“…CADASIL is caused by pathogenic variants in the NOTCH3 gene (*600276) which encodes the NOTCH3 protein, the extracellular domain consists of 34 epidermal growth factor‐like repeats (EGFr), each including 6 cysteine residues. The majority of pathogenic variants in NOTCH3 (95%) lead to the loss or gain of a cysteine residue causing protein misfolding and receptor aggregation (Gallardo et al, 2020; Hack et al, 1993; Mizuno, Mizuta, Watanabe‐Hosomi, Mukai, & Koizumi, 2020; Papakonstantinou et al, 2019; Wang, 2018). There is no evidence that other missense variants cause CADASIL, but some splice‐site variants, insertions, and deletions, which also lead to numerical cysteine change within EGFr, have been reported associated with disease (Hack et al, 1993).…”