Table 5.
Genetic screening results for obesity-related genes in our population of subjects with obesity
| No. | Gene | Genetic defect | Sex | Classa | Variation | Explanation |
|---|---|---|---|---|---|---|
| Definitive diagnosis of genetic obesity | ||||||
| 1 | MC4R | Pathogenic | F | III | Heterozygous c.105C>A, p.(Tyr35*) | |
| 2 | MC4R | Pathogenic | F | III | Heterozygous c.105C>A, p.(Tyr35*) | |
| 3 | POMC | Pathogenic | F | III | Heterozygous c.662A>G, p.(Tyr221Cys) | |
| Possible diagnosis of genetic obesity or risk factor for obesity | ||||||
| 4 | LEPR | VUS | F | II | Heterozygous c.1835G>A, p.(Arg612His) | Pathogenic heterozygousLEPR mutations are a known risk factor for obesity; segregation analysis needed; this mutation is described in patients with a leptin receptor deficiency in combination with other pathogenicLEPR mutations |
| 5 | LEPR | VUS | F | III | Heterozygous c.2963C>T, p.(Thr988Met) | Pathogenic heterozygousLEPR mutations are a known risk factor for obesity; segregation analysis needed |
| 6 | MRAP2 CEP290 | Likely pathogenic Pathogenic | F | II | Heterozygous c.373C>T, p.(Arg125Cys) Heterozygous c.4723A>T, p.(Lys1575*) | MRAP2 is likely a pathogenic variant; segregation analysis needed;CEP290carrier status autosomal recessive disease; probably no or a low-risk factor for obesity |
| 7 | MRAP2 | Likely pathogenic | F | III | Heterozygous c.373C>T, p.(Arg125Cys) | Likely a pathogenic variant; segregation analysis needed |
| 8 | MRAP2 | Likely pathogenic | F | III | Heterozygous c.520C>T, p.(Gln174*) | Likely a pathogenic variant |
| 9 | PCK1 PCK1 | VUS VUS | M | III | Heterozygous c.1397C>T, p.(Ala466Val) Heterozygous c.1628G>A, p.(Arg543Gln) | Segregation analysis showed that a skinny sib did not have any of the variants |
| 10 | POMC | VUS | M | III | Heterozygous c.229T>G, p.(Tyr77Asp) | Pathogenic heterozygousPOMC mutations are a known risk factor for obesity; segregation analysis identified the mutation in an obese brother, which makes pathogenicity more likely |
| 11 | SNRPN | Likely pathogenic | F | I | Heterozygous c.193C>T, p.(Arg65Trp) | Likely pathogenic variant fitting with the phenotype, but first described missense mutations, further segregation analysis and/or functional study is needed |
| 12 | TBX3 | VUS | F | III | Heterozygous c.2177G>T, p.(Arg726Leu) | Autosomal dominant diseases, segregation analysis not yet performed |
| No genetic explanation for obesity (yet): VUS or noninterpretable status | ||||||
| 13 | BBS1 | Pathogenic | F | I | Heterozygous c.1570_1572del, p.(Asn524del) | Carrier status autosomal recessive disease; probably no or low-risk factor for obesity |
| 14 | BBS1 | VUS | F | II | Heterozygous c.742C>A, p.(Pro248Thr) | Carrier status autosomal recessive disease; probably no or low-risk factor for obesity |
| 15 | BBS4 | VUS | M | II | Heterozygous c.137A>G, p.(Lys46Arg) | Carrier status autosomal recessive disease; probably no or low-risk factor for obesity |
| 16 | BBS5 | VUS | M | III | Heterozygous c.110T>C, p.(Ile37Thr) | Carrier status autosomal recessive disease; probably no or low-risk factor for obesity |
| 17 | BBS9 | VUS | F | III | Heterozygous c.1600A>G, p.(Ile534Val) | Carrier status autosomal recessive disease; probably no or low-risk factor for obesity |
| 18 | BBS12 | VUS | M | III | Heterozygous c.1367A>G, p.(Tyr456Cys) | Carrier status autosomal recessive disease; probably no or low-risk factor for obesity |
| 19 | BBS12 | Pathogenic | M | III | Heterozygous c.476C>T, p.(Pro159Leu) | Carrier status autosomal recessive disease; probably no or low-risk factor for obesity |
| 20 | CEP290 | Pathogenic VUS | F | II | Heterozygous c.6516del, p.(Lys2172fs) Heterozygous c.564T>G, p.(Asp188Glu) | No clinical features of Bardet-Biedl syndrome; probably no or low-risk factor for obesity |
| 21 | CEP290 | VUS VUS | F | III | Heterozygous c.7190T>C, p.(Leu2397Pro) Heterozygous c.7394_7395del, p.(Glu2465fs) | Carrier status autosomal recessive disease; probably no or low-risk factor for obesity; variants incis |
| 22 | PCK1 | VUS | F | III | Heterozygous c.1526C>T, p.(Pro509Leu) | Carrier status autosomal recessive disease; no known dominant phenotype |
| 23 | SPG11 | VUS | F | III | Heterozygous c.5121G>T, p.(Glu1707Asp) | Carrier status autosomal recessive disease; no known dominant phenotype |
| 24 | SPG11 | Pathogenic | F | III | Heterozygous c.5989_5992del, p.(Leu1997fs) | Carrier status autosomal recessive disease; no known dominant phenotype |
| 25 | TMEM67 | Pathogenic | F | II | Heterozygous c.958A>T, p.(Ser320Cys) | Carrier status autosomal recessive disease; probably no or low-risk factor for obesity |
| 26 | TMEM67 | Pathogenic | M | II | Heterozygous c.622A>T, p.(Arg208*) | Carrier status autosomal recessive disease; probably no or low-risk factor for obesity |
| 27 | WDPCP | Pathogenic | F | II | Heterozygous c.160G>A, p.(Asp54Asn) | Carrier status autosomal recessive disease; probably no or low-risk factor for obesity |
| Mutations in comorbidity risk genes | ||||||
| 28 | IRS1 | VUS | F | I | Heterozygous c.1835A>G, p.(Tyr612Cys) | |
| 29 | IRS2 | VUS | F | II | Heterozygous c.319G>T, p.(Ala107Ser) | |
VUS, variant of unknown clinical significance.
a
According to the WHO classification [24], i.e., class I, BMI between 30.00 and 34.99; class II, BMI between 35.00 and 39.99; and class III, BMI equal to or greater than 40.00.