Human Molecular Genetics, 2001, Vol. 10, No. 15 1591-1600
© 2001 Oxford University Press
Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype–phenotype correlation
1Department of Medical Genetics and 2Department of Ophthalmology, Ghent University Hospital, B-9000 Ghent, Belgium, 3School of Biological Sciences, Stopford Building, University of Manchester, Manchester, UK, 4The Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA 90095, USA, 5Institute of Genetic Medicine, Department of Pediatrics, Department of Medicine and Department of Plastic Surgery, The Johns Hopkins University School of Medicine, Baltimore, USA, 6Centre for Human Genetics, B-3000 Leuven, Belgium, 7Centre de Génétique Humaine, Institut de Pathologie et de Génétique, B-6280 Gerpinnes (Loverval), Belgium, 8Universitair Verplegingscentrum Brugmann-UKZKF, Brussels, Belgium, 9The John F. Kennedy Institute, Glostrup, Denmark, 10WHO Collaborating Center for Community Control of Inherited Diseases, Department of Medical Genetics, Peking Union Medical College, Beijing 100005, China, 11Department of Medical Genetics, University Hospital, Free University of Brussels, Belgium, 12Centre de Génétique, Hôpital Erasme, ULB, Brussels, Belgium, 13Department of Endocrinology and Reproductive Medicine, Hôpital Necker, Paris, France, 14Wallonia Center for Human Genetics, Liège University, Liège, Belgium and 15Immunogénétique Humaine, Institut Pasteur, Université Denis Didérot, Paris, France
Received April 18, 2001; Revised and Accepted May 25, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mutations in FOXL2, a forkhead transcription factor gene, have recently been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II, a rare genetic disorder. In BPES type I a complex eyelid malformation is associated with premature ovarian failure (POF), whereas in BPES type II the eyelid defect occurs as an isolated entity. In this study, we describe the identification of novel mutations in the FOXL2 gene in BPES types I and II families, in sporadic BPES patients, and in BPES families where the type could not be established. In 67% of the patients studied, we identified a mutation in the FOXL2 gene. In total, 21 mutations (17 of which are novel) and one microdeletion were identified. Thirteen of these FOXL2 mutations are unique. In this study, we demonstrate that there is a genotype–phenotype correlation for either types of BPES by the finding that mutations predicted to result in a truncated protein either lacking or containing the forkhead domain lead to BPES type I. In contrast, duplications within or downstream of the forkhead domain, and a frameshift downstream of them, all predicted to result in an extended protein, cause BPES type II. In addition, in 30 unrelated patients with isolated POF no causal mutations were identified in FOXL2. Our study provides further evidence that FOXL2 haploinsufficiency may cause BPES types I and II by the effect of a null allele and a hypomorphic allele, respectively. Furthermore, we propose that in a fraction of the BPES patients the genetic defect does not reside within the coding region of the FOXL2 gene and may be caused by a position effect.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) (MIM 110100) is a rare genetic disease occuring either sporadically or as an autosomal dominant disorder. In BPES type I, a complex eyelid malformation is associated with premature ovarian failure (POF); whereas in BPES type II, the eyelid defect occurs as an isolated entity (1). BPES has been mapped to chromosome 3q23, on the basis of cytogenetic rearrangements (2–5) and linkage analyses (6–10). However, the results of a single linkage study provided evidence for a second BPES locus on chromosome 7p21–p13 (MIM 601649) (11).
Positional cloning efforts resulted in the refined mapping of the BPES locus at 3q23 (12–14) and in the identification of BPESC1 (15) and C3orf5 (16), two candidate genes for BPES at 3q23 which are disrupted by the respective translocation breakpoints at 3q23 of two different BPES patients carrying a t(3;4) and a t(3;7) translocation (2,4). However, no disease-causing mutations of these genes were found in cytogenetically normal BPES patients, suggesting a position effect as the possible mechanism underlying the disorder in these patients.
This hypothesis was confirmed by the recent identification of a novel forkhead transcription factor gene FOXL2, which was shown to be mutated in seven cases of BPES which included both BPES types I and II (16,17). The FOXL2 gene belongs to the family of winged-helix/forkhead transcription factors, which are involved in a variety of developmental processes (18). The predicted FOXL2 protein of 376 amino acids contains a characteristic monomeric 100 amino acid DNA-binding forkhead domain which is identical to the mouse ortholog Pfrk/Foxl2. An alanine-rich domain, which is believed to be responsible for transcriptional repression activity, is found downstream of the forkhead domain. Similar alanine-rich regions are found in other developmental DNA-binding proteins, including the homeobox protein EVX1, the Msx-1 homeotic gene and the Drosophila homeotic genes kruppel and engrailed (19). With the exception of these two domains, no similarities to other known proteins or domains have been identified. Expression studies have shown that mouse Foxl2 is predominantly expressed in the mesenchyme of the protruding ridges of developing mouse eyelids during the most critical period for eyelid development, and in ovarian follicular cells, but not in the oocyte of the adult mouse ovary, consistent with the presumed role of FOXL2 in early eyelid development and ovarian maintenance (16). In addition to the FOXL2 gene, only five other human forkhead genes have been shown to be mutated in genetic syndromes (20–29) (Table 1).
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POF or amenorrhea for more than 6 months associated with elevated gonadotrophins before the age of 40 affects 1% of women in the general population (30). POF can be caused by chemotherapeutical, immunological or genetic mechanisms, such as defects in X-linked and autosomal recessive and dominant genes. BPES is an autosomal dominant disorder associated with POF, and FOXL2 should therefore be considered as a candidate gene for isolated POF.
In this study we have screened for FOXL2 mutations in a cohort of patients with BPES type I, type II or with an unknown type of BPES, and in 30 POF patients. In 67% of the BPES patients tested, 21 FOXL2 mutations (17 of which are novel), and one microdeletion were detected. Thirteen of these FOXL2 mutations are unique. No causal mutations were detected in the patients with isolated POF. The spectrum of mutations detected in FOXL2 strongly suggests that there is a genotype–phenotype correlation for BPES types I and II and that BPES types I and II are caused by FOXL2 haploinsufficiency resulting in a null allele and a hypomorphic allele, respectively.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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As a result of our screening, we identified 21 FOXL2 mutations (Fig. 1A), and one microdeletion. None of these mutations were present in 200 normal control chromosomes nor in any of the unaffected family members analyzed. All relevant information is summarized in Table 2 and Figures 1A and B and 2.
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Mutations leading to a truncated FOXL2 protein
In eight families that were screened, one previously reported and seven novel mutations were found which lead to a truncated predicted protein resulting in complete (Fig. 1BA), incomplete (Fig. 1BB–E) or no loss of the forkhead domain (Fig. 1BF–H).
A dinucleotide deletion (290–291delCA) resulting in a truncated predicted protein which lacks the forkhead domain (Figs 1BA and 2A) causes BPES type I in family f-50/F1.
A novel nonsense mutation 486C
G (Y83X) was found in f-25/F (Fig. 2B), and a single base pair deletion (404delC) was found in family f-20/F (Fig. 2C). A de novo 23 bp deletion (672–694del23) was found in a sporadic BPES patient (f-29/S) (Fig. 2D). A single base pair insertion (568–569insT) was found in all affected persons of family f-28/F (Fig. 2E). All four of these mutations were located within the forkhead domain and lead to a truncated predicted protein, containing an incomplete forkhead domain (Fig. 1BB–E, respectively).
The previously reported nonsense mutation 892CT (Q219X) was found in affected members of family f-27/F1, a large BPES type I pedigree (Fig. 2F) (31). In a male sporadic BPES patient (f-19/S) we identified a de novo single base pair insertion (945–946insC) (Fig. 2G). In a BPES type I family f-57/F1 (Fig. 2H) (7), an 8 bp duplication was found (1149–1156dup8). These three mutations were located downstream of the forkhead domain and lead to truncated predicted proteins containing an intact forkhead domain (Fig. 1BF–H, respectively).
Mutations causing an in-frame deletion of a single amino acid and a missense mutation
A de novo in-frame deletion within the forkhead domain (490–492delATC) (I85del) was found in a sporadic BPES patient f-18/S (Fig. 2I) (family data not shown). This mutation causes a deletion of an isoleucine in the forkhead domain (Fig. 1BI), which is conserved in mouse Pfrk/Foxl2 and the human FOXN2 and FOXN3 genes.
A novel CT transition (887CT) (S217F) causing a missense mutation downstream of the forkhead domain was found in the affected individuals of family f-17/F (Figs 1BJ and 2J), but was not present in unaffected persons and in 200 normal controls.
Mutations leading to extension of the FOXL2 protein
We found seven different mutations, of which six were novel and one has previously been reported, in 11 BPES families. These mutations lead to an extension of the predicted protein (Fig. 1BK–Q). A novel in-frame duplication within the forkhead domain (415–429dup15), extending the forkhead domain with five hydrophobic amino acids (VALIA) (Figs 1BK and 2K) causes BPES type II in family f-12/F2, since individual I:2 has an offspring (Fig. 2K). However, in her clinical history we notice menstrual problems.
In one BPES type II family (f-03/F2) we identified a combined in-frame deletion and duplication within the polyalanine tract (909–911delAGC; 912–938dup27), extending the polyalanine tract of the predicted protein with eight alanines (Figs 1BL and 2L). Interestingly, in the clinical history of affected individuals II:2 and II:3 fertility problems were present. In family f-34/F2 (Fig. 2M) (8) and in the sporadic BPES patients f-13/S and f-40/S (family data not shown), we found the previously reported in-frame 30 bp duplication (909–938dup30) within the polyalanine tract. A similar previously unreported 30 bp in-frame duplication in the polyalanine tract (900–929dup30) was found in family f-37/F2 (Fig. 2N) and in a sporadic BPES patient f-10/S (family data not shown). Both in-frame duplications result in 10 additional alanines in the polyalanine tract of the predicted protein (Fig. 1BM and N). They cause BPES type II in families f-34/F2 and f-37/F2, since affected females transmit the mutation to their offspring, and an unassigned type of BPES in sporadic cases in which the mutations were shown to be de novo.
In the sporadic patient f-36/S we identified a de novo single base pair deletion (1335delG) (Fig. 2O). Two novel single base pair insertions (1164–1165insA and 1041–1042insC) were identified in a sporadic BPES patient f-11/S (Fig. 2P) and in two unrelated BPES type II families, f-51/F2 and f-56/F2 (Fig. 2Q) (7), respectively. These three frameshift mutations, located downstream of the polyalanine tract result in an extension of the predicted protein downstream of the polyalanine tract (Fig. 1BO–Q, respectively).
Microdeletion of FOXL2 and other genes
In one BPES family (f-60) (family data not shown) a girl and her father were affected with BPES and mental retardation. Karyotypes were normal, but in both patients we found a microdeletion by fluorescence in situ hybridization (FISH) analysis using PACs previously mapped in the BPES critical region (14); in 100% of the mitoses studied (50 per probe), we found a heterozygous deletion of PACs 108-L15 (Fig. 3), 169-C10, 50-I6, 204-J22, 204-O7 and 300-F16 containing FOXL2, C3orf5 (16), BPESC1 (15), the retinol-binding protein 1 and 2 genes (RBP1 and RBP2), ß '-COP (14) and other as yet unidentified genes. The breakpoints of this microdeletion and the contribution of each of the genes to the patients’ phenotype will be determined in further studies.
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FOXL2 screening in POF patients
We screened 30 patients with isolated POF for FOXL2 mutations and no pathogenic mutations were identified.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In this study, we present a broad spectrum of non-synonymous FOXL2 mutations within, upstream and downstream of the FOXL2 forkhead domain in BPES patients. Interestingly, no obvious neutral base substitutions were detected. The positions of the FOXL2 mutations with respect to the forkhead domain are similar to those described in other FOX genes (Table 1), but FOXL2 mutations within and upstream of the forkhead domain have not been reported previously (Table 2).
Our data confirm that the eyelid defect and the POF in BPES type I are caused by the pleiotropic effect of FOXL2 by the identification of two novel and one known mutation in BPES type I families, leading to a predicted truncated protein either lacking or containing the forkhead domain, respectively. Furthermore, we described additional unique mutations resulting in predicted truncated proteins with incomplete loss of the forkhead domain in families where we could not determine the type of BPES, mainly due to lack of endocrinological data of the pre-pubertal affected females or because the affected patient was a sporadic male. The previous study presented only predicted truncated proteins which retained the forkhead domain in the causation of BPES type I (16).
In the case of mutations predicted to produce a truncated protein containing a partial or a complete forkhead domain, a dominant negative effect cannot be excluded because the truncated protein may still be able to bind to DNA but fail to activate transcription. However, FOXL2 haploinsufficiency may be the more likely mechanism since such mutations may lead to an unstable mutant transcript undergoing nonsense-mediated decay (32).
The novel mutation reported in this study which causes absence of the forkhead domain, and thus disruption of the function of DNA-binding, provides stronger support to the hypothesis of FOXL2 haploinsufficiency resulting in the presence of a null allele as a causative mechanism for BPES type I.
Another argument for the mechanism of haploinsufficiency and the effect of a null allele is provided by the identification of a microdeletion including FOXL2 and other genes in a father and his daughter both affected with BPES and mental retardation. Furthermore, three BPES patients carrying a balanced translocation have been reported in whom the BPES phenotype is caused by a position effect instead of direct disruption of FOXL2 (5,15,16). Interestingly, position effects are specifically prevalent in human genetic diseases involving haploinsufficiency of developmental transcription factors that have a spatially and temporally restricted pattern of expression, such as the PAX6 and the PITX2 genes, which are involved in aniridia and the Rieger syndrome, respectively (33).
In clinically well characterized BPES type II families we identified mutations that are predicted to result in extended proteins, consistent with the findings of Crisponi et al. (16). In a BPES type II family we identified a unique in-frame duplication in the forkhead domain, which is the first duplication within the forkhead domain presumed to cause BPES type II. The pathogenic effect of this duplication may be suspected by the co-segregation with the disease in this family, by the absence in 200 control chromosomes, and by extension of the highly conserved and functionally important forkhead domain with five hydrophobic amino acids (VALIA). A recent study indicated that the forkhead domain of the FOXC1 gene contains separable DNA-binding and transactivation functions (34). Consistent with the hypothesis of haploinsufficiency being the mechanism underlying BPES and supposing that the forkhead domain in FOXL2 has similar functional characteristics, this mutation may be expected to act as a hypomorphic allele by reducing transactivation properties of the forkhead domain, rather than acting as a null allele by disturbing the DNA-binding activities.
In addition, we identified three different duplications in the polyalanine tract in BPES type II families as well as in sporadic patients. The in-frame duplications (900–929dup30 and 909–938dup30) are not present in 200 control chromosomes and have been proven to be de novo in the current study as well as in the study of Crisponi et al. (16), providing strong arguments for their causality. Causality of the combined deletion and duplication (909–911delAGC; 912–938dup27), which co-segregates with the disease in a BPES type II family and which is absent in 200 normal chromosomes, may be suspected from the fact that it has the same effect as the two other causal in-frame duplications in the polyalanine tract and that it arises by the same mechanism as these two duplications. The three types of duplications extending the polyalanine tract are hypothesized to act as a hypomorphic allele, therefore causing BPES type II. Nine of the 28 FOXL2 mutations reported so far (32%) are duplications in the polyalanine tract. Since these duplications occur in unrelated families originating from different ethnic backgrounds, this domain may be considered as a mutational hotspot. Duplications around position 900 may be explained by a replication error. The sequence involved in the recurrent duplication 909–938dup30 is an almost perfect palindrome itself. Besides, the first half of this palindrome is self-complementary with the sequence immediately upstream of it. Therefore, the second half is a direct repeat with respect to the sequence just upstream of the 909–938 palindrome. During replication, temporary fusion of the new helix of the lagging strand most likely may lead to formation of a hairpin involving the first half of this palindrome and the sequence preceding it. Then, the second half will be free to hybridize with the template DNA just 5' of 909. After resuming replication, the insertion will be fixed due to newly synthesized strand slippage if it escapes the repair mechanisms. A similar mechanism can be proposed for duplication 900–929. However, two hairpins may be needed to account for the facts (900–906 and 907–927). This makes the template available for the 928–930 GGC that might prime replication. Mechanisms involving DNA hairpins have been proposed to explain ‘indel’ mutations in other disorders (35,36).
Apart from the duplications, we found three frameshift mutations downstream of the polyalanine tract in BPES type II families and in sporadic BPES patients. These mutations, resulting in a predicted extended protein downstream of the polyalanine tract, have not been described thus far in the causation of BPES type II. They are supposed to act by the same effect as the duplications.
The unique missense mutation located immediately upstream of the polyalanine tract is the first one reported in FOXL2. This missense mutation causes the non-conservative substitution of a serine, a polar amino acid, by a phenylalanine, a bulky hydrophobic amino acid. By BLASTP analysis no orthologs other than the highly conserved mouse Pfrk/Foxl2 and the goat ortholog (unpublished data) were identified in which the evolutionary conservation of this amino acid could be assessed. As this mutation co-segregates with the disease, as no other FOXL2 mutation was found in this family, as the missense was not found in 200 normal control patients, and as this causes a drastic amino acid change, we presume that it is pathogenic and may point to another functionally important region of the protein. The identification of this mutation is important because all previously reported missense mutations in other FOX genes were located within the forkhead domain (Table 1). This missense change could act as a loss-of-function mutation by decreasing transcriptional control, which is known to be strictly regulated in those rare developmental genetic diseases in which involvement of FOX genes has been demonstrated. The effect of this missense mutation and of the other disease causing mutations will be further studied by molecular modeling and DNA binding experiments similar to those described by Saleem et al. (34).
In this study we showed that menstrual abnormalities and reduced female fertility were present in two BPES type II families in which two different duplications were found, suggesting that there may be phenotypic overlap between the two types of BPES and that the menstrual history and fertility should also be carefully monitored in affected females of BPES type II families.
In 67% of the patients studied a FOXL2 mutation including a microdeletion was found: in the three BPES type I families included in this study a FOXL2 mutation was found (100%), in the nine BPES type II families six FOXL2 mutations were found (67%) and in five of seven (71%) BPES families of unknown type and eight of 14 (57%) sporadic BPES patients a FOXL2 mutation and one microdeletion was found. Among the families in which no FOXL2 mutations were found (33%), there was one large BPES type II family that had previously been linked to 3q23 (10). Further studies in the FOXL2 gene and in the surrounding region may elucidate whether, for instance, a large FOXL2 deletion or a position effect is causing the disorder in this family. Moreover, in other BPES families in which no linkage analysis has been performed and in sporadic patients it cannot be excluded that the disorder is caused by another gene located at the second BPES locus at 7p.
Since the FOX genes involved in human genetic diseases typically have a pleiotropic phenotypic effect it was a logical step to screen the FOXL2 gene in 30 POF patients without any evidence of an eyelid defect. However, no causal mutations were detected in these patients, which suggests that FOXL2 mutations play a minor, if any, role in the pathogenesis of this disorder.
In conclusion, this study is the second report documenting FOXL2 mutations in BPES patients. It provides new insights into the causation of BPES in that a wide mutation spectrum containing a large number of novel and unique mutations at previously unreported positions are presented. In addition, our data provide strong evidence for FOXL2 haploinsufficiency as a causative mechanism for BPES types I and II, by the effect of a null allele and a hypomorphic allele, respectively. However, when the DNA-binding domain is present in the mutant protein, a dominant negative effect cannot be excluded. This study provides further evidence for a genotype–phenotype correlation, which predicts truncated proteins to result in BPES type I and extended proteins to result in BPES type II. To elucidate the molecular mechanisms underlying the pathogenesis (haploinsufficiency and/or dominant negative effect) as well as to produce clear-cut predictions of the phenotypic effects of the mutations, more in-depth biochemical and mutational studies will be required.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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BPES patients
A total of 33 probands from three BPES type I families, nine type II families, 14 sporadic cases and seven BPES families whose BPES type we were unable to assess were screened for mutations by direct sequencing of the entire coding region of FOXL2. For all mutations found, we analyzed the segregation within the family for familial cases and both parents for most sporadic patients to confirm the de novo nature of the mutation. The BPES patients included in this study presented with blepharophimosis, ptosis, epicanthus inversus and telecanthus. They all had a normal karyotype. None of the families or individuals had been included in previous FOXL2 mutation studies. Clinical data on the following families have been reported previously: f-56, f-57 (7), f-34 (8) and f-27 (31).
POF patients
Thirty patients presenting with POF without BPES were also included in the FOXL2 mutation screening. These women, aged from 18 to 31 years, were initially referred for secondary amenorrhea. All of them had a normal pubarche and telarche. Diagnosis of POF was confirmed by high levels of follicle stimulating hormone (FSH) (>50 mUI/l) and low plasma estradiol levels. Their karyotypes were normal and no anti-ovarian antibodies were detected.
FOXL2 screening
For mutation analysis, PCR amplification of the FOXL2 coding region on genomic DNA was performed essentially as described by Crisponi et al. (16), with the exception that primers C and F were modified in order to match perfectly to the complementary sequence: C, 5'-CAG CCT CAA CGA GTG CTT CA-3'; F, 5'-GAG GAG CGA CAG GAG CTT AGG-3'. Direct sequencing of the PCR products was performed with primers A, B, G, H, F and a nested sequencing primer 871U18, 5'-CCC ATG CCC TAT GCC TCC-3' using BigDye Terminators (Applied Biosystems). Fragments were electrophoresed on an ABI Prism 377 sequencer (Applied Biosystems).
FISH
Probes were labeled with digoxygenin (digoxygenin-11-dUTP, Boehringer, 0.4 mM) by standard nick-translation. FISH was performed as described previously (14). Slides were mounted in Vectashield (Vector Laboratories) and diamidinophenylindole (DAPI) for counterstaining and observed under a standard epifluorescence microscope equipped with a 100 W mercury lamp. Images were recorded with the ISIS digital imaging system (Meta Systems).
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ACKNOWLEDGEMENTS |
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We are indebted to Nathalie Goderis for her expert technical assistance. We are most grateful to the families who participated in this study and to the clinicians and researchers who made this work possible: H. Shi, H. Ilyina, P. De Sutter, J. Schuil, C. Toomes, K. Nield and J.J. Delaey. This work was supported by the Fund for Scientific Research grant KAN 315-201.99N (E.D.B. and L.M.), and by the National Institutes of Health grants P60DE13078 (E.W.J.) and T32GM7471 (V.P.).
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FOOTNOTES |
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+ To whom correspondence should be addressed at: Department of Medical Genetics, Ghent University Hospital-OK5, De Pintelaan 185, B- 9000 Ghent, Belgium. Tel: +32 9 240 3603; Fax: +32 9 240 4970; Email: Ludwine.Messiaen@rug.ac.be
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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