The prevalence, penetrance, and expressivity of etiologic IRF6 variants in orofacial clefts patients from sub-Saharan Africa.

Autor: Gowans LJ; Department of Biochemistry and BiotechnologyKwame Nkrumah University of Science and Technology (KNUST)KumasiGhana; Cleft ClinicKomfo Anokye Teaching HospitalKumasiGhana; Department of PaediatricsUniversity of IowaIowa CityIowa; Department of Oral PathologyRadiology and MedicineUniversity of IowaIowa CityIowa., Busch TD; Department of Oral Pathology Radiology and Medicine University of Iowa Iowa City Iowa., Mossey PA; Department of Orthodontics University of Dundee Dundee Scotland., Eshete MA; Addis Ababa University Addis Ababa Ethiopia., Adeyemo WL; College of Medicine University of Lagos Lagos Nigeria., Aregbesola B; Obafemi Awolowo University Teaching Hospital Ile-Ife Nigeria., Donkor P; Cleft ClinicKomfo Anokye Teaching HospitalKumasiGhana; Department of SurgerySchool of Medical SciencesKNUSTKumasiGhana., Arthur FK; Department of Biochemistry and Biotechnology Kwame Nkrumah University of Science and Technology (KNUST) Kumasi Ghana., Agbenorku P; Cleft ClinicKomfo Anokye Teaching HospitalKumasiGhana; Department of SurgerySchool of Medical SciencesKNUSTKumasiGhana., Olutayo J; College of Medicine University of Lagos Lagos Nigeria., Twumasi P; Department of Biochemistry and Biotechnology Kwame Nkrumah University of Science and Technology (KNUST) Kumasi Ghana., Braimah R; Obafemi Awolowo University Teaching Hospital Ile-Ife Nigeria., Oti AA; Cleft ClinicKomfo Anokye Teaching HospitalKumasiGhana; Department of SurgerySchool of Medical SciencesKNUSTKumasiGhana., Plange-Rhule G; Cleft Clinic Komfo Anokye Teaching Hospital Kumasi Ghana., Obiri-Yeboah S; Cleft ClinicKomfo Anokye Teaching HospitalKumasiGhana; Department of SurgerySchool of Medical SciencesKNUSTKumasiGhana., Abate F; Addis Ababa University Addis Ababa Ethiopia., Hoyte-Williams PE; Cleft Clinic Komfo Anokye Teaching Hospital Kumasi Ghana., Hailu T; Addis Ababa University Addis Ababa Ethiopia., Murray JC; Department of Paediatrics University of Iowa Iowa City Iowa., Butali A; Department of Oral Pathology Radiology and Medicine University of Iowa Iowa City Iowa.
Jazyk: angličtina
Zdroj: Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2017 Jan 12; Vol. 5 (2), pp. 164-171. Date of Electronic Publication: 2017 Jan 12 (Print Publication: 2017).
DOI: 10.1002/mgg3.273
Abstrakt: Background: Orofacial clefts are congenital malformations of the orofacial region, with a global incidence of one per 700 live births. Interferon Regulatory Factor 6 ( IRF6 ) (OMIM:607199) gene has been associated with the etiology of both syndromic and nonsyndromic orofacial clefts. The aim of this study was to show evidence of potentially pathogenic variants in IRF6 in orofacial clefts cohorts from Africa.
Methods: We carried out Sanger Sequencing on DNA from 184 patients with nonsyndromic orofacial clefts and 80 individuals with multiple congenital anomalies that presented with orofacial clefts. We sequenced all the nine exons of IRF6 as well as the 5' and 3' untranslated regions. In our analyses pipeline, we used various bioinformatics tools to detect and describe the potentially etiologic variants.
Results: We observed that potentially etiologic exonic and splice site variants were nonrandomly distributed among the nine exons of IRF6 , with 92% of these variants occurring in exons 4 and 7. Novel variants were also observed in both nonsyndromic orofacial clefts (p.Glu69Lys, p.Asn185Thr, c.175-2A>C and c.1060+26C>T) and multiple congenital anomalies (p.Gly65Val, p.Lys320Asn and c.379+1G>T) patients. Our data also show evidence of compound heterozygotes that may modify phenotypes that emanate from IRF6 variants.
Conclusions: This study demonstrates that exons 4 and 7 of IRF6 are mutational 'hotspots' in our cohort and that IRF6 mutants-induced orofacial clefts may be prevalent in the Africa population, however, with variable penetrance and expressivity. These observations are relevant for detection of high-risk families as well as genetic counseling. In conclusion, we have shown that there may be a need to combine both molecular and clinical evidence in the grouping of orofacial clefts into syndromic and nonsyndromic forms.
Databáze: MEDLINE
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