Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal

Figure 1

Overview of TSC1 and TSC2 variants identified using HaloPlex custom capture. The coding (open boxes) and noncoding exons (shaded grey) of both genes are shown, and the approximate positions of the identified variants indicated with arrows, except for the 2 large TSC2 deletions which are shown as black bars. Germline variants (see Table 1) are shown above the corresponding gene; post-zygotic variants (see Table 2) are below. Variants of uncertain clinical significance and unconfirmed variants (see Table 3) are shown in italics. (a) Variants identified at the TSC1 locus. (b) Variants identified at the TSC2 locus. (c) Comparison of the variant allele frequencies (VAF) of the variants shown in (a) and (b) per TSC NMI subject. Subjects (-axis) were ranked according to the percentage VAF (%VAF) and plotted according to a normal (left) and logarithmic scale (right). Dotted lines indicate the expected VAF for variants arising during the initial embryonic cell divisions. NMI: no mutation identified.

(a) TSC1 locus

(b) TSC2 locus

(c) VAF per TSC NMI subject