SHORT syndrome with microcephaly and developmental delay

Abstract

We report a boy with typical clinical features of SHORT syndrome alongside a significant microcephaly and severe developmental delay associated with a de novo single nucleotide missense DNA variant resulting in a single amino acid change in codon 486 of the PIK3R1 gene (PIK3R1 c.1456G>A (p.Ala486Thr)). Our report strikingly coincides with another recently published case from Brazil, describing a 23-year-old woman with the same de novo PIK3R1 DNA variant, who also exhibits SHORT syndrome with severe secondary microcephaly and intellectual disability. On review of the literature, we have identified further cases of PIK3R1-related SHORT Syndrome with a similar phenotype. We note all these cases (including ours) have variants located in the -inter SH2 domain (iSH2); we speculate that pathogenic iSH2 located PIK3R1 variants are associated with a different and otherwise unreported clinical picture of SHORT syndrome that presents with microcephaly and/or significant developmental delay/intellectual disability. The pathogenic mechanism of why these variants apparently lead to a different clinical picture of SHORT syndrome remains unknown.

Keywords: PIK3R1; SHORT syndrome; developmental delay; intellectual disability; microcephaly.