Severe early-onset obesity
Gene: MRAP2EnsemblGeneIds (GRCh38): ENSG00000135324
EnsemblGeneIds (GRCh37): ENSG00000135324
OMIM: 615410, Gene2Phenotype
MRAP2 is in 1 panel
4 reviews
Achchuthan Shanmugasundram (Genomics England Curator)
OMIM reports this gene as a susceptibility gene for obesity (MIM #615457). All available evidence suggests that variants in this gene confer increased risk to severe obesity in children and adults. However, all these are large cohort studies and detailed phenotypic information on individual cases is not available on them.
As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years.
As we cannot find the age of onset and severity from these publications and the available evidence points more to susceptibility than monogenic cause of disease, this gene cannot be rated green on this panel with the current evidence.Created: 17 Jun 2025, 5:33 a.m. | Last Modified: 17 Jun 2025, 5:33 a.m.
Panel Version: 5.10
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
{?Obesity, susceptibility to, BMIQ18}, OMIM:615457
Publications
Dmitrijs Rots (Children's Clinical University Hospital)
In the paper PMID: 31700171 authors describe: "Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, with hyperglycemia and hypertension.". In addition to evidence previously mentioned by Ellen McDonagh (including mouse model) - can be classified as green now?Created: 12 Jan 2025, 10:47 a.m. | Last Modified: 12 Jan 2025, 10:47 a.m.
Panel Version: 4.12
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
obesity
Publications
- PMID: 31700171
Ismaa Farooqi (University of Cambridge)
Ellen McDonagh (Genomics England Curator)
Comment on list classification: Gene added by expert reviewer. Not associated with a phenotype/disease in Gene2Phenotype, Orphanet or HPO. In OMIM it is associated with susceptibility to obesity, marked with a question mark due to a report in one individual (PMID: 23869016), and in a literature study further support for this susceptibility was found in PMID: 27474872. MRAP2 knockout mice of both genders gradually became extremely obese on a diet of regular chow ad libitum (PMID: 23869016). PMID:23869016 and PMID:27474872 report variants in this gene in individuals with early-onset obesity, and a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients (PMID: 26795956). Evidence that disease-causing mutations follow a Mendelian parrern of causatiion appropriate for reporting in a diagnostic setting is still lacking, therefore this gene should be kept red (see notes regarding each publication...either segregation was not shown or family members were not available).Created: 17 Oct 2016, 10:27 a.m.
Details
- Mode of Inheritance
- MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
- Sources
-
- Expert list
- Expert Review Red
- Phenotypes
-
- {?Obesity, susceptibility to, BMIQ18}, OMIM:615457
- OMIM
- 615410
- Clinvar variants
- Variants in MRAP2
- Penetrance
- Complete
- Publications
- Panels with this gene
History Filter Activity
Set Phenotypes
Achchuthan Shanmugasundram (Genomics England Curator)Phenotypes for gene: MRAP2 were changed from obesity; {?Obesity, susceptibility to, BMIQ18}; Prader-Willi syndrome to {?Obesity, susceptibility to, BMIQ18}, OMIM:615457
Set publications
Achchuthan Shanmugasundram (Genomics England Curator)Publications for gene: MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls, nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a 10-year old boy with overall obesity in combination with intellectual disability in a screen of Prader-Willi syndrome (PWS) patients. The clinically diagnosed PWS could not be confirmed molecularly with MS-MLPA and CNV analysis of the 6q14.1–q16.3 region also showed no deletions in this patient. No further family data were available to determine whether the variant segregates with obesity in this family. It was shown to be (probably) damaging by in silico analysis and found in only one European (non-Finnish) individual in the ExAC database (since this database cannot release phenotype information about the screened individuals, no conclusions regarding causality of this variant can be drawn).
Added New Source
Ivone Leong (Genomics England Curator)Source Expert list was added to MRAP2.
panel promoted to version 1
Ellen McDonagh (Genomics England Curator)25/Oct/2016: Panel revised according to expert review and additional curation with internal discussion. Ready to be promoted to version 1.
Gene classified by Genomics England curator
Ellen McDonagh (Genomics England Curator)This gene has been classified as Red List (Low Evidence).
Set publications
Ellen McDonagh (Genomics England Curator)Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls, nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a 10-year old boy with overall obesity in combination with intellectual disability in a screen of Prader-Willi syndrome (PWS) patients. The clinically diagnosed PWS could not be confirmed molecularly with MS-MLPA and CNV analysis of the 6q14.1–q16.3 region also showed no deletions in this patient. No further family data were available to determine whether the variant segregates with obesity in this family. It was shown to be (probably) damaging by in silico analysis and found in only one European (non-Finnish) individual in the ExAC database (since this database cannot release phenotype information about the screened individuals, no conclusions regarding causality of this variant can be drawn).
Set publications
Ellen McDonagh (Genomics England Curator)Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls, nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a 10-year old boy with overall obesity in combination with intellectual disability in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype. The clinically diagnosed PWS could not be confirmed molecularly with MS-MLPA and CNV analysis of the 6q14.1–q16.3 region also showed no deletions in this patient. No further family data were available to determine whether the variant segregates with obesity in this family. It was shown to be (probably) damaging by in silico analysis and found in only one European (non-Finnish) individual in the ExAC database (since this database cannot release phenotype information about the screened individuals, no conclusions regarding causality of this variant can be drawn).
Set publications
Ellen McDonagh (Genomics England Curator)Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls, nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Set publications
Ellen McDonagh (Genomics England Curator)Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls, nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - identified a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Set publications
Ellen McDonagh (Genomics England Curator)Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls; nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - identified a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Set publications
Ellen McDonagh (Genomics England Curator)Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity; they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls; nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - identified a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Set publications
Ellen McDonagh (Genomics England Curator)Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in we genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity; they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls; nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - identified a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Set publications
Ellen McDonagh (Genomics England Curator)Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in we genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity; they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls; nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - identified a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Set Phenotypes
Ellen McDonagh (Genomics England Curator)Phenotypes for MRAP2 were set to obesity; {?Obesity, susceptibility to, BMIQ18};Prader-Willi syndrome
Set publications
Ellen McDonagh (Genomics England Curator)Publications for MRAP2 were set to 23869016; 27474872;26795956
Set publications
Ellen McDonagh (Genomics England Curator)Publications for MRAP2 were set to 23869016;27474872
Gene classified by Genomics England curator
Ellen McDonagh (Genomics England Curator)This gene has been classified as Red List (Low Evidence).
Set publications
Ellen McDonagh (Genomics England Curator)Publications for MRAP2 were set to 23869016
Set Phenotypes
Ellen McDonagh (Genomics England Curator)Phenotypes for MRAP2 were set to obesity;{?Obesity, susceptibility to, BMIQ18}
Gene classified by Genomics England curator
Ellen McDonagh (Genomics England Curator)This gene has been classified as Red List (Low Evidence).
Added New Source
stephen o'rahilly (university of cambridge)MRAP2 was added to Significant early-onset obesity +/- other endocrine features and short staturepanel. Sources: Expert Review
Created
stephen o'rahilly (university of cambridge)MRAP2 was created by [email protected]