
The prevalence, penetrance, and expressivity of etiologic IRF 6 variants in orofacial clefts patients from sub‐Saharan Africa
Author(s) -
Gowans Lord Jephthah Joojo,
Busch Tamara D.,
Mossey Peter A.,
Eshete Mekonen A.,
Adeyemo Wasiu L.,
Aregbesola Babatunde,
Donkor Peter,
Arthur Fareed K. N.,
Agbenorku Pius,
Olutayo James,
Twumasi Peter,
Braimah Rahman,
Oti Alexander A.,
PlangeRhule Gyikua,
ObiriYeboah Solomon,
Abate Fikre,
HoyteWilliams Paa E.,
Hailu Taye,
Murray Jeffrey C.,
Butali Azeez
Publication year - 2017
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.273
Subject(s) - penetrance , expressivity , genetics , medicine , biology , phenotype , gene
Background Orofacial clefts are congenital malformations of the orofacial region, with a global incidence of one per 700 live births. Interferon Regulatory Factor 6 ( IRF 6 ) ( 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 IRF 6 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 IRF 6 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 IRF 6 , 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 IRF 6 variants. Conclusions This study demonstrates that exons 4 and 7 of IRF 6 are mutational ‘hotspots’ in our cohort and that IRF 6 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.