Mutation and association analysis of the PVR and PVRL2 genes in patients with non-syndromic cleft lip and palate

Orofacial clefts (OFC; MIM 119530) are among the most common major birth defects. Here, we carried out mutation screening of the PVR and PVRL2 genes, which are both located at an OFC linkage region at 19q13 (OFC3) and are closely related to PVRL1, which has been associated with both syndromic and non-syndromic cleft lip and palate (nsCLP). We screened a total of 73 nsCLP patients and 105 non-cleft controls from the USA for variants in PVR and PVRL2, including all exons and encompassing all isoforms. We identified four variants in PVR and five in PVRL2. One non-synonymous PVR variant, A67T, was more frequent among nsCLP patients than among normal controls, but this difference did not achieve statistical significance

Lack of mutations in the PVRL3 gene in North American caucasians with non-syndromic cleft lip/palate

Cleft lip with or without cleft palate (CLP) is one of the most common birth defects. In about 70% of cases, CLP occurs as an isolated anomaly, denoted non-syndromic CLP (nsCLP). Genetic linkage and association studies have implicated many loci in susceptibility to nsCLP, including some members of the nectin gene family. We performed mutation screening of the PVRL3 gene that encodes nectin-3 in 73 unrelated Caucasian nsCLP patients and 105 unrelated controls from North America. We detected no sequence variants in the PVRL3 gene in either the nsCLP patients or the controls. These data suggest that PVRL3 is not an important susceptibility gene for nsCLP in the North American Caucasian population

Study Of The Clptm1 Gene In South American Non-Syndromic Cleft Lip Patients With Or Without Palate

Aim: The CLPTM1 gene is considered as a candidate gene based on the fact that it is localized in the human chromosomal region 19q13 which maps in the candidate region OFC3. This study aims to test the involvement of this candidate gene, CLPTM1, in non-syndromic cleft lip with or without cleft palate (CL/P, MIM 119530) and to analyze particularly a CLPTM1 variant, A88A if there is an allelic association with non-syndromic cleft lip and palate. Methods: A total of 171 non-syndromic cleft lip patients with or without palate and 181 healthy controls from Venezuela and a total of 92 non-syndromic CL/P patients and 76 healthy controls from Argentina were screened for CLPTM1 Exon 3 variation, A88A using Single Stranded Conformation Polymorphism technique. Results: We found no significant difference for the A88A mutation of CLPTM1 gene between nsCL/P patients and controls neither in Venezuela nor in Argentina, although the first cohort from Venezuela showed a significant difference in terms of CLPTM1 88A mutant allele frequency in particular. Conclusion: The CLPTM1 variant, A88A, was not found to be associated with the disease in the two populations studied. These data suggest that CLPTM1 gene do not seem to participate in the development of nsCL/P in the South American populations studied. These results also suggest that larger sample size in the study of the allelic association might be more informative than the smaller ones

Mutation analysis of ACOD4 gene in cases with Non-syndromic Cleft lip/palate

Non-sendromik yarık dudak ve/veya damak (nsYD/D= nsCL/P, MİM 119530) en yaygın başlıca do¬ğum defektlerinden biridir. Birçok aday gen alel ilişkilen- dirme metodu ile non-sendromik yarık dudak/damak malformasyonunda olası rol alıp almadığını test etmek için çalışılmıştır. Kromozom yeniden düzenlemelerine sahip nadir olgular, ilgilenilen bir hastalık için aday genleri be-lirlemede eşsiz ipuçları sağlayabilir. Son zamanlarda, bu şekildeki iki çalışma yeni kromozom yeniden düzenlenmeleri belirlemiş ve bu suretle non-sendromik yarık dudak/damak hastalığı için iki yeni aday gen ortaya çıkarmıştır: CLPTMİ ve ACOD4. Buna dayalı olarak, biz ACOD4 geninin non-sendromik yarık dudak/damak hastalığındaki potansiyel rolünü belirlemek için ilgili gende mutasyon analizi gerçekleştirdik. Kuzey Venezüella’dan toplam 96 hastada ACOD4 geninin kodlayan beş ekzonunda mutasyon taraması gerçekleştirdik. İki hastada ACOD4 geninin 4. ekzonunda bir sessiz mutasyon, Ala241Ala, belirledik ve başka herhangi bir varyant bulamadık. Sonuç olarak, bu bulgular ACOD4 geninin nsYD/D malformasyonu gelişiminde yaygın bir genetik risk faktörü olduğunu, en azından bu araştırmada çalışılan güney Amerika’ lı (Venezüella) populasyonda, desteklememektedir.Non-syndromic cleft lip with or without cleft palate (CL/P, MIM 119530) is perhaps the most common major birth defect. A large number of candidate genes have been studied by allelic association studies to test possible involvement in non-syndromic cleft lip and palate. Rare patients with de novo chromosomal rearrangements and a rare disease can offer unique clues for identifying candidate genes for a disorder of interest. Two recent studies identified novel chromosomal rearrangements and thereby identified two novel candidate genes for nsCL/P: CLPTM1 and ACOD4. Based on this, we carried out mutation analysis of the ACOD4 gene for its potential involvement in nsCL/P. We screened a total of 96 nsCL/P patients from Venezuela for variation in the five coding exons of ACOD4. We detected a silent variant, Ala242Ala, in exon 4 in two patients, but found no other variants. Altogether, our data do not support ACOD4 as a common genetic risk factor for nsCL/P malformation, at least in the South American (Venezuelan) population studied here

Mutation analysis of ACOD4 gene in cases with Non-syndromic Cleft lip/palate

Non-sendromik yarık dudak ve/veya damak (nsYD/D= nsCL/P, MİM 119530) en yaygın başlıca do¬ğum defektlerinden biridir. Birçok aday gen alel ilişkilen- dirme metodu ile non-sendromik yarık dudak/damak malformasyonunda olası rol alıp almadığını test etmek için çalışılmıştır. Kromozom yeniden düzenlemelerine sahip nadir olgular, ilgilenilen bir hastalık için aday genleri be-lirlemede eşsiz ipuçları sağlayabilir. Son zamanlarda, bu şekildeki iki çalışma yeni kromozom yeniden düzenlenmeleri belirlemiş ve bu suretle non-sendromik yarık dudak/damak hastalığı için iki yeni aday gen ortaya çıkarmıştır: CLPTMİ ve ACOD4. Buna dayalı olarak, biz ACOD4 geninin non-sendromik yarık dudak/damak hastalığındaki potansiyel rolünü belirlemek için ilgili gende mutasyon analizi gerçekleştirdik. Kuzey Venezüella’dan toplam 96 hastada ACOD4 geninin kodlayan beş ekzonunda mutasyon taraması gerçekleştirdik. İki hastada ACOD4 geninin 4. ekzonunda bir sessiz mutasyon, Ala241Ala, belirledik ve başka herhangi bir varyant bulamadık. Sonuç olarak, bu bulgular ACOD4 geninin nsYD/D malformasyonu gelişiminde yaygın bir genetik risk faktörü olduğunu, en azından bu araştırmada çalışılan güney Amerika’ lı (Venezüella) populasyonda, desteklememektedir.Non-syndromic cleft lip with or without cleft palate (CL/P, MIM 119530) is perhaps the most common major birth defect. A large number of candidate genes have been studied by allelic association studies to test possible involvement in non-syndromic cleft lip and palate. Rare patients with de novo chromosomal rearrangements and a rare disease can offer unique clues for identifying candidate genes for a disorder of interest. Two recent studies identified novel chromosomal rearrangements and thereby identified two novel candidate genes for nsCL/P: CLPTM1 and ACOD4. Based on this, we carried out mutation analysis of the ACOD4 gene for its potential involvement in nsCL/P. We screened a total of 96 nsCL/P patients from Venezuela for variation in the five coding exons of ACOD4. We detected a silent variant, Ala242Ala, in exon 4 in two patients, but found no other variants. Altogether, our data do not support ACOD4 as a common genetic risk factor for nsCL/P malformation, at least in the South American (Venezuelan) population studied here

Mutation Analysis of the PVRL1 Gene in Caucasians with Nonsyndromic Cleft Lip/Palate

Nonsyndromic cleft lip with or without cleft palate (nsCL/P, MIM 119530) is perhaps the most common major birth defect. Homozygous PVRL1 loss-of-function mutations result in an autosomal recessive CL/P syndrome, CLPED1, and a PVRL1 nonsense mutation is associated with sporadic nsCL/P in Northern Venezuela. To address the more general role of PVRL1 variation in risk of nsCL/P, we carried out mutation analysis of PVRL1 in North American and Australian nsCL/P cases and population-matched controls. We identified a total of 15 variants, 5 of which were seen in both populations and 1 of which, an in-frame insertion at Glu442, was more frequent in patients than in controls in both populations, though the difference was not statistically significant. Another variant, which is specific to the PVRL1 β (HIgR) isoform, S447L, was marginally associated with nsCL/P in North American Caucasian patients, but not in Australian patients, and overall variants that affect the β-isoform were significantly more frequent among North American patients. One Australian patient had a splice junction mutation of PVRL1. Our results suggest that PVRL1 may play a minor role in susceptibility to the occurrence of nsCL/P in some Caucasian populations, and that variation involving the β (HIgR) isoform might have particular importance for risk of orofacial clefts. Nevertheless, these results underscore the need for studies that involve very large numbers when assessing the possible role of rare variants in risk of complex traits such as nsCL/P