The prevalence, penetrance, and expressivity of etiologic<i><scp>IRF</scp>6</i>variants in orofacial clefts patients from sub‐Saharan Africa

Gowans, Lord Jephthah Joojo; Busch, Tamara; Mossey, Peter; Eshete, Mekonen; Adeyemo, WL; Aregbesola, Babatunde S.; Donkor, Peter; Arthur, Fareed K. N.; Agbenorku, Pius; Olutayo, James; Twumasi, Peter; Braimah, Ramat Oyebunmi; Oti, Alexander Acheampong; Plange‐Rhule, Gyikua; Obiri‐Yeboah, Solomon; Abate, Fikre; Hoyte-Williams, Paa Ekow; Hailu, Tsegaye; Murray, Jeffrey C.; Butali, Azeez

doi:10.1002/mgg3.273

Cited by 10 publications

(13 citation statements)

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“…Several previous studies had screened for IRF6 PV in patients with nonsyndromic OFC, with the goal of identifying their frequency and any related clinical characteristics. These studies found that patients with VWS accounted for 0% to 3.7% of OFC cases initially cataloged as nonsyndromic forms (Zucchero et al, 2004; Birnbaum et al, 2008; Pegelow et al, 2008; Jehee et al, 2009; Desmyter et al, 2010; Larrabee et al, 2011; Salahshourifar et al, 2012; Wu-Chou et al, 2013; Khandelwal et al, 2016; Leslie et al, 2016; Gowans et al, 2017). A posteriori clinical evaluation suggested that there was minimal expression of lower lip pits in 31.8% of the patients with IRF6 PV (7 of 22 with information available).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous groups have screened the IRF6 gene for PV in patients with an OFC to determine the proportion of patients with VWS that have been erroneously classified with a nonsyndromic form. Indeed, PV in IRF6 have been identified in 0% to 3.7% of patients with an OFC (Zucchero et al, 2004; Birnbaum et al, 2008; Pegelow et al, 2008; Jehee et al, 2009; Desmyter et al, 2010; Larrabee et al, 2011; Salahshourifar et al, 2012; Wu-Chou et al, 2013; Khandelwal et al, 2016; Leslie et al, 2016; Gowans et al, 2017). A posteriori clinical evaluation of patients in which an IRF6 PV was identified revealed that around 31% of these patients showed a minimal expression of lip pits and 50% had a first-degree relative with mixed OFC.…”

Section: Introductionmentioning

confidence: 99%

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Screening of IRF6 Variants in Patients Subjected to Genetic Association Studies for Nonsyndromic Cleft Lip/Palate

Velázquez-Aragón¹,

Ángel²,

Alcántara-Ortigoza³

et al. 2020

The Cleft Palate-Craniofacial Journal

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Objective: To screen for interferon regulatory factor 6 (IRF6) pathogenic variants in patients clinically diagnosed with nonsyndromic cleft lip palate (NSCL/P) and establish the proportion of misdiagnosed Van der Woude syndrome (VWS) cases, which could have biased previous NSCL/P case–control association studies. Design: Retrospective case series. Setting: Tertiary care children’s hospital. Participants: One hundred seventy-two unrelated Mexican patients with NSCL/P, 128 of whom had previously been included in a NSCL/P case–control association study. Main Outcomes Measurements: Sanger sequencing of the 9 IRF6 exons were performed, all variants respect with sequence reference were reported and classified for their pathogenic significance according to the American College of Medical Genetics and Genomics guidelines. Results: Seven percent of cases were familial. No pathogenic variant was identified in IRF6. We identified 12 previously reported benign variants; their frequencies did not significantly differ from those reported for individuals of Mexican ancestry. Three of them were uncommon intronic variants not reported in ClinVar. The rs2235371 and rs2235375 variants, which were previously analyzed in a NSCL/P case–control association study (containing 132 patients, 128 of whom were analyzed herein) did not show discordant association results comparing to the 370 controls from the previous study. Conclusions: The misdiagnosis of IRF6-related VWS as NSCL/P appears to be infrequent in our sample, suggesting that mutational screening of IRF6 would have a low diagnostic yield in patients with NSCL/P. The absence of IRF6 pathogenic alleles could be related to the application of an exhaustive clinical evaluation that discarded the syndromic forms and/or the low proportion of familial cases included.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Screening of IRF6 Variants in Patients Subjected to Genetic Association Studies for Nonsyndromic Cleft Lip/Palate

Velázquez-Aragón¹,

Ángel²,

Alcántara-Ortigoza³

et al. 2020

The Cleft Palate-Craniofacial Journal

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“…OFCs have multifactorial etiology, with genetic, stochastic, environmental, and gene‐environment factors playing crucial roles (Dixon et al, 2011). Various studies have demonstrated that both syndromic and nonsyndromic forms of OFCs may exhibit variable penetrance and expressivity, with molecular genetic mechanisms such as compound heterozygosity and gene‐gene interactions being suggested as possible underlying mechanisms (Dixon et al, 2011; Gowans et al, 2017). Moreover, genes for syndromic cases, such as IRF6 (OMIM:607199), have been implicated in the etiology of nonsyndromic cases (Kondo et al, 2002; Zucchero et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Co‐occurrence of orofacial clefts and clubfoot phenotypes in a sub‐Saharan African cohort: Whole‐exome sequencing implicates multiple syndromes and genes

Gowans

Dhaheri

et al. 2021

Molec Gen & Gen Med

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Background Orofacial clefts (OFCs) are congenital malformations of the face and palate, with an incidence of 1 per 700 live births. Clubfoot or congenital talipes equinovarus (CTEV) is a three‐dimensional abnormality of the leg, ankle, and feet that leads to the anomalous positioning of foot and ankle joints and has an incidence of 1 per 1000 live births. OFCs and CTEV may occur together or separately in certain genetic syndromes in addition to other congenital abnormalities. Here, we sought to decipher the genetic etiology of OFC and CTEV that occurred together in six probands. Methods At the time of recruitment, the most clinically obvious congenital anomalies in these individuals were the OFC and CTEV. We carried out whole‐exome sequencing (WES) on DNA samples from probands and available parents employing the Agilent SureSelect XT kit and Illumina HiSeq2500 platform, followed by bioinformatics analyses. WES variants were validated by clinical Sanger Sequencing. Results Of the six probands, we observed probable pathogenic genetic variants in four. In three probands with probable pathogenic genetic variants, each individual had variants in three different genes, whereas one proband had probable pathogenic variant in just one gene. In one proband, we observed variants in DIS3L2, a gene associated with Perlman syndrome. A second proband had variants in EPG5 (associated with Vici Syndrome), BARX1 and MKI67, while another proband had potentially etiologic variants in FRAS1 (associated with Fraser Syndrome 1), TCOF1 (associated with Treacher Collins Syndrome 1) and MKI67. The last proband had variants in FRAS1, PRDM16 (associated with Cardiomyopathy, dilated, 1LL/Left ventricular noncompaction 8) and CHD7 (associated with CHARGE syndrome/Hypogonadotropic hypogonadism 5 with or without anosmia). Conclusion Our results suggest that clubfoot and OFCs are two congenital abnormalities that can co‐occur in certain individuals with varying genetic causes and expressivity, warranting the need for deep phenotyping.

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“…The Interferon Regulatory Factor 6 gene has been associated with syndromic and nonsyndromic orofacial clefts. Gowans LJ et al [4] carried out Sanger Sequencing on DNA from184 patients with nonsyndromic orofacial clefts and 80 individuals with multiple congenital anomalies that presented with orofacial clefts. They sequenced all the nine exons of IRF6 as well as the 5' and 3' untranslated regions.…”

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confidence: 99%

“…In Africa population, prevalent of the porofacial clefts with variable penetrance and expressivity is induced by IRF6 mutants. Their observations are relevant for detection of high-risk families as well as genetic counseling [4]. The etiology of nonsyndromic cleft palate remains elusive, but it has been suggested that causative genes of syndromic CL/P might also contribute to NSCL/P.…”

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confidence: 99%

Van Der Woude Syndrome

Ambarkova¹

2017

JDHODT

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

Cited by 10 publications

References 27 publications

Screening of IRF6 Variants in Patients Subjected to Genetic Association Studies for Nonsyndromic Cleft Lip/Palate

Screening of IRF6 Variants in Patients Subjected to Genetic Association Studies for Nonsyndromic Cleft Lip/Palate

Co‐occurrence of orofacial clefts and clubfoot phenotypes in a sub‐Saharan African cohort: Whole‐exome sequencing implicates multiple syndromes and genes

Van Der Woude Syndrome

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