Abstract
Purpose: INSR encodes the insulin receptor, the essential entrainer of growth and metabolism
to nutritional cues. INSR variants cause a spectrum of monogenic insulin resistance (IR)
syndromes, namely type A insulin resistance, Rabson-Mendenhall (RMS), and Donohue (DS)
syndromes. However, no large cohort studies focused on variant classification and its diagnostic value have been described.
Methods: This multicentric cohort study included 73 patients carrying INSR variants, referred
for IR by 52 centers from six countries. Variants were classified using new bioinformatic tools
relying on different prediction mechanisms, and the American College of Medical Genetics and
Genomics (ACMG) guidelines.
Results: Besides expanding the INSR mutational spectrum, this study suggested a semi-dominant inheritance in several DS/RMS families. Questioning strictly Mendelian inheritance,
heterozygous loss-of-function (LoF) variants were mostly found in overweight patients, with a
higher LoF frequency in IR patients than in the general population (OR: 5.77). Diagnostic
challenges arose when trying to refine classification criteria for variants of uncertain
significance. Among the variant effect predictors assessed, MISTIC and AlphaMissense
outperformed REVEL.
Conclusion: The spectrum of INSR-related disorders extends beyond traditional entities.
Heterozygous INSR LoF variants may increase IR susceptibility. International collaboration
and functional assays are needed to drive precision medicine forward.
to nutritional cues. INSR variants cause a spectrum of monogenic insulin resistance (IR)
syndromes, namely type A insulin resistance, Rabson-Mendenhall (RMS), and Donohue (DS)
syndromes. However, no large cohort studies focused on variant classification and its diagnostic value have been described.
Methods: This multicentric cohort study included 73 patients carrying INSR variants, referred
for IR by 52 centers from six countries. Variants were classified using new bioinformatic tools
relying on different prediction mechanisms, and the American College of Medical Genetics and
Genomics (ACMG) guidelines.
Results: Besides expanding the INSR mutational spectrum, this study suggested a semi-dominant inheritance in several DS/RMS families. Questioning strictly Mendelian inheritance,
heterozygous loss-of-function (LoF) variants were mostly found in overweight patients, with a
higher LoF frequency in IR patients than in the general population (OR: 5.77). Diagnostic
challenges arose when trying to refine classification criteria for variants of uncertain
significance. Among the variant effect predictors assessed, MISTIC and AlphaMissense
outperformed REVEL.
Conclusion: The spectrum of INSR-related disorders extends beyond traditional entities.
Heterozygous INSR LoF variants may increase IR susceptibility. International collaboration
and functional assays are needed to drive precision medicine forward.
| Original language | English |
|---|---|
| Pages (from-to) | 101404 |
| Journal | Genetics in Medicine |
| DOIs | |
| Publication status | Published - 13 Mar 2025 |