title: The prevalence, penetrance, and expressivity of etiologicIRF6variants in orofacial clefts patients from sub-Saharan Africa.
abstract: 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 inIRF6in 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 ofIRF6as 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 ofIRF6, 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 fromIRF6variants.
  
  
  CONCLUSIONS
  This study demonstrates that exons 4 and 7 ofIRF6are mutational 'hotspots' in our cohort and thatIRF6mutants-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.
authors.affiliation: 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.
authors.forename: Lord Jephthah Joojo
authors.identifier: 0000-0003-0080-9101
authors.initials: LJ
authors.lastname: Gowans
authors.affiliation: Department of Oral Pathology Radiology and Medicine University of Iowa Iowa City Iowa.
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Busch
authors.affiliation: Department of Orthodontics University of Dundee Dundee Scotland.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Mossey
authors.affiliation: Addis Ababa University Addis Ababa Ethiopia.
authors.forename: Mekonen A
authors.initials: MA
authors.lastname: Eshete
authors.affiliation: College of Medicine University of Lagos Lagos Nigeria.
authors.forename: Wasiu L
authors.identifier: 0000-0002-0257-7853
authors.initials: WL
authors.lastname: Adeyemo
authors.affiliation: Obafemi Awolowo University Teaching Hospital Ile-Ife Nigeria.
authors.forename: Babatunde
authors.initials: B
authors.lastname: Aregbesola
authors.affiliation: Cleft ClinicKomfo Anokye Teaching HospitalKumasiGhana; Department of SurgerySchool of Medical SciencesKNUSTKumasiGhana.
authors.forename: Peter
authors.initials: P
authors.lastname: Donkor
authors.affiliation: Department of Biochemistry and Biotechnology Kwame Nkrumah University of Science and Technology (KNUST) Kumasi Ghana.
authors.forename: Fareed K N
authors.initials: FK
authors.lastname: Arthur
authors.affiliation: Cleft ClinicKomfo Anokye Teaching HospitalKumasiGhana; Department of SurgerySchool of Medical SciencesKNUSTKumasiGhana.
authors.forename: Pius
authors.initials: P
authors.lastname: Agbenorku
authors.affiliation: College of Medicine University of Lagos Lagos Nigeria.
authors.forename: James
authors.initials: J
authors.lastname: Olutayo
authors.affiliation: Department of Biochemistry and Biotechnology Kwame Nkrumah University of Science and Technology (KNUST) Kumasi Ghana.
authors.forename: Peter
authors.initials: P
authors.lastname: Twumasi
authors.affiliation: Obafemi Awolowo University Teaching Hospital Ile-Ife Nigeria.
authors.forename: Rahman
authors.initials: R
authors.lastname: Braimah
authors.affiliation: Cleft ClinicKomfo Anokye Teaching HospitalKumasiGhana; Department of SurgerySchool of Medical SciencesKNUSTKumasiGhana.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Oti
authors.affiliation: Cleft Clinic Komfo Anokye Teaching Hospital Kumasi Ghana.
authors.forename: Gyikua
authors.initials: G
authors.lastname: Plange-Rhule
authors.affiliation: Cleft ClinicKomfo Anokye Teaching HospitalKumasiGhana; Department of SurgerySchool of Medical SciencesKNUSTKumasiGhana.
authors.forename: Solomon
authors.initials: S
authors.lastname: Obiri-Yeboah
authors.affiliation: Addis Ababa University Addis Ababa Ethiopia.
authors.forename: Fikre
authors.initials: F
authors.lastname: Abate
authors.affiliation: Cleft Clinic Komfo Anokye Teaching Hospital Kumasi Ghana.
authors.forename: Paa E
authors.initials: PE
authors.lastname: Hoyte-Williams
authors.affiliation: Addis Ababa University Addis Ababa Ethiopia.
authors.forename: Taye
authors.initials: T
authors.lastname: Hailu
authors.affiliation: Department of Paediatrics University of Iowa Iowa City Iowa.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Department of Oral Pathology Radiology and Medicine University of Iowa Iowa City Iowa.
authors.forename: Azeez
authors.initials: A
authors.lastname: Butali
keywords: Craniofacial genetics; Van der Woude syndrome; expressivity; penetrance; population genetics; rare variants