INSR

Inheritance Pattern: AR

Disease ID:MONDO:0012520

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0012520

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009517

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0012520

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0012381

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009874

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009874

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0012381

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009517

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012381

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0009874

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0012520

Submitter: ClinGen

*Monoallelic* pathogenic variants in *INSR*, which encodes the insulin receptor protein, were first reported in association with type A insulin resistance syndrome described by C. Ronald Kahn et al. in 1976. In the current curation, we have curated the inheritance pattern for autosomal dominant monoallelic cases causing type A insulin resistance. Autosomal recessive *INSR*-related severe insulin resistance syndromes, known historically as Donohue syndrome and Rabson–Mendenhall syndrome, are curated separately. INSR protein is a heterotetrameric glycoprotein composed of two extracellular α-subunits and two transmembrane β-subunits (α₂β₂), linked by disulfide bonds. The α-subunits are responsible for binding insulin, while the β-subunits span the membrane and contain an intracellular tyrosine kinase domain. When insulin binds to the receptor, it induces a conformational change that activates the kinase domain, leading to autophosphorylation of tyrosine residues and initiation of downstream signaling pathways such as the PI3K–AKT pathway and MAPK pathway. These signaling cascades mediate key biological effects of insulin, including glucose uptake, glycogen synthesis, lipid metabolism, protein synthesis, and cell growth (PMIDs: 1327927, 3009519; Taylor et al., 1992 review). Individuals with autosomal dominant (monoallelic) *INSR* variants typically present with type A insulin resistance syndrome, representing the mildest end of the clinical spectrum. Affected individuals usually develop insulin resistance in adolescence or early adulthood, characterized by marked hyperinsulinemia, acanthosis nigricans, and, in females, hyperandrogenism with features such as oligomenorrhea or polycystic ovarian syndrome (PMIDs:15232309,29877041,33995269). In contrast to the severe recessive forms, these individuals generally lack significant growth abnormalities, dysmorphic features, or early-life metabolic decompensation. Most monoallelic variants are heterozygous missense changes affecting the tyrosine kinase domain of the receptor, leading to impaired insulin signaling through a dominant mechanism while preserving partial receptor function (PMIDs: 1327927, 20339196). This residual activity accounts for the milder clinical presentation and later onset compared to biallelic *INSR*-related disorders. Rare cases show that homozygous or compound heterozygous *INSR* variants can also cause a milder phenotype similar to type A insulin resistance, likely due to partial preservation of receptor function (PMID: 32018348,12970295,10733238), highlighting that *INSR*-related disorders exist on a clinical spectrum with variable genotype–phenotype correlation. Several kindreds with dominantly inherited insulin resistance segregating with simple loss of function of one allele have been reported (PMIDs: 9356044, 2687060, 8530617, 20339196, 9356044, 8175972), but the expressivity/penetrance of insulin resistance related to simple heterozygous deficiency is yet to be fully defined. Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we identified differences in inheritance patterns and phenotypic variability among variants associated with biallelic and monoallelic *INSR*-related insulin resistance syndromes. Therefore, the curation of *INSR* has been split into (1) autosomal recessive Donohue and/or Rabson–Mendenhall syndrome and (2) autosomal dominant type A insulin resistance syndrome. Evidence supporting the relationship of this gene with autosomal dominant type A insulin resistance includes case-level data and experimental data. Variants in this gene have been curated in at least 22 probands in 18 publications (PMIDs; 41360184, 35634501, 38289143,1890161, 2168397, 35661079,8390949, 8096518, 8243830, 33728347, 9356044, 39619220, 7989492, 29877041, 28181734,8082780,10733238,16127220) with clinical and phenotypic features consistent with type A insulin resistance syndrome. More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached, this has not been curated exhaustively. This gene–disease relationship is supported by in vitro functional assays, protein interactions, expression studies, and mouse models (PMIDs:28181734, 23715323, 7935368, 15713666, 9038347)., and mouse models. Total points for the experimental evidence are 6. Total points for genetic and experimental evidence together are 18. In summary, *INSR* is definitively associated with autosomal dominant type A insulin resistance syndrome, with most cases presenting in adolescence or early adulthood. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the Monogenic Diabetes GCEP on May 13, 2026. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP12.

Inheritance Pattern: AR

Disease ID:MONDO:0009874

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009517

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009517

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012520

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012520

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0012381

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009517

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009517

Submitter: ClinGen

Bi-allelic pathogenic variants in *INSR*, which encodes the insulin receptor protein, were first reported in association with severe and moderate insulin resistance syndromes, including Donohue syndrome (OMIM:246200) described in 1948 by Donohue, and Rabson–Mendenhall syndrome (OMIM:262190) described in 1956 by Rabson and Mendenhall. We have curated the inheritance pattern for *INSR*-related severe insulin resistance syndrome as autosomal recessive; however, autosomal dominant monoallelic cases causing type A insulin resistance have also been reported and will be curated separately. INSR protein is a heterotetrameric glycoprotein composed of two extracellular α-subunits and two transmembrane β-subunits (α₂β₂), linked by disulfide bonds. The α-subunits are responsible for binding insulin, while the β-subunits span the membrane and contain an intracellular tyrosine kinase domain. When insulin binds to the receptor, it induces a conformational change that activates the kinase domain, leading to autophosphorylation of tyrosine residues and initiation of downstream signaling pathways such as the PI3K–AKT pathway and MAPK pathway. These signaling cascades mediate key biological effects of insulin, including glucose uptake, glycogen synthesis, lipid metabolism, protein synthesis, and cell growth (Taylor et al, 1986, 1992: PMIDs: 1327927, 3009519). Individuals with autosomal recessive (biallelic) *INSR* variants present with a spectrum of severe insulin resistance syndromes that reflect the underlying functional severity of the receptor defect. When two pathogenic alleles are present, the phenotype may range from Donohue syndrome (formerly sometimes known as “leprechaunism”), the most severe form characterized by profound insulin resistance, extreme growth failure, dysmorphic features, and early infant mortality, to a form of type A insulin resistance that tends to be more severe than the monoallelic form. An intermediate form of bi-allelic disease in which affected individuals survive beyond infancy but exhibit marked insulin resistance along with short stature, dental abnormalities, characteristic facial features, and other developmental abnormalities, is historically known as Rabson-Mendenhall syndrome. These disorders arise from diverse molecular mechanisms affecting receptor function, including impaired biosynthesis, defective intracellular processing or trafficking, reduced insulin binding, diminished tyrosine kinase signaling, or increased receptor degradation, all of which ultimately compromise insulin receptor activity and lead to severe metabolic dysregulation (PMID’s:3009519,1327927,1730618). Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we identified differences in inheritance patterns and phenotypic variability among variants associated with biallelic and monoallelic *INSR*-related insulin resistance syndromes. Therefore, the curation of INSR has been split into (1) the spectrum of autosomal recessive disease that includes Donohue and Rabson–Mendenhall syndromes as well as severe type A insulin resistance and (2) autosomal dominant type A insulin resistance syndrome due to functionally significant variants in the kinase domain. Evidence supporting the relationship of this gene with autosomal recessive severe insulin resistance includes case-level data and experimental data. The *INSR* gene including nonsense, splice site, deletions and missense variants have been reported in association with autosomal recessive insulin resistance syndrome in humans. Variants in this gene have been curated in at least 8 probands in 7 publications (PMIDs; 26974131, 22399506, 81101305, 8270132,17201797,2834824,26160152), with clinical and phenotypic features consistent with Donohue and Mendenhall syndrome. More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached this has not been curated exhaustively. This gene–disease relationship is supported by functional assays, expression studies, and animal models. The Insr⁻/⁻ mouse model exhibits severe growth retardation, and profound metabolic dysregulation due to complete loss of insulin receptor function (PMID: 8528241). In mice, neonatal death is caused by ketoacidosis. Human patients with biallelic loss-of-function INSR variants, such as those with Donohue syndrome, present with severe intrauterine and postnatal growth failure, extreme insulin resistance, hyperinsulinemia, hyperglycemia, and early mortality, often within the first year of life, due to a variety of causes, usually infection. Together, these findings demonstrate that complete loss of insulin receptor signaling leads to a severe and lethal phenotype in both mice and humans, providing further functional evidence supporting the pathogenicity of null *INSR* variants. Total points for the experimental evidence are 5.5. Total points for genetic and experimental evidence together are 17.5. In summary, *INSR* is definitively associated with autosomal recessive severe insulin resistance syndrome, with most cases presenting prenatally or in early infancy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the MDGCEP on April 8, 2026. Gene-Disease Clinical Validity Standard Operating Procedure (SOP) – SOP12.

Inheritance Pattern: AD

Disease ID:MONDO:0012381

Submitter: Orphanet