Fig. 8. Validation of selected predicted disorder-associated genes: CDK16 and TRPC5.

Schematic representation of the coding exons, protein domains, and variants of CDK16 (a) and TRPC5 (b). Variant types: loss-of-function (LoF, red), missense (blue). Protein functional domains are shown: protein kinase domain (light red), transmembrane segments (purple), ANK repeats (light blue). Details of variants displayed in this figure appear in Supplementary Data 11. The schemes were generated with ggplot2. c Pedigrees of the three families with CDK16 variants. The pedigree of family with c.976_977del, p.(Trp326Valfs*5) was adapted from Hu et al.¹⁸. The two remaining families are unpublished. d Pedigrees of the three families with TRPC5 variants. The family with an intragenic exon deletion was reported in Mignon-Ravix et al.⁵². The two other families are novel. e–g, Functional characterization of TRPC5 p.R175C by whole-cell patch-clamp recordings showing that the mutation renders the mutant channel constitutively opened. e Time course of inward and outward current amplitudes measured at +80 mV and −80 mV in HEK293 cells transiently expressing WT (black) and mutant TRPC5 (blue) in presence of 100 nM free Ca²⁺ in the pipette. Values are reported as mean ± SEM (WT: n = 18 (0 s), n = 19 (5–70 s), n = 17 (75–100 s), n = 15 (105 s), n = 14 (110 s), n = 13 (115–135 s), n = 12 (140 s), n = 11 (145–150 s); mutant TRPC5: n = 22 (0–45 s), n = 21 (50–70 s), n = 18 (75–85 s), n = 17 (90–125 s), n = 16 (130–145 s), n = 15 (150 s)). Recordings started few seconds after the rupture. f Representative whole-cell current-voltage (I-V) relationships of WT and mutant TRPC5 channels current obtained shortly after break-in (≤10 s) with 100 nM free Ca²⁺ in the pipette. g Boxplot of WT and mutant whole-cell current at −80 mV and +80 mV after break-in. Box plot elements are defined as follows: center line: median; box limits: upper and lower quartiles; whiskers: 1.5× interquartile range. The number of independent recordings appears in brackets. Statistical analyses were performed using Kruskal-Wallis one-way ANOVA on ranks Source data are provided as a Source Data file.