Identification of Two Rare Homozygote Missense Variants in the IRS1 Gene in a Patient With Early Gestational Diabetes: A Case Study

Abstract

Background: Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and has a rising prevalence worldwide. Environmental and genetic factors contribute to GDM risk. Describing familial cases of GDM can help identify the diseases genetic components.

Methods: Here, we report the case of an Emirati female patient affected with early GDM and familial history of diabetes with a significant level of insulin resistance. As a first step, we investigated the GCK and HNF1A gene sequences by direct sequencing and then performed a clinical exome sequencing (CES) of the patients genomic DNA covering 6,670 genes.

Results: Our findings showed the absence of any pathogenic variants in the GCK and HNF1A gene sequences. In addition, the CES excluded all maturity-onset diabetes of the young (MODY)-related genes. However, two rare homozygous variants in the insulin receptor substrate 1 (IRS1) gene were identified: p.Pro948Leu (gnomAD minor allele frequency (MAF) = 7.5 10^-5) and p.Arg1221Cys (gnomAD MAF = 5.6 10^-5). These variants were absent in a set of healthy Emirati individuals. Both variants are highly conserved among mammalians but have never previously been reported among the same haplotype or individual. p.Pro948Leu and p.Arg1221Cys are localized close to two important functional phosphorylation sites recognized by PI3K (hTyr941) and SHP2 (hTyr1229), respectively. Moreover, the independent and combined effect of the two variants on protein stability was predicted to be destabilizing.

Conclusion: Our investigation emphasized the role of downstream regulators of insulin signaling in GDM pathophysiology and identified IRS1 as a candidate gene to explain chronic insulin resistance. In addition, the patient showed significant health improvement after lifestyle modifications and oral antidiabetic administration, even after withdrawing insulin injections.

J Endocrinol Metab. 2022;12(6):188-197
doi: https://doi.org/10.14740/jem842