Maternal Transmission of the PAX7 Single Nucleotide Polymorphisms among Indian Cleft Trios

Abstract

Cleft lip and/or cleft palate (CL/P) is one of the most common congenital anomalies of the human face with a complex etiology involving multiple genetic and environmental factors. Several studies have shown the association of the paired box 7 (PAX7) gene with CL/P in different populations worldwide. However, the current literature reveals no reported case-parent trio studies to evaluate the association between the PAX7 gene and the risk of nonsyndromic cleft lip and/or palate (NSCL/P) in the Indian population. Hence, the purpose of this study was to assess the PAX7 gene single nucleotide polymorphisms (SNPs) in the etiology of NSCL/P among the Indian cleft trios. Forty Indian case-parent trios of NSCL/P were included. The cases and their parents' genomic DNA were extracted. The SNPs rs9439714, rs1339062, rs6695765, rs742071, and rs618941of the PAX7 gene were genotyped using the Agena Bio MassARRAY analysis. The allelic transmission disequilibrium test was performed using PLINK software while pair-wise linkage disequilibrium by the Haploview program. The SNP rs9439714 showed evidence of association (p-value = 0.02, odds ratio = 3) with NSCL/P. Considering the parent-of-origin effects, the SNPs rs9439714 and rs618941 showed an excess maternal transmission of allele C at rs9439714 (p-value = 0.05) and G allele at rs618941 (p-value = 0.04). The results of the present study suggested that the SNPs rs9439714 and rs618941 showed an excess maternal transmission of alleles suggestive of the possible role of the PAX7 gene involvement in the etiology of NSCL/P in the Indian population.

Keywords

Cleft lip and/or cleft palate - SNP - genotyping - MassARRAY

Publication History

Article published online:
24 January 2023

• References

• 1 Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 2011; 12 (03) 167-178
• 2 Bender PL. Genetics of cleft lip and palate. J Pediatr Nurs 2000; 15 (04) 242-249
• 3 Worley ML, Patel KG, Kilpatrick LA. Cleft lip and palate. Clin Perinatol 2018; 45 (04) 661-678
• 4 Leslie EJ, Marazita ML. Genetics of cleft lip and cleft palate. Am J Med Genet C Semin Med Genet 2013; 163C [phone]
• 5 Stanier P, Moore GE. Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts. Hum Mol Genet 2004; 13 (Spec No 1): R73-R81
• 6 Mossey P, Little J. Addressing the challenges of cleft lip and palate research in India. Indian J Plast Surg 2009; 42 (Suppl): S9-S18
• 7 Jugessur A, Farlie PG, Kilpatrick N. The genetics of isolated orofacial clefts: from genotypes to subphenotypes. Oral Dis 2009; 15 (07) 437-453
• 8 Mossey P. Epidemiology underpinning research in the aetiology of orofacial clefts. Orthod Craniofac Res 2007; 10 (03) 114-120
• 9 Yang J, Carmichael SL, Canfield M, Song J, Shaw GM. National Birth Defects Prevention Study. Socioeconomic status in relation to selected birth defects in a large multicentered US case-control study. Am J Epidemiol 2008; 167 (02) 145-154
• 10 Khan MI, Cs P, Srinath NM. Genetic factors in nonsyndromic orofacial clefts. Glob Med Genet 2020; 7 (04) 101-108
• 11 Reddy SG, Reddy RR, Bronkhorst EM. et al. Incidence of cleft lip and palate in the state of Andhra Pradesh, South India. Indian J Plast Surg 2010; 43 (02) 184-189
• 12 Neela PK, Gosla SR, Husain A, Mohan V. CRISPLD2 gene polymorphisms with nonsyndromic cleft lip palate in Indian population. Glob Med Genet 2020; 7 (01) 22-25
• 13 Mansouri A, Stoykova A, Torres M, Gruss P. Dysgenesis of cephalic neural crest derivatives in Pax7-/- mutant mice. Development 1996; 122 (03) 831-838
• 14 Khan MI, Cs P. Case-parent trio studies in cleft lip and palate. Glob Med Genet 2020; 7 (03) 75-79
• 15 Infante-Rivard C, Weinberg CR. Parent-of-origin transmission of thrombophilic alleles to intrauterine growth-restricted newborns and transmission-ratio distortion in unaffected newborns. Am J Epidemiol 2005; 162 (09) 891-897
• 16 Weinberg CR. Methods for detection of parent-of-origin effects in genetic studies of case-parents triads. Am J Hum Genet 1999; 65 (01) 229-235
• 17 Weinberg CR, Wilcox AJ, Lie RT. A log-linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am J Hum Genet 1998; 62 (04) 969-978
• 18 Reik W, Walter J. Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001; 2 (01) 21-32
• 19 Sivertsen A, Wilcox AJ, Skjaerven R. et al. Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives. BMJ 2008; 336 (7641): 432-434
• 20 Grosen D, Chevrier C, Skytthe A. et al. A cohort study of recurrence patterns among more than 54,000 relatives of oral cleft cases in Denmark: support for the multifactorial threshold model of inheritance. J Med Genet 2010; 47 (03) 162-168
• 21 Purcell S, Neale B, Todd-Brown K. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81 (03) 559-575
• 22 Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52 (03) 506-516
• 23 Zalc A, Rattenbach R, Auradé F, Cadot B, Relaix F. Pax3 and Pax7 play essential safeguard functions against environmental stress-induced birth defects. Dev Cell 2015; 33 (01) 56-66
• 24 Sull JW, Liang KY, Hetmanski JB. et al. Maternal transmission effects of the PAX genes among cleft case-parent trios from four populations. Eur J Hum Genet 2009; 17 (06) 831-839
• 25 Butali A, Suzuki S, Cooper ME. et al. Replication of genome wide association identified candidate genes confirm the role of common and rare variants in PAX7 and VAX1 in the etiology of nonsyndromic CL(P). Am J Med Genet A 2013; 161A [phone]
• 26 Guo Q, Li D, Meng X. et al. Association between PAX7 and NTN1 gene polymorphisms and nonsyndromic orofacial clefts in a northern Chinese population. Medicine (Baltimore) 2017; 96 (19) e6724
• 27 Neela PK, Gosla SR, Husain A, Mohan V, Thumoju S, Rajeshwari R. Analysis of single nucleotide polymorphisms on locus 13q33.1–34 in multigenerational families of cleft lip palate using MassArray. Indones Biomed J 2021; 13 (01) 27-33
• 28 Wilcox AJ, Weinberg CR, Lie RT. Distinguishing the effects of maternal and offspring genes through studies of “case-parent triads”. Am J Epidemiol 1998; 148 (09) 893-901
• 29 Umbach DM, Weinberg CR. The use of case-parent triads to study joint effects of genotype and exposure. Am J Hum Genet 2000; 66 (01) 251-261
• 30 Shi M, Murray JC, Marazita ML. et al. Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts. Am J Med Genet A 2012; 158A [phone]
• 31 Neela PK, Gosla SR, Husain A, Mohan V, Thumoju S, Bv R. Association of MAPK4 and SOX1-OT gene polymorphisms with cleft lip palate in multiplex families: a genetic study. J Dent Res Dent Clin Dent Prospect 2020; 14 (02) 93-96
• 32 Leslie EJ, Carlson JC, Shaffer JR. et al. Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate. Hum Genet 2017; 136 (03) 275-286
• 33 Speca S, Rousseaux C, Dubuquoy C. et al. Novel PPARγ modulator GED-0507-34 Levo ameliorates inflammation-driven intestinal fibrosis. Inflamm Bowel Dis 2016; 22 (02) 279-292
• 34 Gaczkowska A, Biedziak B, Budner M. et al. PAX7 nucleotide variants and the risk of non-syndromic orofacial clefts in the Polish population. Oral Dis 2019; 25 (06) 1608-1618
• 35 Leslie EJ, Taub MA, Liu H. et al. Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci. Am J Hum Genet 2015; 96 (03) 397-411
• 36 Ludwig KU, Mangold E, Herms S. et al. Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci. Nat Genet 2012; 44 (09) 968-971
• 37 Duan SJ, Huang N, Zhang BH. et al. New insights from GWAS for the cleft palate among han Chinese population. Med Oral Patol Oral Cir Bucal 2017; 22 (02) e219-e227