In humans, significant DNA methylation in the CLDN5 locus, located at chromosomal region 22q11, were observed in patients with early stages of Alzheimer disease-associated cognitive decline [25] and patients with heterozygous pathogenic CLDN5 missense mutants have been reported to present with epilepsy with microcephaly [9, 24]. This evidence concerns the gene CLDN5 and microcephaly.