唇瘘、腭裂及唇裂综合征两个家系的遗传分析

我们在此报道北京地区没有亲缘关系的两个家庭中属于van der woude综合征的常染色体显性遗传病,其临床症状包括下唇近中线处唇瘘(下唇有先天性向下的瘘管)、腭裂、唇裂(具有或不具有腭裂)。这三个临床症状可以同时发生在一个受累个体身上,或任何两个症状出现在一个个体身上。这种人携带了这种致病基因。在我们所报道的家庭中,先证者每人还具有舌系带过短的体征。     

Confirmation of linkage of Van der Woude syndrome to chromosome 1q32: evidence of association with STR alleles suggests possible unique origin of the disease mutation

Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder with high penetrance and variable expression. Its clinical features are variably expressed, but include cleft lip and/or cleft palate, lip pits and hypodontia. All VWS families studied to date map the disease gene to a < 2 cM region of chromosome 1q32, with no evidence of locus heterogeneity. The aim of this study is to refine the localization of the VWS gene and to further assess possible heterogeneity. We analyzed four multiplex VWS families. All available members were clinically assessed and genotyped for 19 short tandem repeat markers on chromosome 1 in the VWS candidate gene region. We performed two-point and multipoint limit of detection (LOD) score analyses using a high penetrance autosomal dominant model. All families showed positive LOD scores without any recombination in the candidate region. The largest two-point LOD score was 5.87. Our assay method for short tandem repeat (STR) markers provided highly accurate size estimation of marker allele fragment sizes, and therefore enabled us to determine the specific alleles segregating with the VWS gene in each of our four families. We observed a striking pattern of STR allele sharing at several closely linked loci among our four Caucasian VWS families recruited at three different locations in the US. These results suggest the possibility of a unique origin for a mutation responsible for many or most cases of VWS.     

Linkage analysis in a large Brazilian family with van der Woude syndrome suggests the existence of a susceptibility locus for cleft palate at 17p11.2-11.1.

van der Woude syndrome (VWS), which has been mapped to 1q32-41, is characterized by pits and/or sinuses of the lower lip, cleft lip/palate (CL/P), cleft palate (CP), bifid uvula, and hypodontia (H). The expression of VWS, which has incomplete penetrance, is highly variable. Both the occurrence of CL/P and CP within the same genealogy and a recurrence risk <40% for CP among descendants with VWS have suggested that the development of clefts in this syndrome is influenced by modifying genes at other loci. To test this hypothesis, we have conducted linkage analysis in a large Brazilian kindred with VWS, considering as affected the individuals with CP, regardless of whether it is associated with other clinical signs of VWS. Our results suggest that a gene at 17p11.2-11.1, together with the VWS gene at 1p32-41, enhances the probability of CP in an individual carrying the two at-risk genes. If this hypothesis is confirmed in other VWS pedigrees, it will represent one of the first examples of a gene, mapped through linkage analysis, which modifies the expression of a major gene. It will also have important implications for genetic counseling, particularly for more accurately predicting recurrence risks of clefts among the offspring of patients with VWS.     

Genetic analysis in families with van der Woude syndrome

We have brought together information on 864 affected individuals in 164 families (including three new pedigrees) reported in the 137 year period since 1845 when Demarquay first described a family with what was later called van der Woude syndrome (VWS). Both types of oral cleft, cleft palate (CP) and cleft lip with or without CP (CLP), segregate in these families together with lower lip pits or fistulae in an autosomal dominant mode with high penetrance estimated to be K = .89 and .99 by different methods. Cleft types (CLP and CP) occur in VWS in the same proportions as in the general non-VWS population, ie, about twice as many cleft-bearing individuals have CLP as have CP. On the other hand, we do not find the usually observed excess of females with CP and excess of males with CLP; in VWS the sex ratios are more nearly equal. Lip pits also are equally distributed between the sexes. Affected males and females are equally likely to transmit VWS. However, there is an excess of less severely affected individuals among transmitters and a deficiency of more severely affected, brought about by a proband bias and differential fecundity. The expression of VWS is significantly modified by the genetic background: More extreme phenotypes in parents tend to produce more extreme expression in their children. For a VWS gene carrier the relative risk of transmitting a cleft is 26.45%; that of transmitting lower lip pits is 23.55%. Three pedigrees of lip pits in the literature show no clefts among a significant number of affected individuals. Control of gene expression in VWS in the three target tissues appears to be independent and separately designated. Mutation rate of the VWS gene is calculated to be 1.8 X 10(-5).     

A novel mutation of the IRF6 gene in an Italian family with Van der Woude syndrome

Van der Woude syndrome (VWS) is the most common type of syndromic orofacial cleft, being characterised by variable association of lower lip pits, cleft lip and cleft palate. VWS is transmitted in an autosomal dominant manner, with high penetrance and variable expressivity, and a gene for this disease has been mapped in 1q32-q41. Very recently, mutations of the interferon regulatory factor 6 (IRF6) gene have been found in VWS patients, suggesting that this gene plays an important role in the orofacial development. We report a novel mutation of the IRF6 in an Italian family with six members affected by VWS with different expression. This mutation, the W217X, produces a stop codon within exon 6 of the IRF6 gene, with loss of the SMIR domain of the IRF6 protein.     

Linkage of an autosomal dominant clefting syndrome (Van der Woude) to loci on chromosome Iq

Van der Woude syndrome (VWS) is an autosomal dominant disorder in which affected individuals have one or more of the following manifestations: cleft lip, cleft palate, hypodontia, or paramedian lower-lip pits. VWS is a well-characterized example of a single-gene abnormality that disturbs normal craniofacial morphogenesis. As a first step in identifying genes involved in human development, we used a candidate-gene-and-region approach to look for a linkage to VWS. Six families with 3 or more generations of affected individuals were studied. Evidence for linkage (theta = 0.02, lod score = 9.09) was found between the renin (REN) gene on 1q and VWS. Other linked loci included CR1, D1S58, and D1S53. The genes for laminin B2 (LAMB2), a basement-membrane protein, and for decay-accelerating factor (DAF) were studied as possible candidate genes on 1q. Recombinants between VWS and both LAMB2 and DAF excluded these genes from a causal role in the etiology of VWS for the families studied in this report. Multipoint linkage analysis indicated that the VWS locus was flanked by REN and D1S65 at a lod score of 10.83. This tight linkage with renin and other nearby loci provides a first step in identifying the molecular abnormality underlying this disturbance of human development.     

Novel mutations in the<Emphasis Type="Italic"> IRF6</Emphasis> gene for Van der Woude syndrome

Van der Woude syndrome (VWS, OMIM 119300) is an autosomal dominant craniofacial disorder characterized by pits of the lower lip, hypodontia, and cleft lip and/or cleft palate. It is the most common form of syndromic orofacial clefting and has very high penetrance with varied expressivity. The disease locus for VWS has been mapped to a 1.6-cM region on 1q32–41 between D1S205 and D1S491. Recently, mutations have been found in the interferon regulatory factor 6 (IRF6) gene in patients with VWS and popliteal pterygium syndrome. To identify novel mutations of IRF6 in VWS patients, we screened four Chinese VWS families in all nine exons and their flanking splice junctions by direct sequencing. We identified three missense mutations and one nonsense mutation in IRF6. Our study further confirmed that IRF6 is essential for craniofacial development.X. Wang and J. Liu contributed equally to this work     

Linkage of Van der Woude syndrome (VWS) to REN and exclusion of the candidate gene TGFB2 from the disease locus in a large pedigree

Van der Woude syndrome (VWS) is an autosomal dominant disorder associated with one or more of the following features: clefting of the primary or secondary palate, hypodontia or lower lip pits. It has been estimated to account for 2% of all cases of cleft lip and palate. VWS is one of the rare disorders in which clefting of the primary and secondary palate may be seen to segregate as components associated with the same gene. Because of its autosomal dominant inheritance, VWS is readily accessable to linkage analysis as a preliminary step in the identification of the molecular abnormality underlying the clefting effect in the primary and secondary palate. A reported linkage between REN and VWS has promoted us to use pHRnX3.6 (REN) and several markers surrounding REN for a linkage analysis in a large Swiss family. In a second step, linkage analysis was performed to study restriction fragment length polymorphisms for the candidate gene TGFB2 and other loci recently mapped to the candidate region 1q32–1q41. Evidence for linkage ( = 0.00, lod score = 3.01) between REN and VWS could be confirmed in this pedigree. TGFB2 demonstrated recombination with the disease locus and is unlikely to be causative in VWS. The results of a multipoint linkage analysis showed that VWS was flanked by D1S65 and TGFB2 at a maximum location score of 20.3.     

Microsatellite-based fine mapping of the Van der Woude syndrome locus to an interval of 4.1 cM between D1S245 and D1S414.

Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder characterized by lip pits, clefting of the primary or secondary palate, and hypodontia. The gene has been localized, by RFLP-based linkage studies, to region 1q32-41 between D1S65-REN and D1S65-TGFB2. In this study we report the linkage analysis of 15 VWS families, using 18 microsatellite markers. Multipoint linkage analysis places the gene, with significant odds of 2,344:1, in a 4.1-cM interval flanked by D1S245 and D1S414. Two-point linkage analysis demonstrates close linkage of VWS with D1S205 (lod score [Z] = 24.41 at theta = .00) and with D1S491 (Z = 21.23 at theta = .00). The results revise the previous assignment of the VWS locus and show in an integrated map of the region 1q32-42 that the VWS gene resides more distally than previously suggested. When information about heterozygosity of the closely linked marker D1S491 in the affected members of the VWS family with a microdeletion is taken into account, the VWS critical region can be further narrowed, to the 3.6-cM interval between D1S491 and D1S414.     

Report of two cases with Van der Woude syndrome: a child and her mother

Report of two cases with Van der Woude syndrome: a child and her mother: Congenital pits of the lower lip are rare malformations. They are closely associated with cleft lip (CL), cleft lip/palate (CL/CP) or isolated cleft palate (CP) and if so this condition is known as Van der Woude syndrome, which is inherited in an autosomal dominant fashion with high penetrance. Two individuals, one with lower lip pits and cleft palate and the other with isolated lower lip pit from the same family are described. Autosomal dominant pattern of inheritance was observed in this family and treatment consisted of complete removal of sinus tracts in one patient. Pathological features of sinus tracts consisted of stratified nonkeratinized squamous epithelium and a lamina propria of dense connective tissue. Importance of genetic counseling is emphasized as at least half of gene carriers have some kind of clefting.     

Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development

Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6^+/−;Grhl3^+/−) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.     

Distinct functions for Bmp signaling in lip and palate fusion in mice

Previous work suggested that cleft lip with or without cleft palate (CL/P) is genetically distinct from isolated cleft secondary palate (CP). Mutations in the Bmp target gene Msx1 in families with both forms of orofacial clefting has implicated Bmp signaling in both pathways. To dissect the function of Bmp signaling in orofacial clefting, we conditionally inactivated the type 1 Bmp receptor Bmpr1a in the facial primordia, using the Nestin cre transgenic line. Nestin cre; Bmpr1a mutants had completely penetrant, bilateral CL/P with arrested tooth formation. The cleft secondary palate of Nestin cre; Bmpr1a mutant embryos was associated with diminished cell proliferation in maxillary process mesenchyme and defective anterior posterior patterning. By contrast, we observed elevated apoptosis in the fusing region of the Nestin cre; Bmpr1a mutant medial nasal process. Moreover, conditional inactivation of the Bmp4 gene using the Nestin cre transgenic line resulted in isolated cleft lip. Our data uncover a Bmp4-Bmpr1a genetic pathway that functions in lip fusion, and reveal that Bmp signaling has distinct roles in lip and palate fusion.     

Cleft lip, cleft palate, and velopharyngeal insufficiency

This article provides an introduction to the anatomical and clinical features of the primary deformities associated with unilateral cleft lip-cleft palate, bilateral cleft lip-cleft palate, and cleft palate. The diagnosis and management of secondary velopharyngeal insufficiency are discussed. The accompanying videos demonstrate the features of the cleft lip nasal deformities and reliable surgical techniques for unilateral cleft lip repair, bilateral cleft lip repair, and radical intravelar veloplasty.     

Identification of a Van der Woude syndrome mutation in the cleft palate 1 mutant mouse

Mutations in Interferon Regulatory Factor 6 (IRF6) have been identified in two human allelic syndromes with cleft lip and/or palate: Van der Woude (VWS) and Popliteal Pterygium syndromes (PPS). Furthermore, common IRF6 haplotypes and single nucleotide polymorphisms (SNP) alleles are strongly associated with nonsyndromic clefting defects in multiple ethnic populations. Mutations in the mouse often provide good models for the study of human diseases and developmental processes. We identified the cleft palate 1 (clft1) mouse mutant in a forward genetic screen for phenotypes modeling human congenital disease. In the clft1 mutant, we have identified a novel missense point mutation in the mouse Irf6 gene, which confers an amino acid alteration that has been found in a VWS family. Phenotypic comparison of clft1 mutants to previously reported Irf6 mutant alleles demonstrates the Irf6^clft1 allele is a hypomorphic allele. The cleft palate seen in these mutants appears to be due to abnormal adhesion between the palate and tongue. The Irf6^clft1 allele provides the first mouse model for the study of an etiologic IRF6 missense mutation observed in a human VWS family. genesis 48:303–308, 2010. © 2010 Wiley‐Liss, Inc.     

Nonsyndromic cleft lip and palate: no evidence of linkage to HLA or factor 13A.

Nonsyndromic cleft lip with or without cleft palate (CLP) is a common craniofacial anomaly, the etiology of which is not known. Population studies have shown that a large proportion of cases occur sporadically. Recently, segregation analyses applied to CLP families have demonstrated that an autosomal dominant/codominant gene(s) may cause clefting in cases. Associations of autosomal dominant CLP and nonsyndromic cleft palate (CP) with HLA and F13A genes on chromosome 6p have been suggested previously. Linkage to these two areas on chromosome 6p were tested in 12 autosomal dominant families with CLP. With a LOD score of -2 or less for exclusion, no evidence of linkage was found to four chromosome 6p markers. Multipoint analysis showed no evidence of a clefting locus in this region spanning 54 cM on chromosome 6p in these CLP families.     

Family history and socioeconomic risk factors for non-syndromic cleft lip and palate: A matched case-control study in a less developed country

Introduction. From an epidemiological point of view, non-syndromic orofacial clefts are the most common oral congenital deformities worldwide. Objective. Family histories were traced and socioeconomic risk factors were identified for non-syndromic cleft lip with or without cleft palate. Material and methods. A case-control study was carried out with 208 cases of non-syndromic cleft lip with or without cleft palate, and matched by age and sex with 416 controls. Cases were patients attending a referral clinic from 2002 through 2004 in Campeche, Mexico. A questionnaire was administered to collect sociodemographic and socioeconomic variables as well as familial background relevant to non-syndromic cleft lip with or without cleft palate. Conditional logistic regression models were used; adjusted odds ratios and 95% confidence intervals were calculated. Results. In the multivariate model, the following risk factors were identified: 1) low socioeconomic status; 2) birth in the southern region of Campeche state; 3) home delivery or delivery in a publicly funded hospital; 4) occurrence of prior non-syndromic cleft lip with or without cleft palate cases in the father′s or mother′s family: 5) having a sibling with non-syndromic cleft lip with or without cleft palate; 6) the proband having another malformation, and 7) a history of infections during pregnancy. Prenatal care consisting of vitamin supplementation was a protective factor for non-syndromic cleft lip with or without cleft palate (odds ratio=0.29). Conclusions. A "social gradient in health" was seen to link oral malformation with diet components, and several socioeconomic and socio-demographic factors broadly encompassed in low socioeconomic status. Further characterization of risk factors will guide the assemblage of a pro-active counseling and prevention program for families at risk for non-syndromic cleft lip and cleft palate.     

Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives

Objective To estimate the relative risk of recurrence of oral cleft in first degree relatives in relation to cleft morphology.Design Population based cohort study.Setting Data from the medical birth registry of Norway linked with clinical data on virtually all cleft patients treated in Norway over a 35 year period.Participants 2.1 million children born in Norway between 1967 and 2001, 4138 of whom were treated for an oral cleft.Main outcome measure Relative risk of recurrence of isolated clefts from parent to child and between full siblings, for anatomic subgroups of clefts.Results Among first degree relatives, the relative risk of recurrence of cleft was 32 (95% confidence interval 24.6 to 40.3) for any cleft lip and 56 (37.2 to 84.8) for cleft palate only (P difference=0.02). The risk of clefts among children of affected mothers and affected fathers was similar. Risks of recurrence were also similar for parent-offspring and sibling-sibling pairs. The “crossover” risk between any cleft lip and cleft palate only was 3.0 (1.3 to 6.7). The severity of the primary case was unrelated to the risk of recurrence.Conclusions The stronger family recurrence of cleft palate only suggests a larger genetic component for cleft palate only than for any cleft lip. The weaker risk of crossover between the two types of cleft indicates relatively distinct causes. The similarity of mother-offspring, father-offspring, and sibling-sibling risks is consistent with genetic risk that works chiefly through fetal genes. Anatomical severity does not affect the recurrence risk in first degree relatives, which argues against a multifactorial threshold model of causation.     

Linkage disequilibrium mapping of the gene for Margarita Island ectodermal dysplasia (ED4) to 11q23.

Margarita Island ectodermal dysplasia (ED4) is an autosomal recessive disorder characterized by unusual facies, dental anomalies, hypotrichosis, palmoplantar hyperkeratosis and onychodysplasia, syndactyly, and cleft lip/cleft palate. We have used an affected-only DNA-pooling strategy to carry out linkage disequilibrium mapping of the ED4 gene to 11q23. Haplotype analysis of four complex Margarita Island ED4 families localized the ED4 gene to an approximately 1-2-Mb interval spanned by just two YACs.     

干扰素调节因子-6基因与非综合征性唇腭裂的关系

先天性唇腭裂常分为综合征性唇腭裂和非综合征性唇腭裂两大类,其中非综合征性唇腭裂（nonsyndromic cleft lip with orwithout cleft palate,NSCL/P）约占先天性唇腭裂的70%-80%。国内外学者在对NSCL/P相关基因进行研究后发现,干扰素调节因子6（Interferon Regulatory Factor 6,IRF6）是迄今发现最有价值的并且与NSCL/P致病有相关性的热点基因之一,但是仍有部分学者通过实验研究后得出了相反的结论,故IRF6基因与NSCL/P之间的相关性说法不一,存在较大的争论,究竟前者是通过何种遗传方式作用于后者、仍然不十分清楚,且需要大样本的研究来证实。本文就IRF6基因与NSCL/P的关系做一综述,为研究两者的关系提供系统性参考。