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.
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