Several studies have also emphasized the importance of moving from gene-wide constraint calculations to protein domain-specific constraints as a method of identifying regions of functional importance.35, 36, 37, 38 This refinement is particularly important for proteins involved in hearing loss, as most have various structurally different domains with distinct functions. Furthermore, some show an extraordinary pleiotropy and cause both autosomal-dominant NSHL (ADNSHL) and autosomal-recessive NSHL (ARNSHL) (TECTA [MIM: 602574] and TMC1 [MIM: 606706]) or both syndromic hearing loss and NSHL (Usher type 1-associated genes, WFS1, TBC1D24 [MIM: 613577], and COL11A1 [MIM: 120290]).39, 40, 41, 42, 43, 44 Classifying variants by domain or regional constraint can minimize both false-positive and false-negative pathogenicity predictions and facilitate proper diagnosis, especially for genes associated with NSHL mimics.