Sistematični pregled genetskih sprememb povezanih s sočasno prisotnostjo orofacialne shize in prirojene srčne napake

Lešnik, Nika (author), Karas Kuželički, Nataša (mentor), Slavec, Lara (comentor)

Prirojene napake veljajo za enega izmed glavnih vzrokov neonatalne umrljivosti v današnjem razvitem svetu. Med najpogostejše spadajo orofacialne shize in prirojene srčne napake. Orofacialna shiza je prirojen razcep ustnice, neba ali čeljustnega grebena, lahko pa gre za kombinacijo vsega. Predstavlja velik estetski in funkcionalni problem, saj v različnih oblikah in stopnjah združuje nosno in ustno votlino. Prirojena srčna napaka pa nastane kot posledica motenega razvoja srca in/ali velikih žil. Pojavlja se v različnih segmentih srca in jih povezuje med sabo. Kljub veliki razširjenosti in pomembnosti orofacialnih shiz in prirojenih srčnih napak, je genetsko ozadje vzroka njunega sočasnega pojava slabo poznano. Število genov, vpletenih v njun razvoj, je namreč zelo veliko. Cilj magistrske naloge je tako bil izboljšati genetsko diagnostiko bolnikov z orofacialnimi shizami in prirojenimi srčnimi napakami, saj lahko le z razumevanjem in prepoznavo mehanizmov njunega sočasnega pojava, delujemo preventivno in takšne primere hitro obravnavamo. V magistrski nalogi smo zato izvedli sistematični pregled literature, kjer smo iskali vse poročane genetske spremembe pri bolnikih s sočasno prisotnostjo orofacialne shize in prirojene srčne napake. Po postavitvi iskalnega profila smo v bazi podatkov PubMed poiskali ustrezno literaturo. Definirali smo vključitvene kriterije in nato obravnavali tiste študije, ki so postavljenim kriterijem ustrezale. Takšnih študij je bilo 210, v sklopu katerih smo identificirali 611 primerov posameznikov z več kot 150 različnimi genetskimi spremembami in s sočasno prisotnostjo obeh fenotipov. Najpogostejša genetska sprememba izmed vseh je bila mikrodelecija 22q11, ki smo jo zaznali kar 364-krat. Ostale pogoste genetske spremembe so bile mutacije v genih PGM1, MEIS2, STAG2, BMP2, PGAP3 in RPL5, delecija 15q14, terminalne delecije 4q in trisomija 22, 10 in 9. Nekatere genetske spremembe so pripadale tudi znanim sindromom, ki so jih že uspeli povezati s sočasno prisotnostjo obeh fenotipov. Najpogostejši sindromi so bili sindromi CATCH 22, CHARGE, Emanuel, Wolf-Hirschhorn, Loeys Dietz tipa 1 in 2, Okamoto, Patau in Say-Barber-Biesecker-Young-Simpson. V vseh spremembah, ki niso bile sekvenčne, smo v literaturi poiskali še vse gene, ki jih povezujemo s hkratno prisotnostjo obeh fenotipov. Takšni geni so bili geni TGFBR1, TGFBR2, CHD7, TBX1, MAPK1, HIC2, HIRA, MEIS2, STAG2, BMP2, PDGFC, PGM1, PGAP3, PTCH1, RPL5, HNRNPK, SORBS2, KAT6B in DGCR2.

• Language: Slovenian
• Keywords: orofacialne shize, prirojene srčne napake, genetske spremembe, sistematični pregled literature
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2022
• PID: 20.500.12556/RUL-140916
• Publication date in RUL: 21.09.2022

Secondary language

• Language: English
• Title: Systematic review of genetic variants associated with the simultaneous presence of orofacial cleft and congenital heart defect

Abstract

Congenital abnormalities are considered to be one of the leading causes of neonatal mortality in the modern world of today. The most common congenital abnormalities are orofacial clefts and congenital heart defects. Orofacial cleft is a congenital opening of the lip, palate or mandibular ridge, or it can be a combination of all of them. It is a major esthetic and functional problem as it unites the nasal and oral cavities in various forms and degrees. Congenital heart defect is the result of abnormal development of the heart and/or large blood vessels. It occurs in different segments of the heart and connects them to each other. Despite the high prevalence and importance of orofacial clefts and congenital heart defects, the genetic background of the cause of their co-occurrence is poorly understood. The number of genes involved in their development is actually very large. The aim of this study was to improve the genetic diagnosis of patients with orofacial clefts and congenital heart defects, as only by understanding and identifying the mechanisms of their co-occurrence can we act preventively and treat such cases promptly. Therefore, in this study, we performed a systematic literature review, searching for all reported genetic variants in patients with coexisting orofacial clefts and congenital heart defects. After defining the search profile, we searched the PubMed database for relevant literature. We defined inclusion criteria and then considered those studies that met the criteria. There were 210 such studies, and we identified 611 cases of individuals with more than 150 different genetic variants and coexisting phenotypes. The most frequent genetic variant of all was the 22q11 microdeletion, which was detected 364 times. Other common genetic variants were mutations in the PGM1, MEIS2, STAG2, BMP2, PGAP3 and RPL5 genes, a deletion of 15q14, terminal deletions of 4q and trisomies 22, 10 and 9. Some of the genetic variants also belonged to known syndromes that have already been associated with the co-occurrence of both phenotypes. The most common syndromes were CATCH 22, CHARGE, Emanuel, Wolf-Hirschhorn, Loeys Dietz types 1 and 2, Okamoto, Patau and Say-Barber-Biesecker-Young-Simpson. In all the non-sequence variants, we also searched the literature for all the genes associated with the simultaneous presence of the two phenotypes. Such identefied genes were TGFBR1, TGFBR2, CHD7, TBX1, MAPK1, HIC2, HIRA, MEIS2, STAG2, BMP2, PDGFC, PGM1, PGAP3, PTCH1, RPL5, HNRNPK, SORBS2, KAT6B and DGCR2.

• Keywords: orofacial clefts, congenital heart defects, genetic variants, systematic literature review