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

ABSTRACT: 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.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.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.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.

SUBMITTER: Gowans LJ

PROVIDER: S-EPMC5370218 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Gowans Lord Jephthah Joojo LJ Busch Tamara D TD Mossey Peter A PA Eshete Mekonen A MA Adeyemo Wasiu L WL Aregbesola Babatunde B Donkor Peter P Arthur Fareed K N FK Agbenorku Pius P Olutayo James J Twumasi Peter P Braimah Rahman R Oti Alexander A AA Plange-Rhule Gyikua G Obiri-Yeboah Solomon S Abate Fikre F Hoyte-Williams Paa E PE Hailu Taye T Murray Jeffrey C JC Butali Azeez A

Molecular genetics & genomic medicine 20170112 2

<h4>Background</h4>Orofacial clefts are congenital malformations of the orofacial region, with a global incidence of one per 700 live births. Interferon Regulatory Factor 6 (<i>IRF6</i>) (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 <i>IRF6</i> in orofacial clefts cohorts from Africa.<h4>Methods</h4>We carried out Sanger Sequencing on DNA from 184 patie ...[more]

PMID: 28361103

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Project description:BackgroundCleft lip and palate are congenital craniofacial anomalies that significantly impact individuals and their families, both medically and psychosocially. The Qatari population has unique characteristics that are suggestive of a high prevalence of congenital anomalies: high consanguinity rate, large family size, advanced paternal age and high prevalence of certain genetic disorders. The lack of existing data concerning the epidemiology of cleft lip and/or palate in Qatar warrants a descriptive study addressing this topic.MethodsA retrospective nationwide hospital-based cross-sectional study conducted to determine the prevalence of orofacial clefts in Qatar from 2016 to 2021. Data were extracted from the corporation's Cerner database and electronic health records. Information concerning the cleft's characteristics, type, affected side, patient's gender, presence of associated syndromes, nationality, and maternal age were collected.ResultsOut of the 147,727 live births, 148 had an orofacial cleft. The prevalence of cleft lip and/or palate was determined to be 1 per 1000 livebirths (95% CI: 0.85, 1.18). The prevalence of cleft lip was 0.18 (95% CI: 0.12, 0.27), cleft palate 0.39 (95% CI: 0.30, 0.51), and cleft lip and palate 0.43 (95% CI: 0.33, 0.55). Qataris had a prevalence of CL 0.25, CP 0.40, and CLP 0.56, compared to 0.16, 0.39, 0.39 for non-Qataris (p-value 0.186). Unilateral clefts predominated over bilateral (74.4% and 25.6%, respectively). Among the unilateral cases, 70.2% occurred on the left side. Most cases were isolated clefts, with only 10.2% having associated syndromes.ConclusionsThe prevalence of orofacial clefts in Qatar is consistent with the globally reported prevalence. Most cases were unilateral and on the left side. Associated syndromes were infrequent and more common with cleft palate alone. Intriguing patterns were revealed between Qatari nationals and non-Qatari residents, with specific subtypes of orofacial clefts showing higher prevalence among nationals.

Dataset Information

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

Publications

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

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