Transmission analysis of candidate genes for nonsyndromic oral clefts in Brazilian parent-child triads with recurrence

Abstract

Cleft lip and/or palate (CL/P) is a major congenital defect with complex etiology, including multiple genetic and environmental factors. Approximately two thirds of the cases are not accompanied by other anomalies and are called nonsyndromic (NS). In the present study, we performed transmission distortion analysis of the MSX1-CA, TGFB3-CA and MTHFR-C677T polymorphisms in 60 parent-child triads, in which the NS-CL/P affected child had at least one affected parent. No association with genes MSX1 or TGFB3 was found, but the results were suggestive of an association of the MTHFR-C677T polymorphism with NS-CL/P. Nonsyndromic cleft lip and/or palate (NS-CL/P) affect about 1/700 livebirths, with wide variability concerning geographic distribution, ethnic background and socioeconomic status (Murray, 2002). The etiology is complex, including multiple genetic and environmental factors. The MSX1 and TGFB3 genes have been suggested as candidate genes based on animal models (Satokata and Maas, 1994;Kaartinen et al., 1995;Proetzel et al., 1995) and association studies in humans with genes MSX1, TGFB3 and MTHFR have pointed to the involvement of these genes in NS-CL/P etiology (Maestri et al., 1997;Lidral et al., 1998;Romitti et al., 1999;Mills et al., 1999; Wyszynsky and Diehl, 2000;Beaty et al., 2001). The MSX1 gene maps to chromosome 4p16. Animal models indicate that this gene plays a role in craniofacial anomalies, leading to a clefting phenotype. Van den Boogaard et al. (2000) identified a stop codon in the MSX1 gene in a three-generation Dutch family with tooth agenesis and combinations of CP only and CLP, providing further evidence for the involvement of this gene in orofacial clefting. Jezewski et al. (2003) sequenced the whole MSX1 gene in a large sample of NS-CL/P patients from different geographic regions, and found mutations in about 2% of the cases.The TGFB3 gene maps to 14q24. Animal model studies demonstrated that TGFB3 plays a role in CP (Kaartinen et al., 1995;1997;Proetzel et al., 1995; Sanford et al., 1997), andLidral et al. (1998) showed an association between TGFB3 markers and NS-CP.The MTHFR gene maps to 1p36.1, and plays a key role in the metabolism of folate by reducing methylenetrahydrofolate to 5-methyltetrahydrofolate, the primary methyl donor for methionine synthesis. The C677T nucleotide variant in the MTHFR gene results in a thermally unstable protein with reduced activity, leading to elevated plasma homocysteine levels. Considerable heterogeneity in the prevalence of the C677T polymorphism throughout the world was reported (Pepe et al., 1998).The present work aimed to investigate if genes TGFB3, MSX1 and MTHFR-C677T are involved in the etiology of NS-CLP, by testing 60 patients, all with an affected parent. We utilized a nuclear family-based approach, to determine for each form of clefting whether these genes were in linkage disequilibrium, as measured by transmission distortion.A total of 60 triads, each one including an affected child and at least one affected parent, were studied. Of...

Potential genetic markers for nonsyndromic oral clefts in the Brazilian population: A systematic review and meta‐analysis

“…In the second phase, the full‐text review was then conducted on the 71 first‐phase selected citations, which lead to the exclusion of 22 studies. In the end of the two phases, 49 studies fulfilled the inclusion criteria (Antunes et al, ; Araújo et al, ; Araujo et al, ; Bagordakis et al, ; Bezerra et al, ; Brandalize et al, ; Brito, Bassi, & Masotti, ; Brito et al, ; Bufalino et al, ; Cardoso et al, ; Choi et al, ; da Silva, Ribeiro, Cooper, Marazita, & Moretti‐Ferreira, ; de Aguiar et al, ; de Aquino et al, a,b; de Souza et al, ; do Rego Borges et al, ; Ehlers Bertoja, Sampaio Alho, De França, Menegotto, & Miriam Robinson, ; Falagan‐Lotsch et al, ; Filézio et al, ; Fontoura, Silva, Granjeiro, & Letra, ; Gaspar et al, ; Jehee et al, ; Küchler et al, ; Letra, Menezes, Granjeiro, & Vieira, ; Letra, Silva, & Menezes, ; Letra et al, a,b; Machado et al, a,b, ; Menezes, Letra, Ruff, Granjeiro, & Vieira, ; Menezes et al, ; Messetti et al, ; Paranaíba et al, ; Passos‐Bueno et al, ; Sabóia et al, ; Souza, Kowalski, Collares, & Félix, ; Souza, Kowalski, Vanz, Giugliani, & Félix, ; Waltrick‐Zambuzzi et al, ; Zucchero et al, ), but only 11 articles were used in the meta‐analysis (Antunes et al, ; Araújo et al, ; Bagordakis et al, ; Brito et al, ; de Aguiar et al, ; do Rego Borges et al, ; Fontoura et al, ; Gaspar et al, ; Paranaíba et al, ;).…”

MSX1 gene polymorphisms in non‐syndromic cleft lip and/or palate

“…Several studies analysed intronic and/or 3′UTR regions using either the case control, the family based or both approaches in combination showing controversial results. In Brazil, a study performed transmission distortion analysis on an intronic CA‐ repeat polymorphism of MSX1 in parent–child triads and found no association between MSX1 and NSCL/P (Silva et al , ). On the other hand, Vieira et al () suggested that MSX1 contributes to clefting in South American populations.…”

Evidence of the involvement of the polymorphisms near MSX1 gene in non-syndromic cleft lip with or without cleft palate

“…Marker position Alleles rs11726039 11.9 kb upstream from transcription start T/C rs868257 9.2 kb upstream from transcription start C/G rs6446693 6.3 kb upstream from transcription start T/C rs1907998 4.8 kb upstream from transcription start A/G rs6832405 18.0 kb downstream from transcription end G/T significant association between intronic CA repeat polymorphisms and NSCL/P [28]. The MSX1 P147Q polymorphism which was not evaluated in our study, found only in the Asian population with very less frequency, showed contrasting results on the association with NSCL/P [29,30].…”