Insulin receptor variants: Extending the traditional Mendelian spectrum

IF 6.6 1区医学 Q1 GENETICS & HEREDITY

Genetics in Medicine Pub Date : 2025-03-13 DOI:10.1016/j.gim.2025.101404

Delphine Collin-Chavagnac , Cécile Saint-Martin , Lotfi Bedidi , Louis Lebreton , Vahid Aslanzadeh , Corinne Vigouroux , Christine Bellanné-Chantelot , Robert K. Semple , Olivier Lascols , Isabelle Jéru

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引用次数: 0

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, and Donohue syndromes. However, to our knowledge, 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 6 countries. Variants were classified using new bioinformatic tools relying on different prediction mechanisms and the American College of Medical Genetics and Genomics guidelines.

Results

Besides expanding the INSR mutational spectrum, this study suggested a semidominant inheritance in several Donohue/Rabson-Mendenhall syndrome 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 (odds ratio 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.

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胰岛素受体变异：扩展传统孟德尔谱。

目的：INSR编码胰岛素受体，胰岛素受体是营养信号生长和代谢的重要载体。INSR变异引起一系列单基因胰岛素抵抗（IR）综合征，即a型胰岛素抵抗、Rabson-Mendenhall （RMS）和Donohue （DS）综合征。然而，尚未有大型队列研究关注变异分类及其诊断价值。方法：这项多中心队列研究包括来自6个国家的52个中心的73例携带INSR变异的患者。根据不同的预测机制和美国医学遗传学与基因组学学院（ACMG）指南，使用新的生物信息学工具对变异进行分类。结果：除了扩大了INSR突变谱外，本研究还提示在多个DS/RMS家族中存在半显性遗传。严格质疑孟德尔遗传，杂合功能丧失（LoF）变异主要发生在超重患者中，IR患者的LoF频率高于普通人群（OR: 5.77）。当试图为不确定意义的变异改进分类标准时，诊断挑战就出现了。在评估的变量效应预测因子中，MISTIC和AlphaMissense优于REVEL。结论：insr相关障碍的范围超出了传统的实体。杂合的INSR LoF变异可能增加IR敏感性。需要国际合作和功能分析来推动精准医疗向前发展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Genetics in Medicine 医学-遗传学

CiteScore

15.20

自引率

6.80%

发文量

857

审稿时长

1.3 weeks

期刊介绍： Genetics in Medicine (GIM) is the official journal of the American College of Medical Genetics and Genomics. The journal''s mission is to enhance the knowledge, understanding, and practice of medical genetics and genomics through publications in clinical and laboratory genetics and genomics, including ethical, legal, and social issues as well as public health. GIM encourages research that combats racism, includes diverse populations and is written by authors from diverse and underrepresented backgrounds.