Further delineation of CDC45-related Meier-Gorlin syndrome with craniosynostosis and review of literature.

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by the triad of short stature, microtia and absent or small patellae. We report on a patient with MGS secondary to biallelic mutations in CDC45 detected on whole exome sequencing (WES). Patients with MGS caused by mutations in CDC45 display a distinct phenotype characterized by craniosynostosis and anorectal malformation. Our patient had craniosynostosis, anorectal malformation and short stature, but did not have the microtia or patella hypoplasia. Our report also highlights the value of WES in aiding diagnosis of patients with rare genetic diseases. In conclusion, our case report and review of the literature illustrates the unique features of CDC45-related MGS as well as the benefits of WES in reducing the diagnostic odyssey for patients with rare genetic disorders.

Breast augmentation surgery using an inframammary fold incision in Southeast Asian women: Patient-reported outcomes.

BACKGROUND: This analysis presents patient-reported outcomes of breast augmentation procedures performed in Singapore using an inframammary fold incision and the "5 Ps" best practice principles for breast augmentation. These data are the first of their kind in Southeast Asian patients. METHODS: Through a retrospective chart review, patients who underwent primary breast augmentation with anatomical form-stable silicone gel breast implants using an inframammary fold incision were followed for ≥6 months postoperatively. The BREAST-Q Augmentation Module (scores standardized to 0 [worst] - 100 [best]) and Patient and Observer Scar Assessment Scale (POSAS; 1 [normal skin] to 10 [worst scar imaginable]) were administered. Responses were summarized using descriptive statistics. Patient-reported events were collected. RESULTS: Twenty-two Southeast Asian patients (mean age, 35.1 years) completed ≥1 postoperative BREAST-Q and POSAS assessment and were assessed 11 months to 5.5 years postoperatively. The mean postoperative BREAST-Q satisfaction with breasts and psychosocial well-being scores were 69.2 and 84.0, respectively. The mean POSAS score for their overall opinion of the scar was 4.2; the mean scores for all scar characteristics ranged from 1.2 to 4.2. Over 90% of patients (20/22) said that they would recommend the procedure. Patient complaints following surgery included anisomastia (possibly pre-existing; n=2), sensory loss at the nipple (n=2) or around the nipple (n=3), scarring (n=4), and slight capsular contracture (n=1). No patients required reoperation. CONCLUSIONS: Southeast Asian patients reported high long-term satisfaction scores on the BREAST-Q scale and with their scar characteristics following breast augmentation using an inframammary fold incision, and nearly all said they would recommend this procedure. No reoperations were necessary in patients assessed for up to 5.5 years postoperatively.

Influence of Bimaxillary Surgery on Pharyngeal Airway in Class III Deformities and Effect on Sleep Apnea: A STOP-BANG Questionnaire and Cone-Beam Computed Tomography Study.

PURPOSE: To evaluate pharyngeal airway space (PAS; nasopharyngeal, oropharyngeal, and total airway) volume and the correlation of an obstructive sleep apnea (OSA) and hypopnea syndrome screening questionnaire (STOP-BANG) with various mandibular setbacks during bimaxillary surgery and compare these findings with an age- and gender-matched skeletal Class I control group. PATIENTS AND METHODS: This retrospective cohort study was composed of patients with skeletal Class III discrepancy who underwent bimaxillary jaw surgery and were assessed with STOP-BANG score, cephalometry, and cone-beam computed tomography (of the PAS). The predictor variable was bimaxillary jaw surgery and included 4-, 6-, and 8-mm setbacks. The primary outcome variables were PAS volume, body mass index, and STOP-BANG score evaluated at 1 week before surgery and after comprehensive orthodontic treatment (11.25 ± 1.95 months). Other variables were grouped into the following categories: demographic and cephalometric parameters. Statistical intragroup and intergroup differences were assessed by paired t and independent t tests (P < .05), respectively. RESULTS: The study sample was composed of 48 patients (18 to 25 yr old); group I received 4-mm setback (n = 16), group II received 6-mm setback (n = 16), and group III received 8-mm setback (n = 16) mandibular surgery, and all test groups received 4-mm maxillary advancement. The entire study group was compared with a skeletal Class I control group (n = 16). The total PAS volume after orthodontic treatment in groups I and II showed a significant decrease compared with the presurgical PAS (P < .001), but the decrease was not less than that in the control group (P > .05). In contrast, the total PAS volume in group III after orthodontic treatment (23,574 ± 1,394 mm3) was less than that in the control group (23,884 ± 1,543 mm3). CONCLUSION: After surgery, patients with Class III discrepancy exhibited a decrease in oropharynx volume; however, the STOP-BANG score showed no change in risk factors scores for OSA at 4- to 8-mm setback surgery of the mandible in bimaxillary jaw surgery.

Comparative Evaluation of the Pharyngeal Airway Space in Unilateral and Bilateral Cleft Lip and Palate Individuals With Noncleft Individuals: A Cone Beam Computed Tomography Study.

OBJECTIVE: To evaluate the pharyngeal airway space changes in complete unilateral cleft lip and palate (UCLP) and bilateral cleft lip and palate (BCLP) individuals, and compare with age and sex-matched noncleft (NC) control subjects. DESIGN: Retrospective study. SETTING: Cleft and Craniofacial Centre, KK Women's and Children's Hospital, Singapore. MATERIALS AND METHODS: Twenty UCLP (mean age: 13.4 ± 0.5 years), 18 BCLP (mean age: 13.5 ± 0.5 years) and 20 skeletal Class I subjects (mean age: 13.4 ± 0.6 years) were included in the study. Cone beam computed tomography scans were assessed for pharyngeal airway space (PAS) (oropharyngeal, nasopharyngeal, total airway space volume), and compared with PAS of age and sex-matched skeletal Class I NC individuals. RESULTS: Pharyngeal airway space showed statistically significant differences in the UCLP, BCLP, and NC control subjects. Oropharyngeal (9338 ± 1108 mm3, P < .05), nasopharyngeal (2911 ± 401 mm3, P < .05), and total airway space (12 250 ± 1185 mm3, P < .05) volumes of BCLP individuals showed significant reduction in comparison to UCLP and NC. There were no gender differences of PAS in any of the groups tested (P > .05). CONCLUSION: The pharyngeal airway space was significantly reduced in the BCLP group than were those in UCLP and control groups. This reduced PAS should be taken into account when planning treatment for these individuals.

Orthodontic-orthognathic interventions in orthognathic surgical cases: "Paper surgery" and "model surgery" concepts in surgical orthodontics.

Thorough planning and execution is the key for successful treatment of dentofacial deformity involving surgical orthodontics. Presurgical planning (paper surgery and model surgery) are the most essential prerequisites of orthognathic surgery, and orthodontist is the one who carries out this procedure by evaluating diagnostic aids such as crucial clinical findings and radiographic assessments. However, literature pertaining to step-by-step orthognathic surgical guidelines is limited. Hence, this article makes an attempt to provide an insight and nuances involved in the planning and execution. The diagnostic information revealed from clinical findings and radiographic assessments is integrated in the "paper surgery" to establish "surgical-plan." Furthermore, the "paper surgery" is emulated in "model surgery" such that surgical bite-wafers are created, which aid surgeon to preview the final outcome and make surgical movements that are deemed essential for the desired skeletal and dental outcomes. Skeletal complexities are corrected by performing "paper surgery" and an occlusion is set up during "model surgery" for the fabrication of surgical bite-wafers. Further, orthodontics is carried out for the proper settling and finishing of occlusion. Article describes the nuances involved in the treatment of Class III skeletal deformity individuals treated with orthognathic surgical approach and illustrates orthodontic-orthognathic step-by-step procedures from "treatment planning" to "execution" for successful management of aforementioned dentofacial deformity.

Novel evidence of association with nonsyndromic cleft lip with or without cleft palate was shown for single nucleotide polymorphisms in FOXF2 gene in an Asian population.

BACKGROUND: The forkhead box F2 gene (FOXF2) located in chromosome 6p25.3 has been shown to play a crucial role in palatal development in mouse and rat models. To date, no evidence of linkage or association has been reported for this gene in humans with oral clefts. METHODS: Allelic transmission disequilibrium tests were used to robustly assess evidence of linkage and association with nonsyndromic cleft lip with or without cleft palate for nine single nucleotide polymorphisms (SNPs) in and around FOXF2 in both Asian and European trios using PLINK. RESULTS: Statistically significant evidence of linkage and association was shown for two SNPs (rs1711968 and rs732835) in 216 Asian trios where the empiric P values with permutation tests were 0.0016 and 0.005, respectively. The corresponding estimated odds ratios for carrying the minor allele at these SNPs were 2.05 (95% confidence interval = 1.41, 2.98) and 1.77 (95% confidence interval = 1.26, 2.49), respectively. CONCLUSION: Our results provided statistical evidence of linkage and association between FOXF2 and nonsyndromic cleft lip with or without cleft palate.

Results of Primary Repair of Submucous Cleft Palate With Furlow Palatoplasty in Both Syndromic and Nonsyndromic Children.

OBJECTIVE: We hypothesize that primary repair of submucous cleft palate (SMCP) with Furlow palatoplasty will not lead to significant differences in speech outcomes for syndromic and nonsyndromic children. DESIGN: Retrospective analysis of patients with primary Furlow repair of SMCP between 2004 and 2012. SETTING: Tertiary care center. PATIENTS/PARTICIPANTS: Thirty-four patients (15 boys; 44%) satisfied our inclusion criteria: multidisciplinary consensus on diagnosis of SMCP, failed trial of speech-language rehabilitation, at least 4 years old at the time of primary surgery, at least 6 months follow-up with a repeat set of postoperative speech assessments. INTERVENTIONS: Primary Furlow palatoplasty for SMCP. MAIN OUTCOME MEASURES: Primary outcomes were based on postoperative perceptual speech assessments and the need for revision surgery. Secondary outcomes included improvement in nasalance scores, postoperative complications, and change in and time to normalization of velar closing ratios. RESULTS: Mean age at surgery = 7.7 years. Of the patients, 17 (50%) were syndromic and 11 (32%) had associated hearing loss. Mean follow-up = 48 months. No patients had postoperative complications, such as wound dehiscence or fistula; however, two patients (one syndromic, one nonsyndromic) required secondary procedures. Velar closing ratios for all patients increased (P < .05) and approached normal at an average of 1.3 years postoperatively. CONCLUSIONS: Although the Furlow palatoplasty can correct anatomic anomalies, it cannot achieve normal perceptual resonance in syndromic patients, possibly because of inherent higher-order deficiencies that affect speech production. Further studies with greater patient numbers are necessary to achieve population statistical significance.

Joint testing of genotypic and gene-environment interaction identified novel association for BMP4 with non-syndromic CL/P in an Asian population using data from an International Cleft Consortium.

BACKGROUND: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common disorder with complex etiology. The Bone Morphogenetic Protein 4 gene (BMP4) has been considered a prime candidate gene with evidence accumulated from animal experimental studies, human linkage studies, as well as candidate gene association studies. The aim of the current study is to test for linkage and association between BMP4 and NSCL/P that could be missed in genome-wide association studies (GWAS) when genotypic (G) main effects alone were considered. METHODOLOGY/PRINCIPAL FINDINGS: We performed the analysis considering G and interactions with multiple maternal environmental exposures using additive conditional logistic regression models in 895 Asian and 681 European complete NSCL/P trios. Single nucleotide polymorphisms (SNPs) that passed the quality control criteria among 122 genotyped and 25 imputed single nucleotide variants in and around the gene were used in analysis. Selected maternal environmental exposures during 3 months prior to and through the first trimester of pregnancy included any personal tobacco smoking, any environmental tobacco smoke in home, work place or any nearby places, any alcohol consumption and any use of multivitamin supplements. A novel significant association held for rs7156227 among Asian NSCL/P and non-syndromic cleft lip and palate (NSCLP) trios after Bonferroni correction which was not seen when G main effects alone were considered in either allelic or genotypic transmission disequilibrium tests. Odds ratios for carrying one copy of the minor allele without maternal exposure to any of the four environmental exposures were 0.58 (95%CI = 0.44, 0.75) and 0.54 (95%CI = 0.40, 0.73) for Asian NSCL/P and NSCLP trios, respectively. The Bonferroni P values corrected for the total number of 117 tested SNPs were 0.0051 (asymptotic P = 4.39*10(-5)) and 0.0065 (asymptotic P = 5.54*10(-5)), accordingly. In European trios, no significant association was seen for any SNPs after Bonferroni corrections for the total number of 120 tested SNPs. CONCLUSIONS/SIGNIFICANCE: Our findings add evidence from GWAS to support the role of BMP4 in susceptibility to NSCL/P originally identified in linkage and candidate gene association studies.

Hearing Loss in Newborns with Cleft Lip and/or Palate.

INTRODUCTION: This study aims to review the results of hearing screens in newborns with cleft deformities. MATERIALS AND METHODS: A retrospective audit of 123 newborns with cleft deformities, born between 1 April 2002 and 1 December 2008, was conducted. Data on the results of universal newborn hearing screens (UNHS) and high-risk hearing screens, age at diagnosis, severity/type of hearing loss and mode of intervention were obtained from a prospectively maintained hearing database. RESULTS: Thirty-one of 123 newborns (25.2%) failed the first automated auditory brainstem response (AABR). Seventy percent of infants (56 out of 80) who passed the UNHS failed the high-risk hearing screens which was conducted at 3 to 6 months of age. Otolaryngology referral rate was 67.5% (83/123); 90.3% of 31 newborns who failed the first AABR eventually required otolaryngology referrals. Incidence of hearing loss was 24.4% (30/123; 25 conductive, 2 mixed and 3 sensorineural), significantly higher than the hospital incidence of 0.3% (OR: 124.9, 95% CI, 81.1 to 192.4, P <0.01). In terms of severity, 8 were mild, 15 moderate, 5 severe, 2 profound. Eighteen out of 30 infants (60%) were detected from the high-risk hearing screens after passing the first AABR. CONCLUSION: These newborns had a higher risk of failing the UNHS and high-risk hearing screen. There was a higher incidence of hearing loss which was mainly conductive. Failure of the first AABR was an accurate predictor of an eventual otolaryngology referral, suggesting that a second AABR may be unnecessary. High-risk hearing screens helped to identify hearing loss which might have been missed out early on in life or which might have evolved later in infancy.

Repair of inferior sternal cleft using bilateral sternal bar turnover flaps in a patient with pentalogy of cantrell.

We report a case of sternal reconstruction using bilateral sternal bar turnover flaps in a 4-year-old boy with an inferior sternal cleft, as part of Cantrell's pentad. When the patient was 10 months old, he underwent sternal reconstruction using a resorbable poly-L-lactic-polyglycolic acid plate in the first stage when there was insufficient autogenous tissue to provide a reliable reconstruction. Bilateral sternal bar turnover was performed in the second stage at 4 years of age. This operative technique is described in this report. This novel technique provides a robust, dynamic, and reliable reconstruction for inferior sternal defects.

Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate.

Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10(-6)

High Le Fort I and bilateral split sagittal osteotomy in Crouzon syndrome.

Crouzon syndrome is a rare, autosomal dominant disease from a fibroblast growth factor receptor 2 gene mutation, characterized by premature craniosynostosis, hypertelorism, orbital proptosis, psittichorina, hypoplastic maxilla, and mandibular prognathism. We present an adult 32-year-old Crouzon syndrome patient who underwent an elective High Le Fort I and bilateral split sagittal osteotomy for midface advancement with a background of jaw malocclusion and obstructive respiratory symptoms. The operation features a potential dynamic movement of the secured airway in the surgical field and close proximity to exposed ocular structures. Permissive hypotensive anesthesia was employed to improve the surgical field and reduce intraoperative blood loss and dose of long-acting opioids. He was extubated at the end of an uneventful surgery and was monitored in the high dependency overnight before he was discharged to the general ward. Perioperative issues include potential difficult airway management; ocular, auditory, and neurological injury prevention; surgery-specific anesthetic technique; and postoperative analgesia. Understanding the multisystemic issues facilitates the dynamic anesthetic management during surgery. Good communication among the multidisciplinary team is essential to ensure a successful operation and uneventful recovery.

X-linked markers in the Duchenne muscular dystrophy gene associated with oral clefts.

As part of an international consortium, case-parent trios were collected for a genome-wide association study of isolated, non-syndromic oral clefts, including cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP). Non-syndromic oral clefts have a complex and heterogeneous etiology. Risk is influenced by genes and environmental factors, and differs markedly by gender. Family-based association tests (FBAT) were used on 14,486 single nucleotide polymorphisms (SNPs) spanning the X chromosome, stratified by type of cleft and racial group. Significant results, even after multiple-comparisons correction, were obtained for the Duchenne muscular dystrophy (DMD) gene, the largest single gene in the human genome, among CL/P (i.e., both CL and CLP combined) trios. When stratified into groups of European and Asian ancestry, stronger signals were obtained for Asian subjects. Although conventional sliding-window haplotype analysis showed no increase in significance, selected combinations of the 25 most significant SNPs in the DMD gene identified four SNPs together that attained genome-wide significance among Asian CL/P trios, raising the possibility of interaction between distant SNPs within the DMD gene.

Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations.

ATP-binding cassette (ABC) proteins in the placenta regulate fetal exposure to xenobiotics. We hypothesized that functional polymorphisms in ABC genes influence risk for non-syndromic oral clefts (NSOC). Both family-based and case-control studies were undertaken to evaluate the association of nine potentially functional single-nucleotide polymorphisms within four ABC genes with risk of NSOC. Peripheral blood DNA from a total of 150 NSOC case-parent trios from Singapore and Taiwan were genotyped, as was cord blood DNA from 189 normal Chinese neonates used as controls. In trios, significant association was observed between the ABCB1 single-nucleotide polymorphisms and NSOC (P<0.05). Only ABCB1 rs1128503 retained significant association after Bonferroni correction (odds ratio (OR)=2.04; 95% confidence interval (CI)=1.42-2.98), while rs2032582 and rs1045642 showed nominal significance. Association with rs1128503 was replicated in a case-control analysis comparing NSOC probands with controls (OR=1.58; 95% CI=1.12-2.23). A comparison between the mothers of probands and controls showed no evidence of association, suggesting NSOC risk is determined by fetal and not maternal ABCB1 genotype. The two studies produced a combined OR of 1.79 (95% CI=1.38-2.30). The T-allele at rs1128503 was associated with higher risk. This study thus provides evidence that potentially functional polymorphisms in fetal ABCB1 modulate risk for NSOC, presumably through suboptimal exclusion of xenobiotics at the fetal-maternal interface.

The FGF and FGFR Gene Family and Risk of Cleft Lip With or Without Cleft Palate.

Background : Isolated, nonsyndromic cleft lip with or without cleft palate is a common human congenital malformation with a complex and heterogeneous etiology. Genes coding for fibroblast growth factors and their receptors (FGF/FGFR genes) are excellent candidate genes. Methods : We tested single-nucleotide polymorphic markers in 10 FGF/FGFR genes (including FGFBP1, FGF2, FGF10, FGF18, FGFR1, FGFR2, FGF19, FGF4, FGF3, and FGF9) for genotypic effects, interactions with one another, and with common maternal environmental exposures in 221 Asian and 76 Maryland case-parent trios ascertained through a child with isolated, nonsyndromic cleft lip with or without cleft palate. Results : Both FGFR1 and FGF19 yielded evidence of linkage and association in the transmission disequilibrium test, confirming previous evidence. Haplotypes of three single-nucleotide polymorphisms in FGFR1 were nominally significant among Asian trios. Estimated odds ratios for individual single-nucleotide polymorphic markers and haplotypes of multiple markers in FGF19 ranged from 1.31 to 1.87. We also found suggestive evidence of maternal genotypic effects for markers in FGF2 and FGF10 among Asian trios. Tests for gene-environment (G × E) interaction between markers in FGFR2 and maternal smoking or multivitamin supplementation yielded significant evidence of G × E interaction separately. Tests of gene-gene (G × G) interaction using Cordell's method yielded significant evidence between single-nucleotide polymorphisms in FGF9 and FGF18, which was confirmed in an independent sample of trios from an international consortium. Conclusion : Our results suggest several genes in the FGF/FGFR family may influence risk for isolated, nonsyndromic cleft lip with or without cleft palate through distinct biological mechanisms.

Repair of ectopia cordis using a resorbable poly-L-lactic-polyglycolic acid plate in a patient with pentalogy of Cantrell.

We present a case of a 10-month-old male infant with thoracoabdominal ectopia cordis, as part of Cantrell pentad, repaired using a poly-L-lactic-polyglycolic acid plate, a resorbable plating system widely used in craniomaxillofacial reconstruction. This is the first reported case of sternal reconstruction using a poly-L-lactic-polyglycolic acid plate. The repair was successfully carried out without cardiopulmonary compromise and good aesthetic outcome was achieved.

Examining markers in 8q24 to explain differences in evidence for association with cleft lip with/without cleft palate between Asians and Europeans.

In a recent genome-wide association study (GWAS) from an international consortium, evidence of linkage and association in chr8q24 was much stronger among nonsyndromic cleft lip/palate (CL/P) case-parent trios of European ancestry than among trios of Asian ancestry. We examined marker information content and haplotype diversity across 13 recruitment sites (from Europe, United States, and Asia) separately, and conducted principal components analysis (PCA) on parents. As expected, PCA revealed large genetic distances between Europeans and Asians, and a north-south cline from Korea to Singapore in Asia, with Filipino parents forming a somewhat distinct Southeast Asian cluster. Hierarchical clustering of SNP heterozygosity revealed two major clades consistent with PCA results. All genotyped SNPs giving P < 10(-6) in the allelic transmission disequilibrium test (TDT) showed higher heterozygosity in Europeans than Asians. On average, European ancestry parents had higher haplotype diversity than Asians. Imputing additional variants across chr8q24 increased the strength of statistical evidence among Europeans and also revealed a significant signal among Asians (although it did not reach genome-wide significance). Tests for SNP-population interaction were negative, indicating the lack of strong signal for 8q24 in families of Asian ancestry was not due to any distinct genetic effect, but could simply reflect low power due to lower allele frequencies in Asians.

ROR2 gene is associated with risk of non-syndromic cleft palate in an Asian population.

BACKGROUND: The receptor tyrosine kinase-like orphan receptor 2 (ROR2) gene has been recently shown to play important roles in palatal development in animal models and resides in the chromosomal region linked to non syndromic cleft lip with or without cleft palate in humans. The aim of this study was to investigate the possible association between ROR2 gene and non-syndromic oral clefts. METHODS: Here we tested 38 eligible single-nucleotide polymorphisms (SNPs) in ROR2 gene in 297 non-syndromic cleft lip with or without cleft palate and in 82 non-syndromic cleft palate case parent trios recruited from Asia and Maryland. Family Based Association Test was used to test for deviation from Mendelian inheritance. Plink software was used to test potential parent of origin effect. Possible maternally mediated in utero effects were assessed using the TRIad Multi-Marker approach under an assumption of mating symmetry in the population. RESULTS: Significant evidence of linkage and association was shown for 3 SNPs (rs7858435, rs10820914 and rs3905385) among 57 Asian non-syndromic cleft palate trios in Family Based Association Tests. P values for these 3 SNPs equaled to 0.000068, 0.000115 and 0.000464 respectively which were all less than the significance level (0.05/38 = 0.0013) adjusted by strict Bonferroni correction. Relevant odds ratios for the risk allele were 3.42 (1.80 - 6.50), 3.45 (1.75 - 6.67) and 2.94 (1.56 - 5.56), respectively. Statistical evidence of linkage and association was not shown for study groups other than non-syndromic cleft palate. Neither evidence for parent-of-origin nor maternal genotypic effect was shown for any of the ROR2 markers in our analysis for all study groups. CONCLUSION: Our results provided evidence of linkage and association between the ROR2 gene and a gene controlling risk to non-syndromic cleft palate.

BMP4 was associated with NSCL/P in an Asian population.

BACKGROUND: The Bone Morphogenetic Protein 4 gene (BMP4) is located in chromosome 14q22-q23 which has shown evidence of linkage for isolated nonsyndromic cleft lip with or without cleft palate (NSCL/P) in a genome wide linkage analysis of human multiplex families. BMP4 has been shown to play crucial roles in lip and palatal development in animal models. Several candidate gene association analyses also supported its potential risk for NSCL/P, however, results across these association studies have been inconsistent. The aim of the current study was to test for possible association between markers in and around the BMP4 gene and NSCL/P in Asian and Maryland trios. METHODOLOGY/PRINCIPAL FINDINGS: Family Based Association Test was used to test for deviation from Mendelian assortment for 12 SNPs in and around BMP4. Nominal significant evidence of linkage and association was seen for three SNPs (rs10130587, rs2738265 and rs2761887) in 221 Asian trios and for one SNP (rs762642) in 76 Maryland trios. Statistical significance still held for rs10130587 after Bonferroni correction (corrected p = 0.019) among the Asian group. Estimated odds ratio for carrying the apparent high risk allele at this SNP was 1.61 (95%CI = 1.20, 2.18). CONCLUSIONS: Our results provided further evidence of association between BMP4 and NSCL/P.