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Mutation screening of IRF6 among families with non-syndromic oral clefts and identification of two novel variants: review of the literature

Salahshourifar I, Wan Sulaiman WA, Halim AS, Zilfalil BA

Eur J Med Genet, 2012 Jun;55(6-7):389-93.
PMID: 22440537 DOI: 10.1016/j.ejmg.2012.02.006

Non-syndromic oral clefts share the main clinical features of Van der Woude Syndrome (VWS), with the exception of the lower lip pit. Thus, about 15% of VWS cases are indistinguishable from cases with non-syndromic oral clefts. IRF6 mutations are the major cause of VWS; however, variants in this gene show strong association with non-syndromic oral clefts, with a higher increased risk among cases with cleft lip only (CLO). A total of 39 individuals, including 16 patients with CLO and 23 patients with a family history of cleft, were examined for IRF6 mutations in the present study. Seven variants, including five known (c.-75-4 A>; G, c.-73T>; C, c.459G>; T 5, c.820G>; A, and c.1060 + 37C>; T) and two novel (c.-75-23G>; C and c.1380G>; T), were found. Both novel variants were inherited from non-affected parents and we did not find also in the 120 control chromosomes. In silico analysis revealed that both c.1380G>; T and c.-75-23G>; C variants may disrupts a putative exonic splicing enhancer and intronic splicing binding site for SC35, respectively. Taken together, the presence of deleterious IRF6 variants in patients with non-syndromic oral clefts could be most likely an evidence for VWS. While, IRF6 variants could, at best, contribute to clefting as part of a complex inheritance pattern, with both additional genes and environmental factors having a role.

Matched MeSH terms: Cleft Palate/genetics*
De novo interstitial deletion of 1q32.2-q32.3 including the entire IRF6 gene in a patient with oral cleft and other dysmorphic features

Salahshourifar I, Halim AS, Sulaiman WA, Ariffin R, Naili Muhamad Nor N, Zilfalil BA

Cytogenet Genome Res, 2011;134(2):83-7.
PMID: 21447942 DOI: 10.1159/000325541

Microdeletion of the Van der Woude syndrome (VWS) critical region is a relatively rare event, and only a few cases have been reported in the medical literature. The extent of the deletion and the genotype-phenotype correlation are 2 crucial issues.

Matched MeSH terms: Cleft Palate/genetics
Contribution of variants in and near the IRF6 gene to the risk of nonsyndromic cleft lip with or without cleft palate in a Malay population

Salahshourifar I, Sulaiman WA, Zilfalil BA, Halim AS

Am J Med Genet A, 2011 Sep;155A(9):2302-7.
PMID: 21834040 DOI: 10.1002/ajmg.a.34169

Several studies have shown evidence for the contribution of interferon regulatory factor 6 (IRF6) variants to the risk of nonsyndromic oral clefts in Asians; however, this has not included the Malay population. The current study attempts to address this research gap using allele and haplotype transmission disequilibrium analyses. The results showed a strong transmission distortion for multiple haplotypes to patients with nonsyndromic cleft lip with or without cleft palate. Haplotypes carrying the 243 bp allele of D1S2136 and common alleles at the rs861019 and rs2235371 were over-transmitted to patients. By contrast, haplotypes consisting of the 251 bp allele of D1S2136 and the rare allele at rs2235371 were more under-transmitted. Furthermore, several variants and haplotypes showed excess maternal transmission, but none of them attained statistical significance in maternal relative risk analyses. In contrast, a significant child genotype effect was observed for several haplotypes, indicating fetal genotype could be the major genetic contribution rather than maternal genotype. The present study therefore further supports a role for IRF6 variants in clefting in this Southeast Asian population. Overall, Asian genetic backgrounds are most likely more susceptible to the haploinsufficiency of IRF6 variants. These variants may contribute to the condition either themselves, or they may be in linkage disequilibrium with other casual variants.

Matched MeSH terms: Cleft Palate/genetics*
Maternal uniparental heterodisomy of chromosome 6 in a boy with an isolated cleft lip and palate

Salahshourifar I, Halim AS, Sulaiman WA, Zilfalil BA

Am J Med Genet A, 2010 Jul;152A(7):1818-21.
PMID: 20583164 DOI: 10.1002/ajmg.a.33526

We describe a chromosome 6 uniparental disomy (UPD6) in a boy, discovered during a screening for the genetic cause of cleft lip and palate. In the medical literature, almost all documented cases of UPD6 are paternal in origin, and only four were maternal. We present here a report of complete maternal chromosome 6 uniparental heterodisomy. Haplotype analysis was performed using highly polymorphic short tandem repeat (STR) markers that span both arms of chromosome 6. Analysis of these markers revealed the presence of two maternal alleles but no paternal allele, indicating an instance of maternal uniparental heterodisomy. Chromosome analysis of peripheral blood lymphocytes confirmed a normal male karyotype. Advanced maternal age at the time of the infant's birth and heterodisomy of markers around the centromere favors a meiosis-I error. No specific phenotype has been reported for maternal UPD6. Therefore, the cleft lip and palate in the present case probably occurred due to other risk factors. This report provides further evidence that maternal UPD6 has no specific clinical consequences and adds to the collective knowledge of this rare chromosomal finding.

Matched MeSH terms: Cleft Palate/genetics*
Transforming growth factor-alpha and nonsyndromic cleft lip with or without palate or cleft palate only in Kelantan, Malaysia

Rahman RA, Ahmad A, Rahman ZA, Mokhtar KI, Lah NA, Zilfalil BA, et al.

Cleft Palate Craniofac J, 2008 Nov;45(6):583-6.
PMID: 18956930 DOI: 10.1597/07-020.1

To determine the frequency of the transforming growth factor-alpha (TGFalpha) Taq1 polymorphism in nonsyndromic cleft lip with or without cleft palate (CL+/-P) and cleft palate only (CP) in Kelantan, Malaysia.

Matched MeSH terms: Cleft Palate/genetics*
Fulltext A neonate with ectodermal dysplasia ectrodactyly clefting syndrome and ventricular septal defect

Ram SP, Noor AR, Ariffin WA, Ariffin NA

Singapore Med J, 1994 Apr;35(2):205-7.
PMID: 7939823

A 37-week gestation male boy was born to a gravida seven para six mother by spontaneous vertex delivery at home. The baby cried at birth. On day 3 of life, he was admitted for respiratory distress. Physical examination revealed ectrodactyly, thin dry skin, anomalous tear duct with cardiomegaly. X-ray revealed absent radii, cardiomegaly and hemivertebra at L1. Echocardiogram revealed perimembranous type of ventricular septal defect. A diagnosis of Ectodermal Dysplasia Ectrodactyly Clefting Syndrome with ventricular septal defect was made. He was managed conservatively in the nursery. However, he expired on day 27 of life following short spell of fever apnoeic episode due to neonatal sepsis.

Matched MeSH terms: Cleft Palate/genetics*
Fulltext Contribution of 6p24 to non-syndromic cleft lip and palate in a Malay population: association of variants in OFC1

Salahshourifar I, Halim AS, Sulaiman WA, Zilfalil BA

J Dent Res, 2011 Mar;90(3):387-91.
PMID: 21297019 DOI: 10.1177/0022034510391798

Non-syndromic cleft lip, with or without cleft palate, is a heterogeneous, complex disease with a high incidence in the Asian population. Several association studies have been done on cleft candidate genes, but no reports have been published thus far on the Orofacial Cleft 1 (OFC1) genomic region in an Asian population. This study investigated the association between the OFC1 genomic region and non-syndromic cleft lip with or without cleft palate in 90 Malay father-mother-offspring trios. Results showed a preferential over-transmission of a 101-bp allele of marker D6S470 in the allele- and haplotype-based transmission disequilibrium test (TDT), as well as an excess of maternal transmission. However, no significant p-value was found for a maternal genotype effect in a log-linear model, although single and double doses of the 101-bp allele showed a slightly increased cleft risk (RR = 1.37, 95% CI, 0.527-3.4, p-value = 0.516). Carrying two copies of the 101-bp allele was significantly associated with an increased cleft risk (RR = 2.53, 95% CI, 1.06-6.12, p-value = 0.035). In conclusion, we report evidence of the contribution of the OFC1 genomic region to the etiology of clefts in a Malay population.

Matched MeSH terms: Cleft Palate/genetics*
Contribution of MSX1 variants to the risk of non-syndromic cleft lip and palate in a Malay population

Salahshourifar I, Halim AS, Wan Sulaiman WA, Zilfalil BA

J Hum Genet, 2011 Nov;56(11):755-8.
PMID: 21866112 DOI: 10.1038/jhg.2011.95

Oral clefts are clinically and genetically heterogeneous disorders that are influenced by both genetic and environmental factors. The present family-based association study investigated the role of the MSX1 and TGFB3 genes in the etiology of non-syndromic oral cleft in a Malay population. No transmission distortion was found in the transmission disequilibrium analysis for either MSX1-CA or TGFB3-CA intragenic markers, whereas TGFB3-CA exhibited a trend to excess maternal transmission. In sequencing the MSX1 coding regions in 124 patients with oral cleft, five variants were found, including three known variants (A34G, G110G and P147Q) and two novel variants (M37L and G267A). The P147Q and M37L variants were not observed in 200 control chromosomes, whereas G267A was found in one control sample, indicating a very rare polymorphic variant. Furthermore, the G110G variant displayed a significant association between patients with non-syndromic cleft lip, with or without cleft palate, and normal controls (P=0.001, odds ratio=2.241, 95% confidence interval, 1.357-3.700). Therefore, these genetic variants may contribute, along with other genetic and environmental factors, to this condition.

Matched MeSH terms: Cleft Palate/genetics*
Screening of Transforming Growth Factor Beta 3 and Jagged2 Genes in the Malay Population With Nonsyndromic Cleft Lip With or Without Cleft Palate

Ghazali N, Rahman NA, Kannan TP, Jaafar S

Cleft Palate Craniofac J, 2015 07;52(4):e88-94.
PMID: 26151095 DOI: 10.1597/14-024

OBJECTIVE: To determine the prevalence of mutations in transforming growth factor beta 3 (TGFβ3) and Jagged2 genes and their association with nonsyndromic cleft lip with or without cleft palate (CL±P) patients.

DESIGN: Cross-sectional study on nonsyndromic CL±P and noncleft patients.

SETTING: Reconstructive clinic and outpatient dental clinic, Hospital Universiti Sains Malaysia.

PATIENTS: Blood samples of 96 nonsyndromic CL±P and 96 noncleft subjects.

MAIN OUTCOME MEASURE: Prevalence and association of mutations in TGFβ3 and Jagged2 genes with nonsyndromic CL±P.

RESULTS: Most of the nonsyndromic CL±P patients (53.1%) had left unilateral CLP. There were slightly more females (56.6%) compared with males. The prevalence of the mutations in the TGFβ3 gene was 17.7% (95% confidence interval [CI]: 9.5, 24.5) and in the Jagged2 gene was 12.5% (95% CI: 5.5, 18.5), which was higher compared with the noncleft group. For the TGFβ3 gene, there was no mutation in the coding region in either of the groups. All variants were single nucleotide polymorphisms located within the intronic flanking region. Two variants were identified (g.15812T>G and g.15966A>G) in both nonsyndromic CL±P and noncleft patients. However, the association was not significant (P > .05). Three variants (g.19779C>T, g.19547G>A, and g.19712C>T) were identified in the Jagged2 gene among nonsyndromic CL±P and noncleft patients. Only g.19712C>T showed a significant association with nonsyndromic CL±P patients (P = .039).

CONCLUSION: g.19712C>T might play a crucial role in the development of cleft lip and palate. To the best of our knowledge, this is the first report of the mutation found within intron 13 of the Jagged2 gene among nonsyndromic CL±P Malay patients.

Study site:Reconstructive and outpatient dental clinic, Hospital Universiti Sains Malaysia (HUSM)

Matched MeSH terms: Cleft Palate/genetics*
Fulltext Two novel genes TOX3 and COL21A1 in large extended Malay families with nonsyndromic cleft lip and/or palate

Mohamad Shah NS, Sulong S, Wan Sulaiman WA, Halim AS

Mol Genet Genomic Med, 2019 May;7(5):e635.
PMID: 30924295 DOI: 10.1002/mgg3.635

BACKGROUND: Nonsyndromic cleft lip and/or palate is one of the most common human birth defects worldwide that affects the lip and/or palate. The incidence of clefts varies among populations through ethnic, race, or geographical differences. The focus on Malay nonsyndromic cleft lip and/or palate (NSCL/P) is because of a scarce report on genetic study in relation to this deformity in Malaysia. We are interested to discuss about the genes that are susceptible to cause orofacial cleft formation in the family.
METHODS: Genome-wide linkage analysis was carried out on eight large extended families of NSCL/P with the total of 91 individuals among Malay population using microarray platform. Based on linkage analyses findings, copy number variation (CNV) of LPHN2, SATB2, PVRL3, COL21A1, and TOX3 were identified in four large extended families that showed linkage evidence using quantitative polymerase chain reaction (qPCR) as for a validation purpose. Copy number calculated (CNC) for each genes were determined with Applied Biosystems CopyCallerTM Software v2.0. Normal CNC of the target sequence expected was set at two.
RESULTS: Genome-wide linkage analysis had discovered several genes including TOX3 and COL21A1 in four different loci 4p15.2-p16.1, 6p11.2-p12.3, 14q13-q21, and 16q12.1. There was significant decreased, p

Matched MeSH terms: Cleft Palate/genetics*
Haplotype diversity in 11 candidate genes across four populations

Beaty TH, Fallin MD, Hetmanski JB, McIntosh I, Chong SS, Ingersoll R, et al.

Genetics, 2005 Sep;171(1):259-67.
PMID: 15965248

Analysis of haplotypes based on multiple single-nucleotide polymorphisms (SNP) is becoming common for both candidate gene and fine-mapping studies. Before embarking on studies of haplotypes from genetically distinct populations, however, it is important to consider variation both in linkage disequilibrium (LD) and in haplotype frequencies within and across populations, as both vary. Such diversity will influence the choice of "tagging" SNPs for candidate gene or whole-genome association studies because some markers will not be polymorphic in all samples and some haplotypes will be poorly represented or completely absent. Here we analyze 11 genes, originally chosen as candidate genes for oral clefts, where multiple markers were genotyped on individuals from four populations. Estimated haplotype frequencies, measures of pairwise LD, and genetic diversity were computed for 135 European-Americans, 57 Chinese-Singaporeans, 45 Malay-Singaporeans, and 46 Indian-Singaporeans. Patterns of pairwise LD were compared across these four populations and haplotype frequencies were used to assess genetic variation. Although these populations are fairly similar in allele frequencies and overall patterns of LD, both haplotype frequencies and genetic diversity varied significantly across populations. Such haplotype diversity has implications for designing studies of association involving samples from genetically distinct populations.

Matched MeSH terms: Cleft Palate/genetics
Fulltext Discovery of candidate genes for nonsyndromic cleft lip palate through genome-wide linkage analysis of large extended families in the Malay population

Mohamad Shah NS, Salahshourifar I, Sulong S, Wan Sulaiman WA, Halim AS

BMC Genet, 2016 Feb 11;17:39.
PMID: 26868259 DOI: 10.1186/s12863-016-0345-x

BACKGROUND: Nonsyndromic orofacial clefts are one of the most common birth defects worldwide. It occurs as a result of genetic or environmental factors. This study investigates the genetic contribution to nonsyndromic cleft lip and/or palate through the analysis of family pedigrees. Candidate genes associated with the condition were identified from large extended families from the Malay population.
RESULTS: A significant nonparametric linkage (NPL) score was detected in family 100. Other suggestive NPL and logarithm of the odds (LOD) scores were attained from families 50, 58, 99 and 100 under autosomal recessive mode. Heterogeneity LOD (HLOD) score ≥ 1 was determined for all families, confirming genetic heterogeneity of the population and indicating that a proportion of families might be linked to each other. Several candidate genes in linkage intervals were determined; LPHN2 at 1p31, SATB2 at 2q33.1-q35, PVRL3 at 3q13.3, COL21A1 at 6p12.1, FOXP2 at 7q22.3-q33, FOXG1 and HECTD1 at 14q12 and TOX3 at 16q12.1.
CONCLUSIONS: We have identified several novel and known candidate genes for nonsyndromic cleft lip and/or palate through genome-wide linkage analysis. Further analysis of the involvement of these genes in the condition will shed light on the disease mechanism. Comprehensive genetic testing of the candidate genes is warranted.

Matched MeSH terms: Cleft Palate/genetics*

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