Novel IRF6 mutations in families with Van Der Woude syndrome and popliteal pterygium syndrome from sub‐Saharan Africa

Abstract

Orofacial clefts (OFC) are complex genetic traits that are often classified as syndromic or nonsyndromic clefts. Currently, there are over 500 types of syndromic clefts in the Online Mendelian Inheritance in Man (OMIM) database, of which Van der Woude syndrome (VWS) is one of the most common (accounting for 2% of all OFC). Popliteal pterygium syndrome (PPS) is considered to be a more severe form of VWS. Mutations in the IRF6 gene have been reported worldwide to cause VWS and PPS. Here, we report studies of families with VWS and PPS in sub-Saharan Africa. We screened the DNA of eight families with VWS and one family with PPS from Nigeria and Ethiopia by Sanger sequencing of the most commonly affected exons in IRF6 (exons 3, 4, 7, and 9). For the VWS families, we found a novel nonsense variant in exon 4 (p.Lys66X), a novel splice-site variant in exon 4 (p.Pro126Pro), a novel missense variant in exon 4 (p.Phe230Leu), a previously reported splice-site variant in exon 7 that changes the acceptor splice site, and a known missense variant in exon 7 (p.Leu251Pro). A previously known missense variant was found in exon 4 (p.Arg84His) in the PPS family. All the mutations segregate in the families. Our data confirm the presence of IRF6-related VWS and PPS in sub-Saharan Africa and highlights the importance of screening for novel mutations in known genes when studying diverse global populations. This is important for counseling and prenatal diagnosis for high-risk families.

The prevalence, penetrance, and expressivity of etiologicIRF6variants in orofacial clefts patients from sub‐Saharan Africa

“…2009; Butali et al. 2014a). This observation is relevant for genetic testing in Africa: with limited resources, one can focus on exons 4 and 7 when the need arises to sequence the DNA of a subject.…”

“…2009; Butali et al. 2014a,b). All DNA processing protocols, PCR conditions and electrophoretic procedure are available at the Murray laboratory website (http://genetics.uiowa.edu/protocols.php).…”

“…2013; Butali et al. 2014a). These variants are usually concentrated in the highly conserved DNA‐binding domain (exons 3 and 4) and less conserved transactivation domain (exons 7 and 9) (Ferreira de Lima et al.…”

“…Recent sequence analyses of these four exons in VWS and PPS patients from Africa confirmed that these four exons are mutational “hot‐spots” in IRF6 (Butali et al. 2014a). The study, however, involved only two African populations, Ethiopia and Nigeria.…”

Medical genetics and genomic medicine in Nigeria

“…The first genetic study on nonsyndromic clefts in sub‐Saharan Africa was conducted in a Nigerian population (Butali et al., ). Subsequent studies from the same research group investigated rare variants in African populations by sequencing GWAS‐identified loci for orofacial clefts (Butali et al., , ,b; Eshete et al., ; Gowans et al., ). The investigators also reported novel IRF6 mutations in families with Van Der Woude syndrome and popliteal pterygium syndrome from sub‐Saharan Africa (Butali et al., ,b).…”