Mothers of children with Down syndrome: a clinical and epidemiological study.

Down syndrome is the main genetic cause of intellectual disability. Many studies describe the clinical characteristics of DS patients; however, few have investigated the clinical profile of mothers who have children with DS. Advanced maternal age (≥ 35 years old) is a risk factor for DS. Although there is an overall increase in pregnancies among women with advanced maternal age, there is still a lack of awareness of the increased risk of aneuploidy. Here, we reported the clinical and epidemiological profile of DS children and their mothers in a public reference hospital in the State of Rio de Janeiro, Brazil. For data collection, we performed a face-to-face interview guided by a structured questionnaire with closed-ended questions. A total of 344 individuals, 172 mothers and their DS children, were included in this study. Our results show that 56% of the mothers sampled were ≥ 35 years of age at childbirth. Although 98% of them received prenatal care, only 4% obtained a prenatal diagnosis of DS. Most mothers reported not drinking alcohol or smoking cigarettes during pregnancy. Furthermore, 91% of women took prenatal vitamins and supplements; however, 47% were not aware of their benefits for a healthy pregnancy. Given the strict correlation between advanced maternal age and DS, prenatal care should include genetic counseling for women over 35 years of age. This study highlights the importance of prenatal care and the urgent need for better DS screening allowing for immediate postnatal care, positively impacting the life expectancy of these patients.

The legacy of ZikaPLAN: a transnational research consortium addressing Zika.

Global health research partnerships with institutions from high-income countries and low- and middle-income countries are one of the European Commission's flagship programmes. Here, we report on the ZikaPLAN research consortium funded by the European Commission with the primary goal of addressing the urgent knowledge gaps related to the Zika epidemic and the secondary goal of building up research capacity and establishing a Latin American-European research network for emerging vector-borne diseases. Five years of collaborative research effort have led to a better understanding of the full clinical spectrum of congenital Zika syndrome in children and the neurological complications of Zika virus infections in adults and helped explore the origins and trajectory of Zika virus transmission. Individual-level data from ZikaPLAN`s cohort studies were shared for joint analyses as part of the Zika Brazilian Cohorts Consortium, the European Commission-funded Zika Cohorts Vertical Transmission Study Group, and the World Health Organization-led Zika Virus Individual Participant Data Consortium. Furthermore, the legacy of ZikaPLAN includes new tools for birth defect surveillance and a Latin American birth defect surveillance network, an enhanced Guillain-Barre Syndrome research collaboration, a de-centralized evaluation platform for diagnostic assays, a global vector control hub, and the REDe network with freely available training resources to enhance global research capacity in vector-borne diseases.

ZikaPLAN: addressing the knowledge gaps and working towards a research preparedness network in the Americas.

Zika Preparedness Latin American Network (ZikaPLAN) is a research consortium funded by the European Commission to address the research gaps in combating Zika and to establish a sustainable network with research capacity building in the Americas. Here we present a report on ZikaPLAN`s mid-term achievements since its initiation in October 2016 to June 2019, illustrating the research objectives of the 15 work packages ranging from virology, diagnostics, entomology and vector control, modelling to clinical cohort studies in pregnant women and neonates, as well as studies on the neurological complications of Zika infections in adolescents and adults. For example, the Neuroviruses Emerging in the Americas Study (NEAS) has set up more than 10 clinical sites in Colombia. Through the Butantan Phase 3 dengue vaccine trial, we have access to samples of 17,000 subjects in 14 different geographic locations in Brazil. To address the lack of access to clinical samples for diagnostic evaluation, ZikaPLAN set up a network of quality sites with access to well-characterized clinical specimens and capacity for independent evaluations. The International Committee for Congenital Anomaly Surveillance Tools was formed with global representation from regional networks conducting birth defects surveillance. We have collated a comprehensive inventory of resources and tools for birth defects surveillance, and developed an App for low resource regions facilitating the coding and description of all major externally visible congenital anomalies including congenital Zika syndrome. Research Capacity Network (REDe) is a shared and open resource centre where researchers and health workers can access tools, resources and support, enabling better and more research in the region. Addressing the gap in research capacity in LMICs is pivotal in ensuring broad-based systems to be prepared for the next outbreak. Our shared and open research space through REDe will be used to maximize the transfer of research into practice by summarizing the research output and by hosting the tools, resources, guidance and recommendations generated by these studies. Leveraging on the research from this consortium, we are working towards a research preparedness network.

ZikaPLAN: addressing the knowledge gaps and working towards a research preparedness network in the Americas

Zika Preparedness Latin American Network (ZikaPLAN) is a research consortium funded by the European Commission to address the research gaps in combating Zika and to establish a sustainable network with research capacity building in the Americas. Here we present a report on ZikaPLAN's mid-term achievements since its initiation in October 2016 to June 2019, illustrating the research objectives of the 15 work packages ranging from virology, diagnostics, entomology and vector control, modelling to clinical cohort studies in pregnant women and neonates, as well as studies on the neurological complications of Zika infections in adolescents and adults. For example, the Neuroviruses Emerging in the Americas Study (NEAS) has set up more than 10 clinical sites in Colombia. Through the Butantan Phase 3 dengue vaccine trial, we have access to samples of 17,000 subjects in 14 different geographic locations in Brazil. To address the lack of access to clinical samples for diagnostic evaluation, ZikaPLAN set up a network of quality sites with access to well-characterized clinical specimens and capacity for independent evaluations. The International Committee for Congenital Anomaly Surveillance Tools was formed with global representation from regional networks conducting birth defects surveillance. We have collated a comprehensive inventory of resources and tools for birth defects surveillance, and developed an App for low resource regions facilitating the coding and description of all major externally visible congenital anomalies including congenital Zika syndrome. Research Capacity Network (REDe) is a shared and open resource centre where researchers and health workers can access tools, resources and support, enabling better and more research in the region. Addressing the gap in research capacity in LMICs is pivotal in ensuring broad-based systems to be prepared for the next outbreak. Our shared and open research space through REDe will be used to maximize the transfer of research into practice by summarizing the research output and by hosting the tools, resources, guidance and recommendations generated by these studies. Leveraging on the research from this consortium, we are working towards a research preparedness network.

ICD-10 impact on ascertainment and accuracy of oral cleft cases as recorded by the Brazilian national live birth information system.

We compared Brazilian oral cleft (OC) frequencies between the population-based Brazilian System of Live Birth (SINASC) and the hospital-based Latin American Collaborative Study of Congenital Malformations (ECLAMC), trying to understand the paucity of cleft of lip and palate (CLP) in the first system. SINASC uses the International Classification of Disease version 10 (ICD-10) for congenital defects coding, ECLAMC uses ICD-8 with modifications. In SINASC, the CLP frequency was 1.7 per 10,000 (95% confidence limits 1.7-1.8), cleft lip (CL) 1.6 (1.5-1.7), and cleft palate (CP) 2.0 (1.9-2.1). In ECLAMC, the CLP frequency was 10.4 per 10,000 (9.0-12.1), CL 5.5 (4.5-6.7), and CP 4.4. (4.5-6.7). In SINASC, only 33% of the oral clefts were CLP, versus 51% in ECLAMC. Part of this discrepancy may have been due to the relative excess of CP and CL cases. Although congenital defect frequencies are usually lower in population than in hospital-based registries, differences in the proportion of the main OC categories are not expected and are probably due to ICD-10 coding issues, such as lumping of unilateral CL and CL without other specifications. ICD-10 codes, whose deficiency for oral clefts is fully explained in the literature, lack modifiers for severity, or clinical subtypes. This paper shows the practical aspect of the ICD-10 system deficiency in capturing cleft lip and palate (CLP) subtypes, as demonstrated in SINASC covering three million births per year. Such errors are expected to occur in any registry that uses the ICD-10 coding system, and must be adjusted, given its relevance worldwide.

PVR/CD155 Ala67Thr Mutation and Cleft Lip/Palate.

The 19q13 locus has been linked to cleft lip and palate by our group and independently by others. Here we fine mapped the region in an attempt to identify an etiological variant that can explain cleft lip and palate occurrence. A total of 2739 individuals born with cleft lip and palate, related to individuals born with cleft lip and palate, and unrelated were studied. We used linkage and association approaches to fine map the interval between D19S714 and D19S433 and genotypes were defined by the use of TaqMan chemistry. We confirmed our previous findings that markers in PVR/CD155 are associated with cleft lip and palate. We studied the mutation Ala67Thr further and calculated its penetrance. We also attempted to detect PVR/CD155 expression in human whole saliva. Our results showed that markers in PVR/CD155 are associated with cleft lip and palate and the penetrance of the Ala67Thr is very low (between 1% and 5%). We could not detect PVR/CD155 expression in adult human whole saliva and PVR/CD155 possibly interacts with maternal infection to predispose children to cleft lip only.

Third molar agenesis as a potential marker for craniofacial deformities.

The identification of clinical patterns of tooth agenesis in individuals born with craniofacial deformities may be a useful tool for risk determination of these defects. We hypothesize that specific craniofacial deformities are associated with third molar agenesis. OBJECTIVE: The aim of this study was to identify if third molar agenesis could have a relation with other craniofacial structure alterations, such as cleft lip and palate, skeletal malocclusion, or specific growth patterns in humans. DESIGN: Data were obtained from 550 individuals ascertained as part of studies aiming to identify genetic contributions to oral clefts. 831 dental records of patients aged over eight years seeking orthodontic treatment were also included. SN-GoGn angle were used to classify the growth pattern (hypo-divergent, normal and hyper-divergent), and the ANB angle was used to verify the skeletal malocclusion pattern (Class I, II and III). Panoramic radiographs were used to determine third molar agenesis. RESULTS: A high frequency of third molar agenesis among individuals born with cleft lip with or without cleft palate (55%), as well as among their relatives (93.5%) was found. Third molar agenesis was not associated to skeletal malocclusion or growth pattern. CONCLUSION: It appears that third molar agenesis is associated with the disturbances that lead to cleft lip and palate.

Prevalence and clinical profile of microcephaly in South America pre-Zika, 2005-14: prevalence and case-control study.

Objective To describe the prevalence and clinical spectrum of microcephaly in South America for the period 2005-14, before the start of the Zika epidemic in 2015, as a baseline for future surveillance as the Zika epidemic spreads and as other infectious causes may emerge in future.Design Prevalence and case-control study.Data sources ECLAMC (Latin American Collaborative Study of Congenital Malformations) database derived from 107 hospitals in 10 South American countries, 2005 to 2014. Data on microcephaly cases, four non-malformed controls per case, and all hospital births (all births for hospital based prevalence, resident within municipality for population based prevalence). For 2010-14, head circumference data were available and compared with Intergrowth charts.Results 552 microcephaly cases were registered, giving a hospital based prevalence of 4.4 (95% confidence interval 4.1 to 4.9) per 10 000 births and a population based prevalence of 3.0 (2.7 to 3.4) per 10 000. Prevalence varied significantly between countries and between regions and hospitals within countries. Thirty two per cent (n=175) of cases were prenatally diagnosed; 29% (n=159) were perinatal deaths. Twenty three per cent (n=128) were associated with a diagnosed genetic syndrome, 34% (n=189) polymalformed without a syndrome diagnosis, 12% (n=65) with associated neural malformations, and 26% (n=145) microcephaly only. In addition, 3.8% (n=21) had a STORCH (syphilis, toxoplasmosis, other including HIV, rubella, cytomegalovirus, and herpes simplex) infection diagnosis and 2.0% (n=11) had consanguineous parents. Head circumference measurements available for 184/235 cases in 2010-14 showed 45% (n=82) more than 3 SD below the mean, 24% (n=44) between 3 SD and 2 SD below the mean, and 32% (n=58) larger than -2 SD.Conclusion Extrapolated to the nearly 7 million annual births in South America, an estimated 2000-2500 microcephaly cases were diagnosed among births each year before the Zika epidemic began in 2015. Clinicians are using more than simple metrics to make microcephaly diagnoses. Endemic infections are important enduring causes of microcephaly.

Analysis of the genetic ancestry of patients with oral clefts from South American admixed populations.

Increased susceptibility to cleft lip, with or without cleft palate (CL±P) has been observed in South America, as related to Amerindian ancestry, using epidemiological data, uniparental markers, and blood groups. In this study, it was evaluated whether this increased risk remains when Amerindian ancestry is estimated using autosomal markers and considered in the predictive model. Ancestry was estimated through genotyping 62 insertion and deletion (INDEL) markers in sample sets of patients with CL±P, patients with cleft palate (CP), and controls, from Patagonia in southern Argentina and Belém in northern Brazil. The Amerindian ancestry in patients from Patagonia with CL±P was greater than in controls although it did not reach statistical significance. The European ancestry in patients with CL±P from Belém and in patients with CP from Belém and Patagonia was higher than in controls and statistically significant for patients with CP who were from Belém. This high contribution of European genetic ancestry among patients with CP who were from Belém has not been previously observed in American populations. Our results do not corroborate the currently accepted risks for CL±P and CP estimated by epidemiological studies in the North American populations and probably reflect the higher admixture found in South American ethnic groups when compared with the same ethnic groups from the North American populations.

Family-based genome-wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate.

The etiology of cleft lip with or without cleft palate (CL±P) is complex and heterogeneous, and multiple genetic and environmental factors are involved. Some candidate genes reported to be associated with oral clefts are located on the X chromosome. At least three genes causing X-linked syndromes [midline 1 (MID1), oral-facial-digital syndrome 1 (OFD1), and dystrophin (DMD)] were previously found to be associated with isolated CL±P. We attempted to confirm the role of X-linked genes in the etiology of isolated CL±P in a South American population through a family-based genome-wide scan. We studied 27 affected children and their mothers, from 26 families, in a Patagonian population with a high prevalence of CL±P. We conducted an exploratory analysis of the X chromosome to identify candidate regions associated with CL±P. Four genomic segments were identified, two of which showed a statistically significant association with CL±P. One is an 11-kb region of Xp21.1 containing the DMD gene, and the other is an intergenic region (8.7 kb; Xp11.4). Our results are consistent with recent data on the involvement of the DMD gene in the etiology of CL±P. The MID1 and OFD1 genes were not included in the four potential CL±P-associated X-chromosome genomic segments.

Genealogical data in population medical genetics: Field guidelines.

This is a guide for fieldwork in Population Medical Genetics research projects. Data collection, handling, and analysis from large pedigrees require the use of specific tools and methods not widely familiar to human geneticists, unfortunately leading to ineffective graphic pedigrees. Initially, the objective of the pedigree must be decided, and the available information sources need to be identified and validated. Data collection and recording by the tabulated method is advocated, and the involved techniques are presented. Genealogical and personal information are the two main components of pedigree data. While the latter is unique to each investigation project, the former is solely represented by gametic links between persons. The triad of a given pedigree member and its two parents constitutes the building unit of a genealogy. Likewise, three ID numbers representing those three elements of the triad is the record field required for any pedigree analysis. Pedigree construction, as well as pedigree and population data analysis, varies according to the pre-established objectives, the existing information, and the available resources.

Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate.

Previous evidence from tooth agenesis studies suggested IRF6 and TGFA interact. Since tooth agenesis is commonly found in individuals with cleft lip/palate (CL/P), we used four large cohorts to evaluate if IRF6 and TGFA interaction contributes to CL/P. Markers within and flanking IRF6 and TGFA genes were tested using Taqman or SYBR green chemistries for case-control analyses in 1,000 Brazilian individuals. We looked for evidence of gene-gene interaction between IRF6 and TGFA by testing if markers associated with CL/P were overtransmitted together in the case-control Brazilian dataset and in the additional family datasets. Genotypes for an additional 142 case-parent trios from South America drawn from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), 154 cases from Latvia, and 8,717 individuals from several cohorts were available for replication of tests for interaction. Tgfa and Irf6 expression at critical stages during palatogenesis was analyzed in wild type and Irf6 knockout mice. Markers in and near IRF6 and TGFA were associated with CL/P in the Brazilian cohort (p<10(-6)). IRF6 was also associated with cleft palate (CP) with impaction of permanent teeth (p<10(-6)). Statistical evidence of interaction between IRF6 and TGFA was found in all data sets (p = 0.013 for Brazilians; p = 0.046 for ECLAMC; p = 10(-6) for Latvians, and p = 0.003 for the 8,717 individuals). Tgfa was not expressed in the palatal tissues of Irf6 knockout mice. IRF6 and TGFA contribute to subsets of CL/P with specific dental anomalies. Moreover, this potential IRF6-TGFA interaction may account for as much as 1% to 10% of CL/P cases. The Irf6-knockout model further supports the evidence of IRF6-TGFA interaction found in humans.

Clinical epidemiology of skeletal dysplasias in South America.

Currently accepted birth prevalence for osteochondrodysplasias (OCD) of about 2/10,000 is based on few studies from small series of cases. We conducted a study based on more than 1.5 million births. OCD cases were detected from 1,544,496 births occurring and examined in 132 hospitals of ECLAMC (Latin American Collaborative Study of Congenital Malformations) between 2000 and 2007. Cases were detected and registered according to a pre-established protocol, and then ranked in four diagnostic evidence levels (DEL), according to available documentation. For the analysis of risk factors, a healthy control sample born in the same period was used. OCD was diagnosed in 492 newborns, resulting in a prevalence per 10,000 of 3.2 (95% CI: 2.9-3.5). Perinatal lethality (stillbirths plus early neonatal deaths) occurred in 50% of cases. Prenatal ultrasound diagnosis was made in 73% of cases (n = 359). Among 211 cases from the best documented group (DEL-1) and according to international classification, 33% of cases fit into the G-25 (osteogenesis imperfecta), 29% in Group-1 (FGFR3), and 8% in Group-18 (Bent bones). The prevalence of the main OCD types were: OI-0.74 (0.61-0.89); thanatophoric dysplasia-0.47 (0.36-0.59); and achondroplasia-0.44 (0.33-0.55). Paternal age (31.2 ± 8.5), parity (2.6), and parental consanguinity rate (5.4%) were higher in cases than in controls (P < 0.001). In conclusion, the OCD overall prevalence of 3.2 per 10,000 found seems to be more realistic than previous estimates. This study also confirmed the high perinatal mortality, and the association with high paternal age, parity, and parental consanguinity rate.

The effect of systematic pediatric care on neonatal mortality and hospitalizations of infants born with oral clefts.

BACKGROUND: Cleft lip and/or palate (CL/P) increase mortality and morbidity risks for affected infants especially in less developed countries. This study aimed at assessing the effects of systematic pediatric care on neonatal mortality and hospitalizations of infants with cleft lip and/or palate (CL/P) in South America. METHODS: The intervention group included live-born infants with isolated or associated CL/P in 47 hospitals between 2003 and 2005. The control group included live-born infants with CL/P between 2001 and 2002 in the same hospitals. The intervention group received systematic pediatric care between the 7th and 28th day of life. The primary outcomes were mortality between the 7th and 28th day of life and hospitalization days in this period among survivors adjusted for relevant baseline covariates. RESULTS: There were no significant mortality differences between the intervention and control groups. However, surviving infants with associated CL/P in the intervention group had fewer hospitalization days by about six days compared to the associated control group. CONCLUSIONS: Early systematic pediatric care may significantly reduce neonatal hospitalizations of infants with CL/P and additional birth defects in South America. Given the large healthcare and financial burden of CL/P on affected families and the relatively low cost of systematic pediatric care, improving access to such care may be a cost-effective public policy intervention. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00097149.

Cyclopia: an epidemiologic study in a large dataset from the International Clearinghouse of Birth Defects Surveillance and Research.

Cyclopia is characterized by the presence of a single eye, with varying degrees of doubling of the intrinsic ocular structures, located in the middle of the face. It is the severest facial expression of the holoprosencephaly (HPE) spectrum. This study describes the prevalence, associated malformations, and maternal characteristics among cases with cyclopia. Data originated in 20 Clearinghouse (ICBDSR) affiliated birth defect surveillance systems, reported according to a single pre-established protocol. A total of 257 infants with cyclopia were identified. Overall prevalence was 1 in 100,000 births (95%CI: 0.89-1.14), with only one program being out of range. Across sites, there was no correlation between cyclopia prevalence and number of births (r = 0.08; P = 0.75) or proportion of elective termination of pregnancy (r = -0.01; P = 0.97). The higher prevalence of cyclopia among older mothers (older than 34) was not statistically significant. The majority of cases were liveborn (122/200; 61%) and females predominated (male/total: 42%). A substantial proportion of cyclopias (31%) were caused by chromosomal anomalies, mainly trisomy 13. Another 31% of the cases of cyclopias were associated with defects not typically related to HPE, with more hydrocephalus, heterotaxia defects, neural tube defects, and preaxial reduction defects than the chromosomal group, suggesting the presence of ciliopathies or other unrecognized syndromes. Cyclopia is a very rare defect without much variability in prevalence by geographic location. The heterogeneous etiology with a high prevalence of chromosomal abnormalities, and female predominance in HPE, were confirmed, but no effect of increased maternal age or association with twinning was observed.

Sirenomelia: an epidemiologic study in a large dataset from the International Clearinghouse of Birth Defects Surveillance and Research, and literature review.

Sirenomelia is a very rare limb anomaly in which the normally paired lower limbs are replaced by a single midline limb. This study describes the prevalence, associated malformations, and maternal characteristics among cases with sirenomelia. Data originated from 19 birth defect surveillance system members of the International Clearinghouse for Birth Defects Surveillance and Research, and were reported according to a single pre-established protocol. Cases were clinically evaluated locally and reviewed centrally. A total of 249 cases with sirenomelia were identified among 25,290,172 births, for a prevalence of 0.98 per 100,000, with higher prevalence in the Mexican registry. An increase of sirenomelia prevalence with maternal age less than 20 years was statistically significant. The proportion of twinning was 9%, higher than the 1% expected. Sex was ambiguous in 47% of cases, and no different from expectation in the rest. The proportion of cases born alive, premature, and weighting less than 2,500 g were 47%, 71.2%, and 88.2%, respectively. Half of the cases with sirenomelia also presented with genital, large bowel, and urinary defects. About 10-15% of the cases had lower spinal column defects, single or anomalous umbilical artery, upper limb, cardiac, and central nervous system defects. There was a greater than expected association of sirenomelia with other very rare defects such as bladder exstrophy, cyclopia/holoprosencephaly, and acardia-acephalus. The application of the new biological network analysis approach, including molecular results, to these associated very rare diseases is suggested for future studies.

Folic acid flour fortification: impact on the frequencies of 52 congenital anomaly types in three South American countries.

The aim of the present investigation was to search for a reduction in birth prevalence estimates of 52 selected types of congenital anomalies, associated with folic acid fortification programs in Chile, Argentina, and Brazil. The material included 3,347,559 total births in 77 hospitals of the three countries during the 1982-2007 period: 596,704 births (17 hospitals) in Chile, 1,643,341 (41 hospitals) in Argentina, and 1,107,514 (19 hospitals) in Brazil. We compared pre- and post-fortification rates within each hospital and the resulting Prevalence Rate Ratios (PRRs) were pooled by country. Statistically significant reductions in birth prevalence estimates after fortification were observed for neural tube defects (NTDs), septal heart defects, transverse limb deficiencies, and subluxation of the hip. However, only the reduction of NTDs appeared to be associated with folic acid fortification and not due to other factors, because of its consistency among the three countries, as well as with previously published reports, and its strong statistical significance. Among the NTDs, the maximum prevalence reduction was observed for isolated cephalic (cervical-thoracic) spina bifida, followed by caudal (lumbo-sacral) spina bifida, anencephaly, and cephalocele. This observation suggests etiologic and pathogenetic heterogeneity among different levels of spina bifida, as well as among different NTD subtypes. We concluded that food fortification with folic acid prevents NTDs but not other types of congenital anomalies.

Follow-up association studies of chromosome region 9q and nonsyndromic cleft lip/palate.

Cleft lip/palate comprises a large fraction of all human birth defects, and is notable for its significant lifelong morbidity and complex etiology. Several studies have shown that genetic factors appear to play a significant role in the etiology of cleft lip/palate. Human chromosomal region 9q21 has been suggested in previous reports to contain putative cleft loci. Moreover, a specific region (9q22.3-34.1) was suggested to present a approximately 45% probability of harboring a cleft susceptibility gene. Fine mapping of 50 SNPs across the 9q22.3-34.11 region was performed to test for association with cleft lip/palate in families from United States, Spain, Turkey, Guatemala, and China. We performed family-based analyses and found evidence of association of cleft lip/palate with STOM (rs306796) in Guatemalan families (P = 0.004) and in all multiplex families pooled together (P = 0.002). This same SNP also showed borderline association in the US families (P = 0.04). Under a nominal value of 0.05, other SNPs also showed association with cleft lip/palate and cleft subgroups. SNPs in STOM and PTCH genes and nearby FOXE1 were further associated with cleft phenotypes in Guatemalan and Chinese families. Gene prioritization analysis revealed PTCH and STOM ranking among the top fourteen candidates for cleft lip/palate among 339 genes present in the region. Our results support the hypothesis that the 9q22.32-34.1 region harbors cleft susceptibility genes. Additional studies with other populations should focus on these loci to further investigate the participation of these genes in human clefting.

Epidemiology of holoprosencephaly: Prevalence and risk factors.

The wide variation in cerebral and facial phenotypes and the recognized etiologic heterogeneity of holoprosencephaly (HPE) contribute to the observed inter-study heterogeneity. High lethality during the early stages of embryonic and fetal development makes HPE detection age dependent. By reviewing 21 HPE epidemiologic articles, the observed prevalence rate differences can be largely explained by the pregnancy outcome status of the studied cohort: livebirth, stillbirth, and terminations of pregnancy (TOPs): lower than 1 per 10,000 when live and still births were included, higher when TOPs were included, and between 40 and 50 per 10,000 in two classical Japanese studies on aborted embryos. The increasing secular trend observed in some studies probably resulted from an increasing use of prenatal sonography. Ethnic variations in birth prevalence rates (BPRs) could occur in HPE, but the available data are not very convincing. Higher BPRs were generally observed in the less favored minorities (Blacks, Hispanics, Pakistanis), suggesting a bias caused by a lower prenatal detection rate of HPE, and consequently less TOPs. Severe ear defects, as well as microstomia, were part of the spectrum of HPE. Non-craniofacial anomalies, more frequently associated with HPE than expected, were genital anomalies (24%), postaxial polydactyly (8%), vertebral defects (5%), limb reduction defects (4%), and transposition of great arteries (4%). The variable female predominance, found in different HPE studies, could also depend on the proportion of early conceptions in each study sample, as males are more likely to be lost through spontaneous abortions.