ClinVar

In 5 patients from 4 families with SHORT syndrome (269880), including a patient previously reported by Bonnel et al. (2000), Thauvin-Robinet et al. (2013) identified heterozygosity for a c.1945C-T transition at chr5:67,592,129 (GRCh37) in the PIK3R1 gene, resulting in an arg649-to-trp (R649W) substitution at a highly conserved residue in the cSH2 domain. In the 1 family for which parental DNA was available, the mutation was shown to be de novo. Thauvin-Robinet et al. (2013) noted that the c.1945C-T mutation occurred within the context of a CpG dinucleotide, which might explain its recurrence.

In affected members of a 3-generation Norwegian family with SHORT syndrome, originally described by Aarskog et al. (1983), and a German mother and son with SHORT syndrome, originally reported by Koenig et al. (2003), Chudasama et al. (2013) identified heterozygosity for the R649W missense mutation in the PIK3R1 gene. The mutation was not found in 340 Norwegian controls. Haplotype analysis showed that the mutations resided on different backgrounds in the 2 families, indicating that they stemmed from 2 independent mutational events. Analysis of patient fibroblasts and reconstituted Pik3r1-knockout preadipocytes demonstrated impaired interaction between p85-alpha and IRS1 (147545) and reduced AKT (see 164730)-mediated insulin signaling.

In a mother and 2 sons from an English family with SHORT syndrome, originally reported by Bankier et al. (1995) and restudied by Reardon and Temple (2008), and in an unrelated male patient, Dyment et al. (2013) identified heterozygosity for the R649W mutation in the PIK3R1 gene.