidate variants. The large dots are the
variants with the highest score in a trio. The colors indicate whether a
candidate was scored only manually (n=2), only by AutoCaSc (n=230), or
by both (n=79). The right part shows a histogram of the achieved CaSc.