Opredelitev kandidatnega diagnostičnega panela genov pri pediatričnih bolnikih z debelostjo

Šenica, Ana (author), Trebušak Podkrajšek, Katarina (mentor), Šket, Robert (comentor)

Debelost opredelimo kot abnormalno ali prekomerno kopičenje maščobe, ki predstavlja tveganje za zdravje. Povezana je z različnimi kratkoročnimi in dolgoročnimi spremljajočimi boleznimi. Pri pediatrični populaciji so za obvladovanje debelosti v ospredju vedenjski ukrepi. Na voljo je tudi farmakološko zdravljenje. Z vidika genetike lahko debelost opišemo s tremi oblikami: monogensko, poligensko in sindromsko obliko. Monogenske oblike so v grobem povezane z geni, vključenimi v leptin-melanokortinsko signalno pot, katera predstavlja tudi glavni mehanizem uravnavanja apetita. Najpogostejšo obliko predstavlja poligenska debelost. V sklopu magistrske naloge smo pri 460 pediatričnih preiskovancih z debelostjo določili spremembe v 504 genih, povezanih z debelostjo. Zasnovali smo tri genetske panele, ki vključujejo gene že znano povezane z debelostjo, in tudi gene, ki so glede na strokovno literaturo ter strokovne podatkovne baze potencialno povezani z debelostjo. Spremembe smo določili na podlagi sekvenciranja celotnega eksoma s sekvenciranjem naslednje generacije in jih klasificirali po priporočilih Ameriškega združenja medicinskih genetikov. Priporočila vpeljujejo petstopenjsko razvrščanje sprememb glede na njihov klinični pomen, ki je bil nadgrajen s točkovnim sistemom za bolj sistematično klasificiranje. Skupno smo opredelili 202 verjetno patogenih in patogenih sprememb ter 3349 sprememb neznanega kliničnega pomena. Opazili smo trend, da z večanjem nabora genov, vključenih v genetski panel, število sprememb neznanega kliničnega pomena narašča hitreje kot število patogenih sprememb. Smo pa z dodajanjem novih genov pojasnili več primerov debelosti. Presodili smo, katere spremembe so klinično pomembne za poročanje in komentirali smiselnost vključitve kandidatnih genov v obstoječi diagnostični panel. Skupno smo pojasnili 30 primerov debelosti (6,5 %). Primerjali smo standardni odklon indeksa telesne mase med skupinama s patogenimi spremembami in spremembami neznanega kliničnega pomena ter prišli do ugotovitve, da je bila mediana standardnega odmika indeksa telesne mase višja pri patogenih spremembah, a razlika ni bila statistično značilna. Z analizo povezav genov s pomočjo orodja STRING smo potrdili, da so kandidatni geni funkcionalno povezani z diagnostičnimi geni za debelost. Glede na to, da pri večini preiskovancev z uporabljenim genetskim pristopom nismo pojasnili debelosti, bi bilo smiselno nadaljevati z določanjem sprememb števila kopij in sprememb, ki se nahajajo v nekodirajočih regijah kandidatnih genov.

• Language: Slovenian
• Keywords: pediatrična debelost, monogenska debelost, genetika, leptin-melanokortinska pot, kandidatni geni
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2025
• PID: 20.500.12556/RUL-170367
• Publication date in RUL: 04.07.2025

Secondary language

• Language: English
• Title: Definition of a candidate diagnostic gene panel in pediatric patients with obesity

Abstract

Obesity is defined as abnormal or excessive accumulation of fat that poses a health risk and is associated with multiple shortterm and longterm comorbidities. Managing obesity in pediatric population usually consists of lifestyle changes although pharmaceutical options are also available. Genetically, we can chategorise obesity into three groups; monogenic, polygenic and syndromic obesity. Monogenic obesity usually involves genes associated with the leptin-melanocortin signalling pathway, which is also teh most important system for reglating appetite and food intake. The most common form is the polygenic obesity. In this masters thesis we determined genetic variants in obesity associated genes in a test group of 460 pediatric patients. We designed three genetic panels with genes known to be associated with obesity and candidate genes reported in scientific articles and databases as potentially connected to obesity. Genetic variants were determined based on sequencing of whole exome with new generation sequencing and were classified based on the American College of Medical Genetics and Genomics guidelines. The guidelines introduce a five-tier classification system based on clinical significance and upgraded with a point based system for a more systematic classification approach. Altogether we identified 202 likely pathogenic and patogenic variants and 3349 variants of unknown significance. We have observed a trend that the number of variants of unknown significance is growing faster than the number of pathogenic variants. With the addition of new genes to the gene panel we were able to explaine more cases of obesity. We evaluated the clinical relevance of the identified variants for reporting and discussed the implementation of the candidate genes into the current diagnostic panel. In total we explained 30 cases of obesity. We compared standard deviation of body mass index between the group of patients with pathogenic variants and those with only variants of unknown significance. We concluded that the median in all genetic panels is higher in a group with pathogenic variants, but the difference is not statistically significant. Using STRING analysis we confirmed that the candidate genes are functionally linked to obesity genes included in the diagnostic panel. As we could not explain the genetic aetiology for obesity in the majority of patients it would be reasonable to continue with the analysis of copy number variants or variants in non coding regions of the candidate genes.

• Keywords: pediatric obesity, monogenic obesity, genetics, leptin-melanocortin pathway, candidate genes