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. 2017 Jan 12;5(2):164-171.
doi: 10.1002/mgg3.273. eCollection 2017 Mar.

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

Lord Jephthah Joojo Gowans  1 , Tamara D Busch  2 , Peter A Mossey  3 , Mekonen A Eshete  4 , Wasiu L Adeyemo  5 , Babatunde Aregbesola  6 , Peter Donkor  7 , Fareed K N Arthur  8 , Pius Agbenorku  7 , James Olutayo  5 , Peter Twumasi  8 , Rahman Braimah  6 , Alexander A Oti  7 , Gyikua Plange-Rhule  9 , Solomon Obiri-Yeboah  7 , Fikre Abate  4 , Paa E Hoyte-Williams  9 , Taye Hailu  4 , Jeffrey C Murray  10 , Azeez Butali  2
Affiliations

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

Lord Jephthah Joojo Gowans et al. Mol Genet Genomic Med. .

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 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.

Keywords: Craniofacial genetics; Van der Woude syndrome; expressivity; penetrance; population genetics; rare variants.

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Figures

Figure 1
Figure 1
A patient with Van der Woude Syndrome that presented with CLP and bilateral lip pits (indicated by arrow heads).
Figure 2
Figure 2
DNA Sequence chromatograms and pedigrees for p.Glu69Lys variant. (A): top chromatogram is from an unaffected individual, whereas the middle and bottom chromatograms are from two patients with p.Glu69Lys variant, (B): a case with IRF6 (RefSeq NM_006147.3) compound heterozygote, (C): a case with IRF6‐PAX7 (RefSeq NM_001135254.1) compound heterozygote.
Figure 3
Figure 3
Substitution of Glutamate for Lysine in p.Glu69Lys mutant in IRF6 (RefSeq NM_006147.3).
Figure 4
Figure 4
Wildtype and mutant amino acid residues for p.Gly65Val variant in IRF6 (RefSeq NM_006147.3).
Figure 5
Figure 5
p.Lys320Asn wild‐type and mutant amino acid residues in IRF6 (RefSeq NM_006147.3).
See this image and copyright information in PMC

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