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1.  Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus 
BMC Biology  2011;9:14.
Evc is essential for Indian Hedgehog (Hh) signalling in the cartilage growth plate. The gene encoding Evc2 is in close proximity in divergent orientation to Evc and mutations in both human genes lead to the chondrodysplasia Ellis-van Creveld syndrome.
Bioinformatic analysis reveals that the Evc and Evc2 genes arose through a duplication event early in metazoan evolution and were subsequently lost in arthropods and nematodes. Here we demonstrate that Evc2 is essential for Hh pathway activation in response to the Smo agonist purmorphamine. A yeast two-hybrid screen using Evc as bait identified Evc2 as an Evc binding partner and we confirmed the interaction by immunoprecipitation. We developed anti-Evc2 antibodies and show that Evc2 and Evc co-localize at the basal body and also on primary cilia. In transfected cells, basal body and cilia localization is observed when Evc and Evc2 constructs are co-transfected but not when either construct is transfected individually. We show that Evc and Evc2 are cilia transmembrane proteins, the C-terminus for both being intracellular and Evc2, but not Evc, having an extracellular portion. Furthermore, Evc is absent at the basal body in Evc2 null cells. Using Western blots of cytoplasmic and nuclear protein, we also demonstrate that full length Evc2 but not Evc, is located in the nucleus.
We demonstrate for the first time that Evc2 is a positive regulator of the Hh signalling pathway and that it is located at the basal body of primary cilia. We show that the presence of Evc and Evc2 at the basal body and cilia membrane is co-dependent. In addition, Evc2, but not Evc, is present in the cell nucleus suggesting movement of Evc2 between the cilium and nucleus.
PMCID: PMC3052239  PMID: 21356043
2.  Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene 
BMC Medical Genetics  2008;9:92.
Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.
Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the EVC/EVC2 locus. The results did not exclude linkage, so samples were sequenced for mutations.
We identified a c.1868T>C mutation in EVC, which predicts p.L623P, and was homozygous in affected individuals.
We conclude that this EVC mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. EVC mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.
PMCID: PMC2584628  PMID: 18947413
3.  Deletion in the EVC2 Gene Causes Chondrodysplastic Dwarfism in Tyrolean Grey Cattle 
PLoS ONE  2014;9(4):e94861.
During the summer of 2013 seven Italian Tyrolean Grey calves were born with abnormally short limbs. Detailed clinical and pathological examination revealed similarities to chondrodysplastic dwarfism. Pedigree analysis showed a common founder, assuming autosomal monogenic recessive transmission of the defective allele. A positional cloning approach combining genome wide association and homozygosity mapping identified a single 1.6 Mb genomic region on BTA 6 that was associated with the disease. Whole genome re-sequencing of an affected calf revealed a single candidate causal mutation in the Ellis van Creveld syndrome 2 (EVC2) gene. This gene is known to be associated with chondrodysplastic dwarfism in Japanese Brown cattle, and dwarfism, abnormal nails and teeth, and dysostosis in humans with Ellis-van Creveld syndrome. Sanger sequencing confirmed the presence of a 2 bp deletion in exon 19 (c.2993_2994ACdel) that led to a premature stop codon in the coding sequence of bovine EVC2, and was concordant with the recessive pattern of inheritance in affected and carrier animals. This loss of function mutation confirms the important role of EVC2 in bone development. Genetic testing can now be used to eliminate this form of chondrodysplastic dwarfism from Tyrolean Grey cattle.
PMCID: PMC3986253  PMID: 24733244
4.  Two Adult Patients with Ellis-van Creveld Syndrome Extending the Clinical Spectrum 
Molecular Syndromology  2011;1(6):301-306.
Ellis-van Creveld (EvC) syndrome is a rare autosomal recessive malformation syndrome with the main features cardiac defects, postaxial hexadactyly, mesomelic shortening of the limbs, short ribs, dysplastic nails and teeth, oral frenula and various other abnormalities while mental function is normal. We describe 2 adult EvC patients with the cardinal skeletal features of mesomelic short stature and severe, progressive genu valgum deformity, resulting from loss of function mutations in the EVC genes. While the genu valgum was the predominating and disabling feature in patient 1, patient 2 showed acroosteolyses in the distal phalanges and a symmetrical synostosis of metacarpals in his hands. Moreover, patient 2 developed synostoses in the additional fingers in adolescence which had not been present at the age of 12 years, suggesting a further progression of skeletal disease. Joint fusion of phalanges so far has not been reported in EvC syndrome. Our data further expand the phenotypic spectrum of EvC related skeletal malformations and contribute important new information on the clinical course of EvC syndrome with increasing age.
PMCID: PMC3214960  PMID: 22190900
Ellis-van Creveld syndrome; EVC genes; Genu valgum; Skeletal manifestation; Treatment
5.  Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2 
Cell Research  2012;22(11):1593-1604.
Hedgehog (Hh) signaling plays pivotal roles in embryonic development and adult tissue homeostasis in species ranging from Drosophila to mammals. The Hh signal is transduced by Smoothened (Smo), a seven-transmembrane protein related to G protein coupled receptors. Despite a conserved mechanism by which Hh activates Smo in Drosophila and mammals, how mammalian Hh signal is transduced from Smo to the Gli transcription factors is poorly understood. Here, we provide evidence that two ciliary proteins, Evc and Evc2, the products of human disease genes responsible for the Ellis-van Creveld syndrome, act downstream of Smo to transduce the Hh signal. We found that loss of Evc/Evc2 does not affect Sonic Hedgehog-induced Smo phosphorylation and ciliary localization but impedes Hh pathway activation mediated by constitutively active forms of Smo. Evc/Evc2 are dispensable for the constitutive Gli activity in Sufu−/− cells, suggesting that Evc/Evc2 act upstream of Sufu to promote Gli activation. Furthermore, we demonstrated that Hh stimulates binding of Evc/Evc2 to Smo depending on phosphorylation of the Smo C-terminal intracellular tail and that the binding is abolished in Kif3a−/− cilium-deficient cells. We propose that Hh activates Smo by inducing its phosphorylation, which recruits Evc/Evc2 to activate Gli proteins by antagonizing Sufu in the primary cilia.
PMCID: PMC3494391  PMID: 22986504
Evc; Evc2; Hedgehog; Smo; Gli
6.  Ellis-Van Creveld syndrome 
Ellis-van Creveld syndrome (EVC) is a chondral and ectodermal dysplasia characterized by short ribs, polydactyly, growth retardation, and ectodermal and heart defects. It is a rare disease with approximately 150 cases reported worldwide. The exact prevalence is unknown, but the syndrome seems more common among the Amish community. Prenatal abnormalities (that may be detected by ultrasound examination) include narrow thorax, shortening of long bones, hexadactyly and cardiac defects. After birth, cardinal features are short stature, short ribs, polydactyly, and dysplastic fingernails and teeth. Heart defects, especially abnormalities of atrial septation, occur in about 60% of cases. Cognitive and motor development is normal. This rare condition is inherited as an autosomal recessive trait with variable expression. Mutations of the EVC1 and EVC2 genes, located in a head to head configuration on chromosome 4p16, have been identified as causative. EVC belongs to the short rib-polydactyly group (SRP) and these SRPs, especially type III (Verma-Naumoff syndrome), are discussed in the prenatal differential diagnosis. Postnatally, the essential differential diagnoses include Jeune dystrophy, McKusick-Kaufman syndrome and Weyers syndrome. The management of EVC is multidisciplinary. Management during the neonatal period is mostly symptomatic, involving treatment of the respiratory distress due to narrow chest and heart failure. Orthopedic follow-up is required to manage the bones deformities. Professional dental care should be considered for management of the oral manifestations. Prognosis is linked to the respiratory difficulties in the first months of life due to thoracic narrowness and possible heart defects. Prognosis of the final body height is difficult to predict.
PMCID: PMC1891277  PMID: 17547743
7.  Growth charts for children with Ellis–van Creveld syndrome 
European Journal of Pediatrics  2010;170(2):207-211.
Ellis–van Creveld (EvC) syndrome is a congenital malformation syndrome with marked growth retardation. In this study, specific growth charts for EvC patients were derived to allow better follow-up of growth and earlier detection of growth patterns unusual for EvC. With the use of 235 observations of 101 EvC patients (49 males, 52 females), growth charts for males and females from 0 to 20 years of age were derived. Longitudinal and cross-sectional data were collected from an earlier review of growth data in EvC, a database of EvC patients, and from recent literature. To model the growth charts, the GAMLSS package for the R statistical program was used. Height of EvC patients was compared to healthy children using Dutch growth charts. Data are presented both on a scale for age and on a scale for the square root of age. Compared to healthy Dutch children, mean height standard deviation score values for male and female EvC patients were −3.1 and −3.0, respectively. The present growth charts should be useful in the follow-up of EvC patients. Most importantly, early detection of growth hormone deficiency, known to occur in EvC, will be facilitated.
PMCID: PMC3022156  PMID: 20830486
Growth; Body height; Ellis–van Creveld syndrome; Growth charts
8.  Ellis-van Creveld syndrome: A rare clinical entity 
Ellis-van Creveld (EVC) syndrome is a genetic disorder with autosomal recessive transmission, which may clinically present as small stature, short limbs, fine sparse hair, hypoplastic fingernails, multiple musculofibrous frenula, conical teeth, hypoplasia of the enamel, hypodontia, and malocclusion. Heart defects, especially abnormalities of atrial septation, have been found in about 60% of cases. The mutation in EVC and EVC2 gene is responsible for this syndrome. The presence of multiple orodental findings makes this syndrome important for dentists. The aim of this article is to present a rare case of EVC syndrome in a 10-year-old girl along with the review of literature.
PMCID: PMC3687170  PMID: 23798848
Chondroectodermal dysplasia; Ellis-van Creveld syndrome; polydactyly
9.  Ellis van Creveld syndrome with unusual association of essential infantile esotropia 
Oman Journal of Ophthalmology  2010;3(1):23-25.
Ellis-van Creveld syndrome is a rare short-limbed disproportionate dwarfism characterized by postaxial polydactyly, several skeletal, oral mucosal and dental anomalies, nail dysplasia and in 50-60% cases of congenital cardiac defects. It is an autosomal recessive disorder with mutations of the EVC1 and EVC2 genes located on chromosome 4p16. Patients with this syndrome usually have a high mortality in early life due to cardiorespiratory problems. We present the case of a six- month-old female infant with Ellis-van Creveld syndrome - essential infantile esotropia, which has been infrequently documented in the literature.
PMCID: PMC2886224  PMID: 20606869
Postaxial polydactyly; disproportionate dwarfism; hypoplastic nails; essential infantile esotropia
10.  Analysis of Ellis van Creveld syndrome gene products: implications for cardiovascular development and disease 
Human Molecular Genetics  2009;18(10):1813-1824.
Mutations identified in a cohort of patients with atrioventricular septal defects as a part of Ellis van Creveld syndrome (EvC syndrome) led us to study the role of two non-homologous genes, EVC and LBN, in heart development and disease pathogenesis. To address the cause of locus heterogeneity resulting in an indistinguishable heart–hand phenotype, we carried out in situ hybridization and immunofluorescence and identified co-localization of Evc and Lbn mRNA and protein. In the heart, expression was identified to be strongest in the secondary heart field, including both the outflow tract and the dorsal mesenchymal protrusion, but was also found in mesenchymal structures of the atrial septum and the atrioventricular cushions. Finally, we studied the transcriptional hierarchy of EVC and LBN but did not find any evidence of direct transcriptional interregulation between the two. Due to the locus heterogeneity of human mutations predicted to result in a loss of protein function, a bidirectional genomic organization and overlapping expression patterns, we speculate that these proteins function coordinately in cardiac development and that loss of this coordinate function results in the characteristics of EvC syndrome.
PMCID: PMC2671989  PMID: 19251731
11.  Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes 
Meckel–Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n=12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis–van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.
PMCID: PMC3722952  PMID: 23169490
autozygome; ciliopathy; encephalocele; EVC2; EXOC4
12.  Ellis Van Creveld Syndrome with Synpolydactyly, an Antenatal Diagnosis with Postnatal Correlation 
Ellis Van Creveld syndrome (EVC), also known as chondroectodermal dysplasia, presents at birth with short limbs accompanied by postaxial polydactyly, nail dysplasia, and dental anomalies. Other manifestations of EVC include atrial septum defects and other congenital heart diseases. We report a case of the EVC syndrome with postaxial polydactyly (Synpolydactyly with seven fingers on the right side and hexadactyly on the left side) and a partial atrioventricular canal defect diagnosed antenatally. This variation of EVS has not been reported in English literature till date.
PMCID: PMC3261597  PMID: 22267994
Antenatal diagnosis; cardiac malformation; ellis van creveld syndrome; synpolydactyly; ultrasonography
13.  Ellis van Creveld Syndrome (EVCS) in an Iranian, Three-Year-old Girl: A Case Report 
Ellis van Creveld syndrome (EVCS) is mainly characterized by dysplatic changes in skeletal structures along with variable inter- and intra-familial patterns. Shortening of bony structures such as ribs and limbs, postaxial polydactyly, and dysplastic teeth and nails are among the clinical presentation of this autosomal recessive disease.
PMCID: PMC4253240  PMID: 25478422
Epidermoid cyst; Enucleation; Impacted wisdom teeth; Mandible
14.  Report of Two Siblings with Overlapping Features of Ellis-van Creveld and Weyers Acrodental Dysostosis 
Skeletal dysplasias are a heterogenous group of disorders combining abnormalities in the skull and other skeletal bones. Weyers acrofacial dysostosis also known as Weyers acrodental dysostosis was first described in 1952, by Weyers, as a postaxial polydactyly, which had features distinct from, yet some in common with the Ellis-van Creveld Syndrome (EvC). Both the syndromes have been mapped to the same chromosome, 4p16. The cases reported here highlight the overlapping features of both syndromes, which are dissimilar in mode of inheritance and phenotypic severity, emphasizing the need for genetic analysis, to categorize these conditions.
PMCID: PMC3352611  PMID: 22616035
Ellis-van Creveld; polydactyly; syndrome; weyers acrodental dysostosis
15.  Late survival in Ellis–van Creveld syndrome – A case report 
Indian Heart Journal  2012;64(4):408-411.
Ellis–van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by chondrodystrophy, polydactyly, ectodermal dysplasia, and cardiac anomalies. Acromelic shortening of upper and lower limbs, genu valgum, multiple frenula, deformed teeth, short ribs and narrow thorax and congenital heart diseases complete the picture. The patients with the syndrome rarely survive into adulthood. Here, we report a lady with EVC presenting for the first time in middle age.
PMCID: PMC3860683  PMID: 22929827
Ellis–van Creveld syndrome; Ciliopathy; Short rib narrow thorax syndromes
16.  From the Transcription of Genes Involved in Ectodermal Dysplasias to the Understanding of Associated Dental Anomalies 
Molecular Syndromology  2012;3(4):158-168.
Orodental anomalies are one aspect of rare diseases and are increasingly identified as diagnostic and predictive traits. To understand the rationale behind gene expression during tooth or other ectodermal derivative development and the disruption of odontogenesis or hair and salivary gland formation in human syndromes we analyzed the expression patterns of a set of genes (Irf6, Nfkbia, Ercc3, Evc2, Map2k1) involved in human ectodermal dysplasias in mouse by in situ hybridization. The expression patterns of Nfkbia, Ercc3 and Evc2 during odontogenesis had never been reported previously. All genes were indeed transcribed in different tissues/organs of ectodermal origin. However, for Nfkbia, Ercc3, Evc2, and Map2k1, signals were also present in the ectomesenchymal components of the tooth germs. These expression patterns were consistent in timing and localization with the known dental anomalies (tooth agenesis, microdontia, conical shape, enamel hypoplasia) encountered in syndromes resulting from mutations in those genes. They could also explain the similar orodental anomalies encountered in some of the corresponding mutant mouse models. Translational approaches in development and medicine are relevant to gain understanding of the molecular events underlying clinical manifestations.
PMCID: PMC3507273  PMID: 23239958
Dental anomalies; Ectodermal dysplasia; Gene expression; Mouse; Tooth development
17.  Ellis–van Creveld 
Journal of Pharmacy & Bioallied Sciences  2012;4(Suppl 2):S153-S156.
Ellis–van Creveld (EVC) syndrome is an autosomal recessive disorder that is also known as chondro-ectodermal dysplasia. The common manifestations of this syndrome are short ribs, postaxial polydactyly, growth retardation, and ectodermal and cardiac defects. The present case report is about an 8-year-old boy who had the features of bilateral hexadactyly, knocked knees, cardiac problems, congenital absence of incisors, fused upper and lower labial frenulum, and mulberry molars.
PMCID: PMC3467917  PMID: 23066239
Abnormal frenal attachments; chondro-ectodermal dysplasia; Ellis–van Creveld syndrome; mulberry molars; polydactyly
18.  Orthopaedic manifestations of chondroectodermal dysplasia: the Ellis–van Creveld syndrome 
Ellis–van Creveld is a dwarfing syndrome transmitted as an autosomal recessive trait. The constant features of the condition include acromelic–micromelic dwarfism, ectodermal dysplasia involving the nails, teeth and gums, postaxial polydactyly of the hands and congenital heart disease. Congenital heart disease affects 50–60 % of all patients and nearly 50 % of patients die by 18 months of age from cardiopulmonary complications. This study is intended to characterise the orthopaedic manifestations of Ellis–van Creveld based on the authors’ unique opportunity to interview and examine the largest group of patients to date in the literature.
Detailed interviews, physical examinations and/or radiographs were available on 71 cases of Ellis–van Creveld syndrome. Data were collected from physical examinations, radiographs, computed tomography (CT) reconstruction and magnetic resonance imaging (MRI) of the knee. Pathoanatomy of the knee was reinforced by the direct surgical observation of 25 limbs surgically managed during adolescence and puberty.
A number of interesting clinical and radiographic abnormalities were noted in the upper extremities and lower extremities, but by far the most significant orthopaedic finding was a severe and relentlessly progressive valgus deformity of the knee. Although many patients had difficulties making a “fist” with the hand, no patient reported any functional disability. The severe valgus deformity of the knee is the result of a combination of profound contractures of the iliotibial band, lateral quadriceps, lateral hamstrings and lateral collateral ligament, leading to lateral patellar subluxation and dislocation. The lateral portion of the upper tibial plateau presents with cupping and progressive depression of the lateral plateau, along with severe valgus angulation of the proximal tibia and fibula. A proximal medial tibial exostosis is seen in nearly all cases.
This is the largest group of Ellis–van Creveld syndrome patients identified in the literature. An understanding of the orthopaedic pathoanatomy of the knee deformity is critical to determining the appropriate surgical management. This paper characterises the orthopaedic manifestations of Ellis–van Creveld syndrome and especially identifies the pathoanatomy of the severe and progressive valgus knee deformity.
Level of evidence
Level II.
Electronic supplementary material
The online version of this article (doi:10.1007/s11832-013-0541-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3886354  PMID: 24432110
Pathoanatomy; Chondroectodermal dysplasia; Ellis–van Creveld syndrome
19.  Genome-Wide Linkage Study Suggests a Susceptibility Locus for Isolated Bilateral Microtia on 4p15.32–4p16.2 
PLoS ONE  2014;9(7):e101152.
Microtia is a congenital deformity where the external ear is underdeveloped. Genetic investigations have identified many susceptibility genes of microtia-related syndromes. However, no causal genes were reported for isolated microtia, the main form of microtia. We conducted a genome-wide linkage analysis on a 5-generation Chinese pedigree with isolated bilateral microtia. We identified a suggestive linkage locus on 4p15.32–4p16.2 with parametric LOD score of 2.70 and nonparametric linkage score (Zmean) of 12.28 (simulated occurrence per genome scan equal to 0.46 and 0.47, respectively). Haplotype reconstruction analysis of the 4p15.32–4p16.2 region further confined the linkage signal to a 10-Mb segment located between rs12505562 and rs12649803 (9.65–30.24 cM; 5.54–15.58 Mb). Various human organ developmental genes reside in this 10-Mb susceptibility region, such as EVC, EVC2, SLC2A9, NKX3-2, and HMX1. The coding regions of three genes, EVC known for cartilage development and NKX3-2, HMX1 involved in microtia, were selected for sequencing with 5 individuals from the pedigree. Of the 38 identified sequence variants, none segregates along with the disease phenotype. Other genes or DNA sequences of the 10-Mb region warrant for further investigation. In conclusion, we report a susceptibility locus of isolated microtia, and this finding will encourage future studies on the genetic basis of ear deformity.
PMCID: PMC4077761  PMID: 24983964
20.  Identification of Mutations Underlying 20 Inborn Errors of Metabolism in the United Arab Emirates Population 
Inborn errors of metabolism (IEM) are frequently encountered by physicians in the United Arab Emirates (UAE). However, the mutations underlying a large number of these disorders have not yet been determined. Therefore, the objective of this study was to identify the mutations underlying a number of IEM disorders among UAE residents from both national and expatriate families. A case series of patients from 34 families attending the metabolic clinic at Tawam Hospital were clinically evaluated, and molecular testing was carried out to determine their causative mutations. The mutation analysis was carried out at molecular genetics diagnostic laboratories. Thirty-eight mutations have been identified as responsible for twenty IEM disorders, including in the metabolism of amino acids, lipids, steroids, metal transport and mitochondrial energy metabolism, and lysosomal storage disorders. Nine of the identified mutations are novel, including two missense mutations, three premature stop codons and four splice site mutations. Mutation analysis of IEM disorders in the UAE population has an important impact on molecular diagnosis and genetic counseling for families affected by these disorders.
PMCID: PMC3354585  PMID: 22106832
21.  Association between genes on chromosome 4p16 and non-syndromic oral clefts in four populations 
Isolated cleft lip with or without cleft palate and cleft palate are among the most common human birth defects. Several candidate gene studies on MSX1 have shown significant association between markers in MSX1 and risk of oral clefts, and re-sequencing studies have identified multiple mutations in MSX1 in a small minority of cases, which may account for 1–2% of all isolated oral clefts cases. We explored the 2-Mb region around MSX1, using a marker map of 393 single nucleotide polymorphisms (SNPs) in 297 cleft lip, with or without cleft palate, case–parent trios and 84 cleft palate trios from Maryland, Taiwan, Singapore, and Korea. Both individual markers and haplotypes of two to five SNPs showed several regions yielding statistical evidence for linkage and disequilibrium. Two genes (STK32B and EVC) yielded consistent evidence from cleft lip, with or without cleft palate, trios in all four populations. These two genes plus EVC2 also yielded suggestive evidence for linkage and disequilibrium among cleft palate trios. This analysis suggests that several genes, not just MSX1, in this region may influence risk of oral clefts.
PMCID: PMC2874614  PMID: 20087401
oral clefts; cleft lip with or without cleft palate; cleft palate; MSX1; chromosome 4p16
22.  Association between genes on chromosome 4p16 and non-syndromic oral clefts in four population 
Isolated cleft lip with or without cleft palate and cleft palate are among the most common human birth defects. Several candidate gene studies of MSX1 have shown significant association between markers in MSX1 and risk of oral clefts, and resequencing studies have identified multiple mutations in MSX1 in a small minority of cases, which may account for 1–2% of all isolated oral clefts. We explored the two megabase region around MSX1, using a marker map of 393 single nucleotide polymorphisms in 297 cleft lip with or without cleft palate case-parent trios and 84 cleft palate trios from Maryland, Taiwan, Singapore, and Korea. Both individual markers and haplotypes of 2-5 SNPs showed several regions yielding statistical evidence of linkage and disequilibrium. Two genes (STK32B and EVC) yielded consistent evidence from cleft lip with or without cleft plate trios in all four populations. These two genes plus EVC2 also yielded suggestive evidence of linkage and disequilibrium among CP trios. This analysis suggests several genes, not just MSX1, in this region may influence risk of oral clefts.
PMCID: PMC2874614  PMID: 20087401
Oral Clefts; Cleft lip with or without cleft palate; Cleft Palate; MSX1; Chromosome 4p16
23.  Genome Scan for Locus Involved in Mandibular Prognathism in Pedigrees from China 
PLoS ONE  2010;5(9):e12678.
It is well known that genetic components play an important role in the etiology of mandibular prognathism, but few susceptibility loci have been mapped.
In order to identify linkage regions for mandibular prognathism, we analyzed two Chinese pedigrees with 6,090 genome-wide single-nucleotide polymorphism (SNP) markers from Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM). Multipoint parametric and non-parametric (model-free) linkage analyses were used for the pedigrees.
Principal Finding
The most statistically significant linkage results were with markers on chromosome 4 (LOD  = 3.166 and NPL = 3.65 with rs 875864, 4p16.1, 8.38 cM). Candidate genes within the 4p16.1 include EVC, EVC2.
We detected a novel suggestive linkage locus for mandibular prognathism in two Chinese pedigrees, and this linkage region provides target for susceptibility gene identification, a process that will provide important insights into the molecular and cellular basis of mandibular prognathism.
PMCID: PMC2937026  PMID: 20844756
24.  A Smoothened-Evc2 Complex Transduces the Hedgehog Signal at Primary Cilia 
Developmental cell  2012;23(4):823-835.
Vertebrate Hedgehog (Hh) signaling is initiated at primary cilia by the ligand-triggered accumulation of Smoothened (Smo) in the ciliary membrane. The underlying biochemical mechanisms remain unknown. We find that Hh agonists promote the association between Smo and Evc2, a ciliary protein that is defective in two human ciliopathies. The formation of the Smo-Evc2 complex is under strict spatial control, being restricted to a distinct ciliary compartment, the EvC zone. Mutant Evc2 proteins that localize in cilia but are displaced from the EvC zone are dominant inhibitors of Hh signaling. Disabling Evc2 function blocks Hh signaling at a specific step between Smo and the downstream regulators protein kinase A and Suppressor of Fused, preventing activation of the Gli transcription factors. Our data suggest that the Smo-Evc2 signaling complex at the EvC zone is required for Hh signal transmission and elucidate the molecular basis of two human ciliopathies.
PMCID: PMC3586260  PMID: 22981989
25.  Role of soluble triggering receptor expressed on myeloid cells-1 for diagnosing ventilator-associated pneumonia after cardiac surgery: an observational study 
The diagnosis of ventilator-associated pneumonia (VAP) is a challenge, particularly after cardiac surgery. The use of biological markers of infection has been suggested to improve the accuracy of VAP diagnosis. We aimed to evaluate the usefulness of soluble triggering receptor expressed on myeloid cells (sTREM)-1 in the diagnosis of VAP following cardiac surgery.
This was a prospective observational cohort study of children with congenital heart disease admitted to the pediatric intensive care unit (PICU) after surgery and who remained intubated and mechanically ventilated for at least 24 hours postoperatively. VAP was defined by the 2007 Centers for Disease Control and Prevention criteria. Blood, modified bronchoalveolar lavage (mBAL) fluid and exhaled ventilator condensate (EVC) were collected daily, starting immediately after surgery until the fifth postoperative day or until extubation for measurement of sTREM-1.
Thirty patients were included, 16 with VAP. Demographic variables, Pediatric Risk of Mortality (PRISM) and Risk Adjustment for Congenital Heart Surgery (RACHS)-1 scores, duration of surgery and length of cardiopulmonary bypass were not significantly diferent in patients with and without VAP. However, time on mechanical ventilation and length of stay in the PICU and in the hospital were significantly longer in the VAP group. Serum and mBAL fluid sTREM-1 concentrations were similar in both groups. In the VAP group, 12 of 16 patients had sTREM-1 detected in EVC, whereas it was undetectable in all but two patients in the non-VAP group over the study period (p = 0.0013) (sensitivity 0.75, specificity 0.86, positive predictive value 0.86, negative predictive value 0.75, positive likelihood ratio (LR) 5.25, negative LR 0.29).
Measurement of sTREM-1 in EVC may be useful for the diagnosis of VAP after cardiac surgery.
PMCID: PMC4219386  PMID: 24289157
Triggering receptor expressed on myeloid cells-1; Ventilator-associated pneumonia; Diagnosis; Cardiac surgery; Postoperative

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