A novel heterozygous variant in exon 4 of the NOTCH3 gene (p.Cys206Trp; NM_000435.3:c.618C>G) was found in a 67‐year‐old woman who suffered from recurrent ischemic strokes, cognitive impairment, depression, and headache, as well as her son, who presented with headache, anxiety disorder, and insomnia. This evidence concerns the gene NOTCH3 and major depressive disorder.