Here we report on two sisters with microcephaly, intellectual disability, and normal brain imaging who carried the homozygous nonsense variant c.376C > T; p.(Gln126*) in the alternatively spliced exon 4 of VLDLR. Data from our VLDLR transcript analysis in patient fibroblasts together with literature data suggest that brain expression of VLDLR transcripts without exon 4 encoding VLDLR isoforms III and IV may have protected both siblings from developing the more severe phenotype. This evidence concerns the gene VLDLR and microcephaly.