Searching for Genes for Cleft Lip and/or Palate Based on Breakpoint Analysis of a Balanced Translocation t(9;17)(q32;q12)

Objective: Identification of the breakpoints of disease-associated chromosome rearrangements can provide informative clues to a positional cloning approach for genes responsible for inherited diseases. Recently, we found a three-generation Japanese family segregating balanced chromosome translocation t(9;17)(q32;q12). One of the subjects had cleft lip and palate. We examined whether regions near the breakpoint could be associated with cleft lip and/or palate. Methods: We determined the breakpoints involved in the translocation by fluorescence in situ hybridization analysis and subsequent long-range polymerase chain reaction. In order to study the role of these disrupted regions in nonsyndromic cleft lip and/or palate, we performed mutation analysis and a haplotype-based transmission disequilibrium test using tagging single-nucleotide polymorphisms in the flanking regions of the breakpoints in white and Filipino nonsyndromic cleft lip and/or palate populations. Results: Sequence analysis demonstrated that two genes, SLC31A1 (solute carrier family 31 member 1) on chromosome 9 and CCL2 (chemokine ligand 2) on chromosome 17, were rearranged with the breaks occurring within their introns. It is interesting that SLC31A1 lies closed to BSPRY (B-box and SPRY domain), which is a candidate for involvement with cleft lip and/or palate. Some of the variants in BSPRY and CCL2 showed significant p values in the cleft lip and/or palate population compared with the control population. There was also statistically significant evidence of transmission distortion for haplotypes on both chromosomes 9 and 17. Conclusions: The data support previous reports that genes on chromosomal regions of 9q and 17q play an important role in facial development.

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Repair of Protruding Bilateral Cleft Lip and Palate With Staged Premaxilla Setback Osteotomy, Cheiloplasty, and Palatoplasty in Trisomy 17p Patient: A Review of Syndromic Clinical Characteristic

The Cleft Palate-Craniofacial Journal ◽

10.1177/10556656211069820 ◽

2021 ◽

pp. 105566562110698

Author(s):

Kristaninta Bangun ◽

Jessica Halim ◽

Vika Tania

Keyword(s):

Cleft Lip ◽

Cleft Lip And Palate ◽

Surgical Techniques ◽

Chromosome 17 ◽

Long Term Effects ◽

Surgical Strategies ◽

Increased Risk ◽

The Cost

Chromosome 17 duplication is correlated with an increased risk of developmental delay, birth defects, and intellectual disability. Here, we reported a female patient with trisomy 17 on the whole short arm with bilateral complete cleft lip and palate (BCLP). This study will review the surgical strategies to reconstruct the protruding premaxillary segment, cleft lip, and palate in trisomy 17p patient. The patient had heterozygous pathogenic duplication of chromosomal region chr17:526-18777088 on almost the entire short arm of chromosome 17. Beside the commonly found features of trisomy 17p, the patient also presented with BCLP with a prominent premaxillary portion. Premaxillary setback surgery was first performed concomitantly with cheiloplasty. The ostectomy was performed posterior to the vomero-premaxillary suture (VPS). The premaxilla was firmly adhered to the lateral segment and the viability of philtral flap was not compromised. Two-flap palatoplasty with modified intravelar veloplasty (IVV) was performed 4 months after. Successful positioning of the premaxilla segment, satisfactory lip aesthetics, and vital palatal flap was obtained from premaxillary setback, primary cheiloplasty, and subsequent palatoplasty in our trisomy 17p patient presenting with BLCP. Postoperative premaxillary stability and patency of the philtral and palatal flap were achieved. Longer follow-up is needed to evaluate the long-term effects of our surgical techniques on inhibition of midfacial growth. However, the benefits that the patient received from the surgery in improving feeding capacity and facial appearance early in life outweigh the cost of possible maxillary retrusion.

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Hypogonadotropic hypogonadism and cleft lip and palate caused by a balanced translocation producing haploinsufficiency for FGFR1

Journal of Medical Genetics ◽

10.1136/jmg.2004.026989 ◽

2005 ◽

Vol 42 (8) ◽

pp. 666-672 ◽

Cited By ~ 38

Author(s):

H. Kim

Keyword(s):

Cleft Lip ◽

Cleft Lip And Palate ◽

Hypogonadotropic Hypogonadism ◽

Balanced Translocation

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Contributions of PTCH Gene Variants to Isolated Cleft Lip and Palate

The Cleft Palate-Craniofacial Journal ◽

10.1597/04-169r.1 ◽

2006 ◽

Vol 43 (1) ◽

pp. 21-29 ◽

Cited By ~ 40

Author(s):

M. A. Mansilla ◽

M. E. Cooper ◽

T. Goldstein ◽

E. E. Castilla ◽

J. S. Lopez Camelo ◽

...

Keyword(s):

Basal Cell Carcinoma ◽

Cell Carcinoma ◽

Basal Cell ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Missense Mutations ◽

Nucleotide Polymorphisms ◽

Normal Variants ◽

Specific Sequence ◽

Orofacial Clefting

Objective Mutations in patched (PTCH) cause the nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin syndrome. Nevoid basal cell carcinoma syndrome may present with developmental anomalies, including rib and craniofacial abnormalities, and predisposes to several tumor types, including basal cell carcinoma and medulloblastoma. Cleft palate is found in 4% of individuals with nevoid basal cell carcinoma syndrome. Because there might be specific sequence alterations in PTCH that limit expression to orofacial clefting, a genetic study of PTCH was undertaken in cases with cleft lip and/or palate (CL/P) known not to have nevoid basal cell carcinoma syndrome. Results Seven new normal variants spread along the entire gene and three missense mutations were found among cases with cleft lip and/or palate. One of these variants (P295S) was not found in any of 1188 control samples. A second variant was found in a case and also in 1 of 1119 controls. The third missense (S827G) was found in 5 of 1369 cases and in 5 of 1104 controls and is likely a rare normal variant. Linkage and linkage desequilibrium also was assessed using normal variants in and adjacent to the PTCH gene in 220 families (1776 individuals), each with two or more individuals with isolated clefting. Although no statistically significant evidence of linkage (multipoint HLOD peak = 2.36) was uncovered, there was borderline evidence of significant transmission distortion for one haplotype of two single nucleotide polymorphisms located within the PTCH gene (p = .08). Conclusion Missense mutations in PTCH may be rare causes of isolated cleft lip and/or palate. An as yet unidentified variant near PTCH may act as a modifier of cleft lip and/or palate.

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A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts

Journal of Dental Research ◽

10.1177/0022034517716914 ◽

2017 ◽

Vol 96 (11) ◽

pp. 1322-1329 ◽

Cited By ~ 22

Author(s):

L.M. Moreno Uribe ◽

T. Fomina ◽

R.G. Munger ◽

P.A. Romitti ◽

M.M. Jenkins ◽

...

Keyword(s):

Multiple Testing ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Association Studies ◽

Total Sample ◽

Population Based ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

European Descent ◽

Oral Clefts

Prior genome-wide association studies for oral clefts have focused on clinic-based samples with unclear generalizability. Prior samples were also small for investigating effects by cleft type and exclusively studied isolated clefts (those occurring without other birth defects). We estimated the effects of 17 top loci on cleft types in both isolated and nonisolated cases in the largest consortium to date of European-descent population-based studies. Our analytic approach focused on a mother-child dyad case-control design, but it also allowed analyzing mother-only or child-only genotypes to maximize power. Our total sample included 1,875 cases with isolated clefts, 459 cases with nonisolated clefts, and 3,749 controls. After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP). Significant associations were observed between isolated CLO and fetal SNPs near TPM1 and NOG1 and between CLP and fetal SNPs at ABCA4-ARHGAP29, THADA, FOXE1, and SPRY2. Overall, effects were similar for isolated CLO and CLP, except for ABCA4-ARHGAP29. A protective effect was observed for the fetal NOG1 SNP on cleft palate only, opposite in direction to the effect on CLO. For most fetal SNPs, a dose-response allelic effect was observed. No evidence of parent-of-origin or maternal genome effects was observed. Overall, effect direction and magnitude were similar between isolated and nonisolated clefts, suggesting that several loci are modifiers of cleft risk in both isolated and nonisolated forms. Our results provide reliable estimates of the effects of top loci on risks of oral clefts in a population of European descent.

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Current concepts in genetics of nonsyndromic clefts

Indian Journal of Plastic Surgery ◽

10.1055/s-0039-1699316 ◽

2009 ◽

Vol 42 (01) ◽

pp. 068-081

Author(s):

Jyotsna Murthy ◽

L. V. K. S. Bhaskar

Keyword(s):

Candidate Genes ◽

Statistical Power ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Genetic Disorder ◽

Cell Signalling ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Complex Genetic Disorder

ABSTRACTNonsyndromic cleft lip and palate is a complex genetic disorder with variable phenotype, largely attributed to the interactions of the environment and multiple genes, each potentially having certain effects. Numerous genes have been reported in studies demonstrating associations and/or linkage of the cleft lip and palate phenotypes to alleles of microsatellite markers and single nucleotide polymorphisms within specific genes that regulate transcription factors, growth factors, cell signalling and detoxification metabolisms. Although the studies reporting these observations are compelling, most of them lack statistical power. This review compiles the evidence that supports linkage and associations to the various genetic loci and candidate genes. Whereas significant progress has been made in the field of cleft lip and palate genetics in the past decade, the role of the genes and genetic variations within the numerous candidate genes that have been found to associate with the expression of the orofacial cleft phenotype remain to be determined.

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Tetrasomy 9p Syndrome in a Filipino Infant

Acta Medica Philippina ◽

10.47895/amp.v54i4.1933 ◽

2020 ◽

Vol 54 (4) ◽

Author(s):

Ebner Bon G. Maceda ◽

Erena S. Kasahara ◽

Edsel Allan G. Salonga ◽

Myrian R. Dela Cruz ◽

Leniza De Castro-Hamoy

Keyword(s):

Chromosomal Abnormality ◽

Congenital Anomalies ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Chromosomal Abnormalities ◽

Chromosome 9 ◽

Palpebral Fissure ◽

Facial Features ◽

Multiple Congenital Anomalies ◽

Common Features

Tetrasomy 9p syndrome is a rare chromosomal abnormality syndrome whose most common features include hypertelorism, malformed ears, bulbous nose and microretrognathia. These features present as a result of an additional two copies of the short arm of chromosome 9. Here we present a neonate with characteristic facial features of hypertelorism, downslanted palpebral fissure, bulbous nose, small cupped ears, cleft lip and palate, and downturned corners of the mouth. Clinical features were consistent with the cytogenetic analysis of tetrasomy 9p. In general, clinicians are not as familiar with the features of tetrasomy 9p syndrome as that of more common chromosomal abnormalities like trisomies 13, 18, and 21. Hence, this case re-emphasizes the importance of doing the standard karyotyping for patients presenting with multiple congenital anomalies. Also, this is the first reported case of Tetrasomy 9p syndrome in Filipinos

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A Family with Craniofrontonasal Syndrome

The Cleft Palate-Craniofacial Journal ◽

10.1597/15-347 ◽

2018 ◽

Vol 55 (7) ◽

pp. 1026-1029 ◽

Cited By ~ 3

Author(s):

Yoshikazu Inoue ◽

Yoshiaki Sakamoto ◽

Masanori Sugimoto ◽

Hidehito Inagaki ◽

Hiroko Boda ◽

...

Keyword(s):

Tyrosine Kinases ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Genetic Disorder ◽

Japanese Family ◽

Eph Receptor ◽

Familial Cases ◽

Bilateral Cleft Lip ◽

Coronal Synostosis ◽

The Common

Craniofrontonasal syndrome (CFNS) is a very rare genetic disorder, the common physical malformations of which include coronal synostosis, widely spaced eyes, clefting of the nasal tip, and various skeletal anomalies. Mutations of EFNB1, which encodes a member of the ephrin family of transmembrane ligands for Eph receptor tyrosine kinases, is the cause of CFNS. Although familial CFNS cases have been reported, no studies in the literature describe familial cases of CFNS expressing bilateral cleft lip and palate. Here, we describe a Japanese family with three cases of CFNS expressing bilateral cleft lip and palate.

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Cystic Dilation of the Aqueductus Sylvii in Case of Trisomy 17p11.2—pter with the Deletion of the Terminal Portion of the Chromosome 6

Case Reports in Medicine ◽

10.1155/2010/354170 ◽

2010 ◽

Vol 2010 ◽

pp. 1-5

Author(s):

Emese Horváth ◽

János Sikovanyecz ◽

Attila Pál ◽

László Kaiser ◽

Bálint L. Bálint ◽

...

Keyword(s):

Intrauterine Growth Retardation ◽

Cleft Lip ◽

Umbilical Artery ◽

Heart Defects ◽

Chromosome 17 ◽

Chromosome 6 ◽

Terminal Portion ◽

Balanced Translocation ◽

Single Umbilical Artery ◽

Intrauterine Growth

Since the 1970s, about 30 cases of partial or complete trisomy 17p have been presented in the literature. Partial trisomies of the short arm of chromosome 17 are somewhat more common, but complete trisomy is quite rare. Most of these cases were described in infants and newborns; and to our knowledge only 3 cases of trisomy 17p have been detected intrauterine. Phenotypic features of trisomy 17p in fetuses are intrauterine growth retardation, ventriculomegaly, cleft lip and cleft palate, micrognathia, horseshoe kidneys, single umbilical artery, and congenital heart defects. The sonographic and foetopathologic findings of a pregnancy trisomy 17p11.2—pter with the deletion of the terminal portion of the chromosome 6 due to paternal balanced translocation are described in this case report.

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A Rare Interstitial Duplication of 8q22.1–8q24.3 Associated with Syndromic Bilateral Cleft Lip/Palate

Case Reports in Dentistry ◽

10.1155/2014/730375 ◽

2014 ◽

Vol 2014 ◽

pp. 1-4 ◽

Cited By ~ 2

Author(s):

Regina Ferreira Rezek ◽

Ana Angélica Rodrigues Abbas ◽

Juliana Forte Mazzeu ◽

Siliana Maria Duarte Miranda ◽

Cibele Velloso-Rodrigues

Keyword(s):

Cleft Lip ◽

Cleft Lip And Palate ◽

Association Studies ◽

Genome Wide Association Studies ◽

Balanced Translocation ◽

Genome Wide ◽

Interstitial Duplication ◽

Bilateral Cleft Lip ◽

Cleft Lip Palate ◽

Balanced Translocations

We present a rare case of 8q interstitial duplication derived from maternal balanced translocations in a patient with bilateral cleft lip and palate in syndromic form associated with other congenital malformations. G-banding cytogenetic analysis revealed a chromosomal abnormality in the form of the karyotype 46,XX der(22)t(8;22)(q22.1;p11.1)mat. Chromosome microarray analysis evidenced a 49 Mb duplicated segment of chromosome 8q with no pathogenic imbalances on chromosome 22. Two siblings also carry the balanced translocation. We have compared this case with other “pure” trisomies of 8q patients reported in the literature and with genome wide association studies recently published. This work highlights the involvement of chromosome 8q in orofacial clefts.

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