Association of ABCA4 Gene Polymorphisms with Cleft Lip with or without Cleft Palate in the Polish Population

Background: Non-syndromic cleft lip with/without cleft palate (NSCL/P) is a common congenital condition with a complex aetiology reflecting multiple genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in ABCA4 have been associated with NSCL/P in several studies, although there are some inconsistent results. This study aimed to evaluate whether two SNPs in ABCA4, namely rs4147811 and rs560426, are associated with NSCL/P occurrence in the Polish population. Methods: The study included 627 participants: 209 paediatric patients with NSCL/P and 418 healthy newborn controls. DNA was isolated from the saliva of NSCL/P patients and from umbilical cord blood in the controls. Genotyping of rs4147811 and rs560426 was performed using quantitative PCR. Results: The rs4147811 (AG genotype) SNP in ABCA4 was associated with a decreased risk of NSCL/P (odds ratio (OR) 0.57; 95% confidence interval (CI) 0.39–0.84; p = 0.004), whereas the rs560426 (GG genotype) SNP was associated with an increased risk of NSCL/P (OR 2.13; 95% CI 1.31–3.48; p = 0.002). Limitations: This study—based on the correlation between single genetic variants and the occurrence of different phenotypes—might have limited power in detecting relevant, complex inheritance patterns. ORs are often low to moderate when investigating the association of single genes with the risk of a complex trait. Another limitation was the small number of available NSCL/P samples. Conclusions: The results suggest that genetic variations in ABCA4 are important risk markers of NSCL/P in the Polish population. Further investigation in a larger study group is warranted.

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The SNP rs560426 Within ABCA4-ARHGAP29 Locus and the Risk of Nonsyndromic Oral Clefts

The Cleft Palate-Craniofacial Journal ◽

10.1177/1055665619899764 ◽

2020 ◽

Vol 57 (6) ◽

pp. 671-677 ◽

Cited By ~ 1

Author(s):

Yah-Huei Wu-Chou ◽

Kuo-Ting Philip Chen ◽

Yi-Chieh Lu ◽

Yin-Ting Lin ◽

Hsien-Fang Chang ◽

...

Keyword(s):

Cleft Palate ◽

Cleft Lip ◽

Strong Association ◽

Nucleotide Polymorphisms ◽

Test Analysis ◽

Oral Clefts ◽

The Family ◽

Abca4 Gene ◽

Family Based ◽

New Evidence

Objective: Nonsyndromic oral clefts are common birth defect with complex etiology. In the present study, we attempt to further validate the possible role for ABCA4 and ARHGAP29 in the susceptibility to nonsyndromic oral clefts. Design: We performed allelic transmission disequilibrium test analysis, on 10 eligible single nucleotide polymorphisms (SNPs) and SNP haplotypes using the Family-Based Association Test. Participants: The study sample consisted of 334 case–parent trios of nonsyndromic oral clefts from Taiwanese population, separated into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO) groups. Results: We found only the SNP rs560426 within the ABCA4 gene showed strong association with NSCPO ( P = .03498; Permuted P = .05382). No association between other 9 selected SNPs in ABCA4-ARHGAP29 region and the risk of nonsyndromic oral clefts was found. For the haplotype analyses, we found only haplotype T-C (rs570926 and rs3789431) in ABCA4 block 2 showed significant association with nonsyndromic NSCL/P in these Taiwanese trios. Conclusions: We used a family-based analysis in 334 Taiwanese case–parent trios to validate the possible role for ABCA4 and ARHGAP29 in the susceptibility to nonsyndromic oral clefts. This study provides a new evidence for an association between the intron variant rs560426 within ABCA4 and nonsyndromic cleft palate which may contribute their regulatory role in craniofacial development.

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Role of ARHGAP29 nucleotide variants in the etiology of non-syndromic cleft lip with or without cleft palate.

Journal of Medical Science ◽

10.20883/medical.e414 ◽

2020 ◽

Vol 89 (2) ◽

pp. e414

Author(s):

Justyna Dąbrowska ◽

Barbara Biedziak ◽

Agnieszka Lasota ◽

Paweł P. Jagodziński ◽

Adrianna Mostowska

Keyword(s):

Cleft Palate ◽

Candidate Gene ◽

Cleft Lip ◽

Association Studies ◽

Missense Variant ◽

P Value ◽

Genome Wide Association Studies ◽

Polish Population ◽

Increased Risk ◽

Strong Candidate

Aim. Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common birth defect of complex and heterogeneous aetiology. Genome-wide association studies (GWAS) of nsCL/P have identified an association for the 1p22.1 chromosomal region, in which ARHGAP29 was suggested as a candidate gene. Thus, the current study aimed to determine the contribution of the common and rare ARHGAP29 nucleotide variants to the risk of nsCL/P in the Polish population. Material and Methods. In total,197 common nucleotide variants (SNVs) and 22 missense variants located within the ARHGAP29 locus at chromosome 1p22.1 were genotyped by SNV microarray. The study was conducted in 269 individuals with nsCL/P and 569 healthy individuals. Results. Statistical analysis revealed that 31 common nucleotide variants located at the ARHGAP29 locus were significantly associated with the increased risk of nsCL/P. The strongest individual SNV was rs2391467 with a p-value = 2.49E-06 (OR = 1.64, 95%CI: 1.34–2.02). Besides, one potentially deleterious missense variant (rs140877322, p. Arg348Leu) was identified in a single patient with nsCLP. Conclusion. These findings confirm ARHGAP29 as a strong candidate gene for nsCL/P, with both common and rare nucleotide variants of this gene involved in the aetiology of nsCL/P in the Polish population.

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Maternal Vitamin B12 Status and Risk of Cleft Lip and Cleft Palate Birth Defects in Tamil Nadu State, India

The Cleft Palate-Craniofacial Journal ◽

10.1177/1055665621998394 ◽

2021 ◽

Vol 58 (5) ◽

pp. 567-576

Author(s):

Ronald G. Munger ◽

Rajarajeswari Kuppuswamy ◽

Jyotsna Murthy ◽

Kalpana Balakrishnan ◽

Gurusamy Thangavel ◽

...

Keyword(s):

Cleft Palate ◽

Tamil Nadu ◽

Cleft Lip ◽

Maternal Nutrition ◽

Case Control ◽

Vitamin B ◽

Plasma Vitamin ◽

Maternal Vitamin ◽

Increased Risk ◽

Tamil Nadu State

Background and Objective: The causal role of maternal nutrition in orofacial clefts is uncertain. We tested hypotheses that low maternal vitamin B12 and low folate status are each associated with an increased risk of isolated cleft lip with or without cleft palate (CL±P) in a case–control study in Tamil Nadu state, India. Methods: Case-mothers of CL±P children (n = 47) and control-mothers of unaffected children (n = 50) were recruited an average of 1.4 years after birth of the index child and plasma vitamin B12, methylmalonic acid (MMA), total homocysteine (tHcy), and folate were measured at that time. Logistic regression analyses estimated associations between nutrient biomarkers and case–control status. Results: Odds ratios (ORs) contrasting biomarker levels showed associations between case-mothers and low versus high plasma vitamin B12 (OR = 2.48, 95% CI, 1.02-6.01) and high versus low plasma MMA, an indicator of poor B12 status (OR = 3.65 95% CI, 1.21-11.05). Case–control status was not consistently associated with folate or tHcy levels. Low vitamin B12 status, when defined by a combination of both plasma vitamin B12 and MMA levels, had an even stronger association with case-mothers (OR = 6.54, 95% CI, 1.33-32.09). Conclusions: Mothers of CL±P children in southern India were 6.5 times more likely to have poor vitamin B12 status, defined by multiple biomarkers, compared to control-mothers. Further studies in populations with diverse nutritional backgrounds are required to determine whether poor maternal vitamin B12 or folate levels or their interactions are causally related to CL±P.

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Association between single-nucleotide polymorphisms on chromosome 1p22 and 20q12 and nonsyndromic cleft lip with or without cleft palate: New data in Han Chinese and meta-analysis

Birth Defects Research Part A Clinical and Molecular Teratology ◽

10.1002/bdra.23013 ◽

2012 ◽

Vol 94 (6) ◽

pp. 469-476 ◽

Cited By ~ 7

Author(s):

Enmin Huang ◽

Hongqiu Cheng ◽

Mingyan Xu ◽

Shenyou Shu ◽

Shijie Tang

Keyword(s):

Single Nucleotide Polymorphisms ◽

Cleft Palate ◽

Cleft Lip ◽

Meta Analysis ◽

Han Chinese ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

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Greater Palatal Cleft Width Predicts an Increased Risk for Unfavorable Outcomes in Cleft Palate Repair

The Cleft Palate-Craniofacial Journal ◽

10.1177/10556656211029537 ◽

2021 ◽

pp. 105566562110295

Author(s):

Åsa C. Okhiria ◽

Fatemeh Jabbari ◽

Malin M. Hakelius ◽

Monica M. Blom Johansson ◽

Daniel J. Nowinski

Keyword(s):

Cleft Palate ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

University Hospital ◽

Velopharyngeal Insufficiency ◽

Secondary Surgery ◽

Increased Risk ◽

Cleft Palate Repair ◽

The Impact ◽

Nasal Emission

Objective: To investigate the impact of cleft width and cleft type on the need for secondary surgery and velopharyngeal competence from a longitudinal perspective. Design: Retrospective, longitudinal study. Setting: A single multidisciplinary craniofacial team at a university hospital. Patients: Consecutive patients with unilateral or bilateral cleft lip and palate and cleft palate only (n = 313) born from 1984 to 2002, treated with 2-stage palatal surgery, were reviewed. A total of 213 patients were included. Main Outcome Measures: The impact of initial cleft width and cleft type on secondary surgery. Assessment of hypernasality, audible nasal emission, and glottal articulation from routine follow-ups from 3 to 16 years of age. The assessments were compared with reassessments of 10% of the recordings. Results: Cleft width, but not cleft type, predicted the need for secondary surgery, either due to palatal dehiscence or velopharyngeal insufficiency. The distribution of cleft width between the scale steps on a 4-point scale for hypernasality and audible nasal emission differed significantly at 5 years of age but not at any other age. Presence of glottal articulation differed significantly at 3 and 5 years of age. No differences between cleft types were seen at any age for any speech variable. Conclusions: Cleft width emerged as a predictor of the need for secondary surgery as well as more deviance in speech variables related to velopharyngeal competence during the preschool years. Cleft type was not related to the need for secondary surgery nor speech outcome at any age.

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Non-syndromic cleft palate: Association analysis on three gene polymorphisms of the folate pathway in Asian and Italian populations

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738419858572 ◽

2019 ◽

Vol 33 ◽

pp. 205873841985857 ◽

Cited By ~ 2

Author(s):

Francesco Carinci ◽

Annalisa Palmieri ◽

Luca Scapoli ◽

Francesca Cura ◽

Francesco Borelli ◽

...

Keyword(s):

Cleft Palate ◽

Cleft Lip ◽

Folic Acid Supplementation ◽

Nucleotide Polymorphisms ◽

Orofacial Clefts ◽

Single Nucleotide ◽

Candidate Gene Association ◽

Folate Pathway ◽

Family Based ◽

Gene Association Study

Periconceptional folic acid supplementation can reduce the risk of inborn malformations, including orofacial clefts. Polymorphisms of MTHFR, TCN2, and CBS folate-related genes seem to modulate the risk of cleft lip with or without cleft palate (CL/P) in some populations. CL/P and cleft palate only (CPO) are different malformations that share several features and possibly etiological causes. In the present investigation, we conducted a family-based, candidate gene association study of non-syndromic CPO. Three single nucleotide polymorphisms, namely, rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS, were investigated in a sample that included 129 Italian and 65 Asian families. No evidence of association between the three genotyped polymorphisms and CPO was found in the Italian and Asian cases, indeed the transmission disequilibrium test did not detect any asymmetry of transmission of alleles. This investigation, although with some limitation, further supports that CL/P and CPO diverge in their genetic background.

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Association of single nucleotide polymorphisms in WNT genes with the risk of nonsyndromic cleft lip with or without cleft palate

Congenital Anomalies ◽

10.1111/cga.12271 ◽

2018 ◽

Vol 58 (4) ◽

pp. 130-135 ◽

Cited By ~ 4

Author(s):

Houshang Rafighdoost ◽

Mohammad Hashemi ◽

Hossein Asadi ◽

Gholamreza Bahari

Keyword(s):

Single Nucleotide Polymorphisms ◽

Cleft Palate ◽

Cleft Lip ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

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Genetics of cleft lip and palate revisited

Journal of Clinical Pediatric Dentistry ◽

10.17796/jcpd.27.4.k7j3628944237392 ◽

2003 ◽

Vol 27 (4) ◽

pp. 311-320 ◽

Cited By ~ 3

Author(s):

Puneet Batra ◽

Ritu Duggal ◽

Hari Parkash

Keyword(s):

Cleft Palate ◽

Cleft Lip ◽

Speech Therapy ◽

Cleft Lip And Palate ◽

Gene List ◽

Complex Trait ◽

Case Control Studies ◽

Systematic Screening ◽

Complex Interactions ◽

Facial Development

Cleft lip with or without cleft palate (CL/CP) is one of the most common structural birth defects, with treatment including multiple surgeries, speech therapy, and dental and orthodontic treatments over the first 18 years of life. Providing care for these patients and families includes educating patients and parents about the genetics of CL/CP, as well as meeting the immediate medical needs.Attempts at identifying susceptibility loci via family and case-control studies have proved inconsistent. It is likely that initial predictions of the complex interactions involved in facial development were underestimated. The candidate gene list for CL/P is getting longer and the need for an impartial, systematic screening technique, to implicate or refute the inclusion of particular loci, is apparent. So we are faced with the question "Can this complex trait be too complex?"The aim of this review is to make the dentist aware of the differences between syndromic and non-syndromic cleft as well as understanding the etiological variation in cleft lip with and without cleft palate. This will aid the dentist in diagnosis and give proper genetic counseling to parents and patients of cleft lip and palate.

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