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.

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.

Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate.

Nonsyndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome-wide association study (GWAS) using 550 case-parent trios, ascertained through a CP case collected in an international consortium. Family-based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption, and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene-environment (G × E) interaction simultaneously, plus a separate 1 df test for G × E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome-wide significance when considered alone, markers in several genes attained or approached genome-wide significance when G × E interaction was included. Among these, MLLT3 and SMC2 on chromosome 9 showed multiple SNPs resulting in an increased risk if the mother consumed alcohol during the peri-conceptual period (3 months prior to conception through the first trimester). TBK1 on chr. 12 and ZNF236 on chr. 18 showed multiple SNPs associated with higher risk of CP in the presence of maternal smoking. Additional evidence of reduced risk due to G × E interaction in the presence of multivitamin supplementation was observed for SNPs in BAALC on chr. 8. These results emphasize the need to consider G × E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as nonsyndromic CP.

Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts.

We performed a genome wide association analysis of maternally-mediated genetic effects and parent-of-origin (POO) effects on risk of orofacial clefting (OC) using over 2,000 case-parent triads collected through an international cleft consortium. We used log-linear regression models to test individual SNPs. For SNPs with a P-value <10(-5) for maternal genotypic effects, we also applied a haplotype-based method, TRIMM, to extract potential information from clusters of correlated SNPs. None of the SNPs were significant at the genome wide level. Our results suggest neither maternal genome nor POO effects play major roles in the etiology of OC in our sample. This finding is consistent with previous genetic studies and recent population-based cohort studies in Norway and Denmark, which showed no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefting. We, however, cannot completely rule out maternal genome or POO effects as risk factors because very small effects might not be detectable with our sample size, they may influence risk through interactions with environmental exposures or may act through a more complex network of interacting genes. Thus, the most promising SNPs identified by this study may still be worth further investigation.

Rhino-orbital-cerebral mucormycosis (ROCM) and associated cerebritis treated with adjuvant retrobulbar amphotericin B.

PURPOSE: We report a case of rhino-orbital-cerebral mucormycosis (ROCM) with focal anterior cerebritis treated favorably with retrobulbar amphotericin B and systemic antifungals. OBSERVATIONS: A 55-year-old diabetic male presented to the emergency department with left sided proptosis, left temple headache, maxillary sinus pain, and diplopia of 3 days duration. Biopsy results from the left middle turbinate, ethmoid, and maxillary sinus revealed broad and irregular non-septate hyphae consistent with mucormycosis. Despite treatment with intravenous antifungals and endoscopic debridement of the sinuses, his condition did not improve. Disease progression included the development of left ophthalmoplegia and left-sided cerebritis. The patient received retrobulbar injection of deoxycholate amphotericin B with eventual disease resolution, without exenteration. CONCLUSIONS: We present a case of ROCM with associated cerebritis that responded to retrobulbar amphotericin B, without exenteration.

Visual outcomes of high-volume compared with low-volume manual small-incision cataract surgery in Nepal.

PURPOSE: To study whether manual small-incision cataract surgery (MSICS) in a high-volume setting gives acceptable postoperative visual outcomes. SETTINGS: Geta Eye Hospital, Kailali, Nepal. DESIGN: Single-center retrospective study. METHODS: One-year records of all MSICS in adult patients without any other ocular comorbidity were analyzed retrospectively. Surgical outcomes of cataract cases when surgeons performed more than 72 surgeries (high volume) in a single operating session (1 day) were compared with when fewer than 30 surgeries (low volume) were performed in a single operating session (1 day). RESULTS: Of 23 717 cases in the study, 20 574 patients (87%) had preoperative visual acuity of less than 3/60; 15 632 patients (66%) achieved good visual outcome (uncorrected distance visual acuity of 6/18 or better) postoperatively. Patients operated during high-volume months achieved good visual outcomes in 9930 cases (66.9%) as compared with 5702 (64.3%) in low-volume months. However, 6235 patients (61.7%) operated on during high-volume days had good visual outcomes as compared with 3053 (71.4%) during low-volume days; 175 patients in the high-volume group and 73 patients in the low-volume group (1.7% each) achieved visual acuity worse than 3/60. There were comparable posterior capsular rupture rates (423 [1.78%]) during high- and low-volume months, and 21 cases (0.09%) of postoperative endophthalmitis were noted. CONCLUSIONS: MSICS can be used to reduce large cataract backlogs in developing countries as good visual outcomes could be achieved in high-volume settings if standard protocols for quality control are followed.