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American Journal of Medical Genetics 98:256–262 (2001) Differences in Complexity of Isolated Brachydactyly Type C Cannot Be Attributed to Locus Heterogeneity Alone R.J.H. Galjaard,1* L.I. van der Ham,2 N.A.S. Posch,2 P.F. Dijkstra,3 B.A. Oostra,1 S.E.R. Hovius,2 E.J.F. Timmenga,4 G.J. Sonneveld,2 A.J.M. Hoogeboom,1 and P. Heutink1 1Department of Clinical Genetics, Erasmus ni ersit Rotterdam ni ersit ospital Rotterdam, Rotterdam, Netherlands 2Department of Plastic and Reconstructi e Sur er , ni ersit ospital Rotterdam, Rotterdam, Netherlands 3Department of Radiolo , an an Breemen Institute, Amsterdam, Netherlands 4Department of Plastic and Reconstructi e Sur er , Reinier de Graaf Gasthuis, Delft, Netherlands Hereditary isolated brachydactyly type C (OMIM 113100) mostly follows an autosomal INTRODUCTION dominant pattern of inheritance with a marked variability in expression. This phe- Inherited isolated brachydactylies (shortening of notype has been mapped to two different loci digits) were classified by Bell [1951] into five different on chromosomes 12q24 and 20q11.2. The types (A–E), including three subtypes (A1–A3). This latter locus contains the cartilage-derived classification is based on anatomical observations. morphogenetic protein (C ) gene, in Fitch [1979] extended this classification, also taking which a null mutation has been found in into account the complexity of the phenotype of patients patients with malformations restricted to the with brachydactylies. upper limbs. A more complex brachydactyly Brachydactyly type C (OMIM 113100) is distin- type C phenotype has been mapped to chro- guished from the other brachydactyly types by: the mosome 12q24. Differences in complexity of presence of short middle phalanges with relative these phenotypes have been attributed to sparing of the fourth phalanx; the usual presence of a locus heterogeneity. Clinical subclassifica- shortened first metacarpal; and hypersegmentation of a tion based on the degree of complexity of the digit, mostly involving the proximal phalanges of the phenotype has therefore been suggested. We second and third digits [Bell, 1951; Fitch, 1979; Wood, present patients with a complex brachydac- 1988]. The isolated brachydactyly type C phenotype tyly type C phenotype in whom there is mostly follows an autosomal dominant mode of inheri- considerable intra- and interfamilial varia- tance [Bell, 1951; Haws, 1963], with marked variability bility in expression. We show that clinical in expression [Haws, 1963; Sanz and Gilgenkrantz, subclassification based on the complexity of 1988; Camera et al., 1994] and penetrance [Haws, 1963; the brachydactyly type C phenotype related Sanz and Gilgenkrantz, 1988]. to the genetic defect is not feasible. We Locus heterogeneity has been described. Brachy- present evidence that differences in complex- dactyly type C with anomalies of the upper and lower ity are not only due to locus heterogeneity, limbs [Haws, 1963] was mapped to chromosome 12q24 but that genetic modifiers and/or environ- [Polymeropoulos et al., 1996]. Brachydactyly type C with mental factors must also play a role. anomalies restricted to the upper limbs [Robin et al., # 2001 Wiley-Liss, Inc. 1997] was mapped to chromosome 20q11.2 [Lin et al., 1996]. A disease-causing mutation was found in this KEY WORDS: Brachydactyly type C; clin- family in the cartilage-derived morphogenetic protein ical heterogeneity; CDMP1 (CDMP)1 gene, which belongs to the transforming mutation; genetic hetero- growth factor (TGF)-b superfamily [Polinkovsky et al., geneity 1997]. It has been suggested that the interfamilial variability of brachydactyly type C could be explained *Correspondence to: R.J.H. Galjaard, Department of Clinical by this locus heterogeneity [Robin et al., 1997; OMIM]. Genetics, Erasmus University Rotterdam, P.O. Box 1738, 3000 In this study we describe two new families with DR Rotterdam, Netherlands. brachydactyly type C. We used these families for E-mail: [email protected] haplotype and mutation analysis. We detected a new Received 1 June 2000; Accepted 18 October 2000 mutation causing brachydactyly type C in one family, Published online 10 January 2001 with involvement of both the upper and lower limbs, ß 2001 Wiley-Liss, Inc. &KDSWHU C mutations cause complex Brachydactyly C 257 clearly showing that differences in complexity cannot 8.5-D12S392. Twenty-three members of family 2 were be attributed to locus heterogeneity alone. genotyped using the microsatellite markers D12S97 and D12S1045. For chromosome 20q11.2, the following SUBJECTS AND METHODS markers were selected with the order and distances according to Ge ne thon: D20S112-10.9-D20S106-30.9- Patients D20S120. Analysis of polymorphisms was performed The index patient of the first family, named hereafter essentially as described by Weber and May [1989]. PCR family 1, was seen for short hands. An interview and conditions were: 10 min denaturation at 948C, followed physical examination was done of 13 available family by 25 cycles of 948C for 30 sec, 558C for 30 sec, 728C for members, shown in the pedigree diagram in which the 90 sec, and final extension at 728C for 5 min. PCR order of birth was changed for the sake of privacy products were separated on denaturing polyacrylamide (Fig. 1). Posterioranterior (PA) radiographs of the gels. Alleles were visualized by autoradiography. hands and feet were made of a subset of these For mutation analysis, the sequence of the CDMP1 individuals. PA radiographs of the hands were made gene (also named the growth/differentiation factor GD 5 from all cases except II7, III10, and III11. Radiographs of ( ) gene) was obtained from Ho tten et al. [1994] the feet were made of the individuals last mentioned, and Genbank X80915. Four sets of primers were used to except for cases I2,II2, and II5. The length of the 19 amplify the ORF and the intron-exon boundaries. The tubular bones of the hand was measured. The results reverse primers for amplification of the second part of were compared to normative data and graphically exons 1 and 2 were obtained from Polinkovsky et al. presented as a Z-score metacarpophalangeal pattern [1997]. The forward primer for amplification of the first (MCPP) profile [Garn et al., 1972; Poznanski, 1984]. part of exon 2 was obtained from Thomas et al. [1997]. The index patient of the second family, named The other primers were based on published sequences. hereafter as family 2, was seen for further evaluation Set 1, forward primer: GCTGCTGCCGCTGTTCT- of a Mallet finger. A pedigree of seven generations was CTTTGGTGTCATTCAGC; reverse primer: GGTGCC- constructed (Fig. 3). Fifteen individuals, thirteen of TTGCCTCCGGGAAGCTGTCCT. Set 2, forward whom are affected with brachydactyly, were evaluated primer: CTGAACCCAAGCCAGGACA. Set 3, reverse by interview, physical examination, and PA radio- primer: ACAGGTACTCATACACGG. Set 4, forward graphs of the hands. The length of the 19 tubular primer: AGAAGGCCCTGTTC CTGGTG. PCR products bones of the left hand were measured, and all were from genomic DNA were analyzed by automated se- given a Z-score MCPP. quencing (ABI Prism 377 DNA sequencer, Perkins- Elmer, Foster City, CA), using big dye chemistry. Molecular Studies Allele-specific oligohybridization (ASO) was used on all members of family 1 and on 100 control chromo- Blood was obtained with informed consent from somes (25 normal Dutch males and 25 normal Dutch thirteen members of family 1, nine of whom are affected females from the general population). The mutation with brachydactyly type C; and from twenty-seven found in family 2 creates a novel Bgl I restriction site. members of family 2, sixteen of whom are affected. The first part of exon 1 of the CDMP1 gene was Genomic DNA was isolated as described before [Miller amplified by PCR, using primerset 1, using genomic et al., 1988]. For genotyping individuals of family 1, DNA from 27 members of family 2 and from 100 control the following five microsatellite markers, located on chromosomes. Bgl I was added to the purified PCR chromosome 12q24, were chosen with the order and products, and the digested products were visualized by distances in cM according to the CLHC) database: ethidiumbromide staining on a 2 agarose gel. D12S342-6.7-D12S2078-12.6-D12S97-0.6-D12S1045- RESULTS Patients Fa ily . The medical history of the index patient (number III5 in the pedigree diagram, Fig. 1, age 10 at the time of evaluation) is unremarkable, except for congenital luxation of the left hip and postaxial polydactyly of her right foot. Results of physical exami- nation are normal except for short hands (Fig. 2, left upper photo) and feet. Radiographs of her right hand show short proximal phalanges (PPh) I–III; middle phalanges (MPh) II–V, with relative sparing of IV; and of PPh II, III, and MPh II-V of her left hand (Fig. 2, left middle photo). Pseudoepiphyses of metacarpal (MC) I, II, and PPh IV, and V were also noted. Radiographs of her feet show short middle phalanges of digits II–V and short distal phalanges (Fig. 2, left lower photo). Her younger sister (number III3 in the pedigree Fig. 1. Pedigree diagram of family 1. diagram, Fig. 1), originally considered to be unaffected, &'03PXWDWLRQVFDXVHFRPSOH[%UDFK\GDFW\O\& *53**;- .= *5 Fig. 2. Left upper photo: hands of the index patient (III5 in the pedigree diagram) of family 1, showing short digits with relative sparing of the fourth digits. Right upper photo: hands of patient III4 of family 1, showing relatively short thumbs. Left middle photo: radiograph of the hands of patient III5 of family 1. (MC, metacarpal; PPh, proximal phalanx; MPh, middle phalanx.) Right hand: short PPh I–III, MPh II–V with relative sparing of MPh IV. Left hand: short PPh II, III, MPh II–V. Pseudoepiphyses of MC I, II, PPh IV,V. Right middle photo: radiograph of the hands of patient III4 of family 1. Short MC I. Pseudoepihyses of MC I, II, PPh III, IV. Left lower photo: radiograph of the feet of patient III5 of family 1. Short middle (II–V) and distal phalanges. Right lower photo: radiograph of the feet of patient III4 of family 1. Short middle phalanges. G1C >?D54 D? 81F5 B5<1D9F575C 97 B978D 51B<95B # + 1>4 #&8 ?> 1 #&& @?>?CC5?EC @?CD1H91< @? &KDSWHU 6>=*=287< ,*><. ,8695.A ;*,1B-*,=B5B 97 &5497B55 4917B1= ?6 61=9 Short hands and feet are present in the other affected DG121 mutation was found in exon 1 of the patients’ members of this family who have been examined. CDMP1 gene (Fig. 4), but not in unaffected individuals Fa ily . The index patient (VI-74 in the pedigree of family 2. The mutation was found in all patients, but diagram, Fig. 3) has no congenital malformations not in 100 normal chromosomes. It also results in a except for short hands. Radiographs of her hands frameshift, a premature stop codon, and presumably a show short MC I–IV, MPh II, III, and PPh III, as truncated protein as described before. well as hypersegmentation of PPh II and III (Fig. 5, Table I). DISCUSSION The results of measurements of the 19 tubular bones of the left hand of this patient and other examined Considerable variation in expression of the brachy- affected members of this family are given in Table I. dactyly type C phenotype is clearly present in the families, and has also been described previously in the literature [Haws, 1963; Sanz and Gilgenkrantz, 1988; Haplotype Analysis Camera et al., 1994]. We do not find that one particular Haplotype analysis shows segregation of the disease middle phalanx is consistently the shortest one in our phenotype with markers on chromosome 20q11.2, but patients (Table I). This agrees with the studies of not on chromosome 12q24, in both families. Herrmann [1974] and Walbaum [1983], which give conflicting data concerning the most severely affected middle phalanx. Therefore, we also do not consider it Mutation Analysis feasible to subtype brachydactyly type C based on Subsequent mutation analysis by sequencing showed clinical criteria alone. a deletion of a single base (DC493) in exon 1 of the Locus heterogeneity has been proposed to explain the CDMP1 gene (Fig. 4) in all patients of family 1. The differences in complexity of brachydactyly type C mutation was found in all patients, but not in 100 [Robin et al., 1997]. The theory is that there could be normal control chromosomes. The mutation results in a a very restricted time in embryonic development during frameshift and leads to a premature stop codon. This is which a CDMP1 gene defect might cause malforma- expected to result in a truncated protein. This mutation tions of only the upper limbs, since the upper limbs has not been described before. Another mutation develop one to two days prior to the lower limbs [Robin &'03PXWDWLRQVFDXVHFRPSOH[%UDFK\GDFW\O\& *53**;- .= *5 et al., 1997]. We reject this hypothesis because we have found that null mutations in this gene can cause malformations of both the upper and lower limbs. Moreover, a restricted time frame does not seem feasible, since the CDMP1 gene is involved in growth [Nakamura et al., 1964; Chang et al., 1994; Storm et al., 1994], and in patterning of the bones of the limbs [Storm and Kingsley, 1996], and because it is expressed in precartilage condensations, in cartilaginous tissues pre-and postnatally, and in hypertrophic chondrocytes [Chang et al., 1994]. We show that patients whose upper and lower limbs are affected by complex brachydactyly have a disease-causing mutation in the CDMP1 gene. Therefore, we conclude that the degree of complexity of brachydactyly type C cannot be explained by locus heterogeneity alone. We attribute differences in complexity of the brachy- dactyly type C phenotype to variation in expression. The phenotypic variation between the families in our study versus those in Robin’s families is most likely not caused by locus heterogeneity, but by genetic modifiers and/or environmental factors. Fig. 4. Left upper photo: normal sequence of exon 1 of the CDMP1 gene ACKNOWLEDGMENTS around base 493, indicated by an arrow. Left lower photo: single base (DC493) deletion, indicated by an arrow, in exon 1 of the CDMP1 gene in a We thank the families for their cooperation. We patient of family 1. The sequences of the two alleles that are now out of acknowledge R. Koppenol and T. de Vries Lentsch for frame are visible following the deletion. Right upper photo: normal sequence of exon 1 of the CDMP1 gene around base 121 which is indicated their contribution to the illustrations. We thank Prof. by an arrow. Right lower photo: single base DG121) deletion, indicated by an Dr. H Galjaard and the Foundation of Clinical Genetics, arrow, in exon 1 of the CDMP1 gene in a patient of family 2. The sequences of the two alleles that are now out of frame are visible following the deletion. Rotterdam, for their support. 97 '149?7B1@8 ?6 D85 81>4C ?6 D85 9>45H @1D95>D + ?6 61=94 8I@5BC57=5>D1D9?> ?6 &&8 1>4 &KDSWHU 262 Galjaard et al. REFERENCES Online Mendelian Inheritance in Man, http://www3.ncbi.nlm.nih.gov/ Omim Bell J. 1951. On brachydactyly and symphalangism. Treasure of Human Inheritance 5:1–30. Polinkovsky A, Robin NH, Thomas JT, Irons M, Lynn A, Goodman FR, Reardon W, Kant SG, Brunner HG, Burgt van der I, Chitayat D, Camera G, Camera A, Costa M, Mantero R. 1994. Pitfalls of genetic McGaughran J, Donnai D, Luyten FP, Warman ML. 1997. Mutations in counselling in brachydactyly type C. Am J Med Genet 53:199–201. CDMP1 cause autosomal dominant brachydactyly type C. Nature Chang SC, Hoang B, Thomas JT, Vukicevic S, Luyten FP, Ryba NJP, Kozak Genet 17:18–19. CA, Reddi AH, Moos Jr M. 1994. Cartilage-derived morphogenetic Polymeropoulos MH, Ide SE, Magyari T, Francomano CA. 1996. Brachy- proteins. 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Nippon Seikeigeka Gakkai Zasshi 58:8:835–845. 13A:883–887. &KDSWHU ;OLQNHGUHFHVVLYHLQKHULWDQFHRIUDGLDOUD\GH¿FLHQFLHV LQDIDPLO\ZLWKIRXUDIIHFWHGPDOHV *DOMDDUG5-+.RVWDNRJOX1+RRJHERRP$-0%UHHGYHOG*-YDQGHU/LQGH+& +RYLXV6(52RVWUD%$6DQGNXLMO/$$NDUVX$1+HXWLQN3(XU-+XP*HQHW European Journal of Human Genetics (2001) 9, 653 ± 658 ã 2001 Nature Publishing Group All rights reserved 1018-4813/01 $15.00 www.nature.com/ejhg ARTICLE X-linked recessive inheritance of radial ray deficiencies in a family with four affected males Robert-Jan H Galjaard*,1, Naci Kostakoglu4, Jeannette JM Hoogeboom1, Guido J Breedveld1, Herma C van der Linde1, Steven ER Hovius2, Ben A Oostra1, Lodewijk A Sandkuijl1, A Nurten Akarsu3 and Peter Heutink1 1Department of Clinical Genetics, Erasmus University/University Hospital, Rotterdam, The Netherlands; 2Department of Plastic and Reconstructive Surgery, University Hospital Rotterdam, The Netherlands; 3Gene Mapping Laboratory, Basic and Applied Research Center of the Department of Pediatrics, Hacettepe University, Ankara, Turkey; 4Department of Plastic and Reconstructive Surgery, Hacettepe University, Ankara, Turkey Radial ray deficiencies are frequently associated with additional clinical anomalies and have a heterogeneous aetiology.X-linked forms are extremely rare.We report a family in which four male relatives show bilateral absence of the radius with presence of the thumbs and associated anomalies.The segregation of the phenotype is suggestive for X-linked recessive inheritance.This is confirmed by performing linkage analysis using 24 markers spanning the X chromosome in which a maximum lod score of 1.93 for DXS8067 and DXS1001 is obtained.We defined a critical region of maximal 16.2cM on the X chromosome with haplotype analysis. European Journal of Human Genetics (2001) 9, 653 ± 658. Keywords: radial ray deficiency; X-linked recessive; linkage mapping Introduction variable associated anomalies. Since all affected individuals Radial ray deficiencies have an incidence of about 1 : 10 000 are male, and no male to male transmission was observed, an live births.1 They occur either isolated or associated with X-linked recessive mode of inheritance was assumed. We additional clinical anomalies.1,2 Radial ray deficiencies are tested 24 microsatellite markers on the X chromosome, clinically and genetically very heterogeneous. Many cases are performed linkage analysis, and constructed haplotypes. The sporadic and considered to be multifactorial in origin. results of these studies indicate that the phenotype of our Although radial ray deficiencies are more commonly present patients is linked to Xq24-25. in males than in females,1 X-linked inheritance has only been described for a few cases. Four families with possibly X- linked VACTERL-H (OMIM 314390) have been published.3,4 Subjects and methods Furthermore, a phenotype of radial aplasia and associated Patients anomalies in a male and his maternal uncle (OMIM 312190), There are no consanguineous marriages in this family of suggestive of X-linked recessive inheritance has been Turkish origin. Physical examination of the index patient described.5 (III-5, Figure 1) and his parents was done several times in We present a family in which four male relatives have total the Netherlands. Patient KM (III-1, Figure 1) and his absence of the radii, presence of the thumbs, and several parents, patient AS and one of his unaffected brothers (II- 6 and II-5, Figure 1), were examined in Turkey. Information of the remaining family members was *Correspondence: R-J H Galjaard, Department of Clinical Genetics, obtained by family history. Photographs were examined Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The of the unaffected sib(s) of patients OS and KM (III-1,2,4, Netherlands.Tel: +31 10 4087214; Fax: +31 10 4087200; E-mail: [email protected] Figure 1) and the other unaffected brother of patient AS Received 2 March 2001; revised 22 May 2001; accepted 30 May 2001 (II-7, Figure 1). X-linked radial ray deficiency R-JH Galjaard et al 654 Figure 1 Pedigree diagram of the family. The markers shown are restricted to those between DXS1059 and DXS8078. Distances between markers in cM: DXS1059-2.71-DXS8055-4.9-DXS8067-0-DXS1001-0-DXS1212-6.26-DXS1047-0.77-DXS994-0-DXS8078. The three patients (II-6, III-1, III-5 pedigree diagram) share an identical haplotype telomeric from DXS990. Two unaffected males (II-5, II-7 pedigree diagram) have also part of this haplotype except for the region between DXS8055 and DXS1212. Cytogenetic studies final extension at 728C for 5 min. PCR products were GTG -banded metaphases from blood lymphocytes were used separated on denaturing polyacrylamide gels. Alleles were for karyotyping the index patient. Skin fibroblasts were tested visualised by autoradiograpy. for chromosome breakage after exposure to diepoxybutane (DEB). Mutation analysis Three sets of primers (available upon request) were designed Molecular studies from genomic sequence obtained from Genbank (Accession Blood was obtained from 18 family members after informed no X98253) to amplify the coding region and intron ± exon consent and genomic DNA was isolated as described before.6 boundaries of the ZNF 183 gene. PCR products from genomic We tested 24 microsatellite markers; 20 from GeÂneÂthon,7 DNA of all the patients and normal (family) members were DXS451 and DXS538 from Reed et al,8 and DXS7132 and sequenced on an automated sequencer (Perkin Elmer's ABI DXS6800 from the integrated genetic map provided by the Prism 377 DNA sequencer, Foster City, USA) using big dye Center of Medical Genetics, Marshfield, USA (htpp:// chemistry. For the IAP 3 gene mRNA sequence was obtained www.marshmed.org). We choose this map because the from Genbank (U45880) to design eight sets of primers distances between most markers, except DXS451, are well (available upon request) for amplification and sequencing of defined. For DXS451 the relative position was estimated cDNA according to standard procedures. according to published data.8 Analysis of polymorphic markers was performed essentially as described before.9 PCR Linkage data conditions were : 10 min denaturation at 948C followed by Two point linkage analysis using the LINKAGE program, 25 cycles of 948C for 30 s, 558C for 30 s, 728C for 90 s, with a version 5.01,10 was performed on all markers tested except for European Journal of Human Genetics X-linked radial ray deficiency R-JH Galjaard et al 655 DXS451, and DXS538, DXS1068, DXS7132, DXS8064 which as OS and an extension deficit of the 2nd to 4th were not informative in this family. X-linked recessive metacarpophalangeal joints of boths hands (Figure 2). His inheritance of radial anomalies was assumed with full lower extremities show abducted hip joints, postnatally penetrance in males, no anomalies in female carriers, and a developed contractures of both knees with popliteal gene frequency of 1 : 1000. Multipoint linkage analysis was pterygiae (Figure 2), and bilateral absence of the patellae performed by subsequent four-point analyses on these (Table 1). There is no history of a bleeding disorder. Standard markers. laboratory tests showed normal results. Cardiac evaluation did not reveal an abnormality. Patient AS (II-6, Figure 1) is a 28-year-old male with short Results stature. He shares the anomalies of the upper extremities Patients with OS. In addition he has hypoplastic middle and distal The abnormalities noticed in the four patients are phalanges of the 2nd to 4th fingers of his left hand. The summarised in Table 1. The index patient OS (III-5, Figure middle and distal phalanges of the index finger of his right 1) was born after an uncomplicated pregnancy and hand are also hypoplastic. All his fingers show an extension delivery. At birth his weight was 3200 g (10th centile), his deficit. He has genu varum of the right leg, but he has also length 50 cm (50th centile) and his head circumference hypoplasia of the 3rd to 5th toes and the 4th and 5th toes of (HC) 35 cm (50th centile). The following congenital his left and right foot, respectively. In the past thrombocy- malformations were noticed: Upper extremities: bilateral topenia was excluded. Cardiac ultrasound revealed a 3rd short curved forearms, radial deviation with an extension degree aortic stenosis attributed to rheumatic fever in the deficit of 908 of the wrists, and short thumbs. Lower extremities: genu varum of the right leg and slight subluxation of the right knee. Radiographs of the upper extremities showed absence of the radii, broad curved ulnae and hypoplasia of the thumbs. Radiographs of the skeleton except for the extremities showed no abnormalities. A Dandy-Walker malformation was seen on a CT-scan. Transposition of the great arteries (TGA), and an atrial septal defect (ASD) type 2 were seen on ultrasound. Ultrasound examination of the abdomen showed no abnormalities. Thrombocytopenia was excluded repeatedly, also during the first year of life. Other hematological disorders were also excluded on routine hematologic laboratory tests. At the age of 2 years and 7 months his mental development was normal. His weight was 11 kg (3rd centile), his length was 86 cm (10th centile), and his HC was 47 cm (3rd centile). His left arm and legs are shown in Figure 2. Patient KM (III-1, Figure 1) is a 7-year-old male with short stature. He has the same anomalies of the upper extremities Table 1 Summary of anomalies in patients of present paper Anomalies OS KM AS 4th Pat Total Short stature 7 + + ? 2/3 Absent radii + + + + 4/4 Hypoplastic thumbs + + 7 ? 2/3 Figure 2 Extremities of the patients OS and KM (III-1, III-5 Hypoplastic fingers 77 + ? 1/3 pedigree diagram, resp.). Left upper photo: Short curved left Contracture fingers + + + ? 3/3 Hypoplastic toes 77 + ? 1/3 forearm with radial deviation and an extension deficit of the Genu varum knee + 7 + ? 2/3 wrist, and hypoplastic thumb of patient OS. Right upper photo: Contractures knees 7 + 7 ? 1/3 Genu varum of the right leg of patient OS. Left lower photo: Absent patellae 7 + 7 ? 1/3 Bilateral short curved forearms, extension deficit of the elbows Cardiac anomaly + 7 + ? 2/3 and 2nd to 4th MCP joints of the hands, hypoplastic thumbs, Dandy-Walker malf. + 77? 1/3 abducted hip joints, and contractures of the knees with pterigiae + indicates presence; 7 indicates absence of anomaly; ? indicates poplitiae of patient KM. Right lower photo: Absent radius, short not known. curved ulna and hypoplastic thumb. European Journal of Human Genetics X-linked radial ray deficiency R-JH Galjaard et al 656 past. Ultrasound of the abdomen did not show anomalies. is in accordance with data from GeÂneÂthon and Nagaraja et The fourth patient (II-10, Figure 1) had bilateral short curved al.7,11 Therefore, we choose the order DXS8067, DXS1001, forearms with an extension deficit of his wrists. He did not and DXS1212 (Figure 1). The unaffected males II-5, and II-7 have associated anomalies. He died of an infectious disease share part of the haplotype of the patients except for the about 2-3 months after birth. All the other relatives of the region between DXS8055 and DXS1212 (Figure 1). The results male patients are healthy. A radiograph of the forearm of the of the linkage and haplotype analysis show the responsible mother of our index patient did not show an abnormality. gene defect must be localised between these two markers. According to the genetic map of the X chromosome of Cytogenetic studies Marshfield, this interval is about 4.9 cM. According the The index patient has a normal male karyotype. No genetic map of GeÂneÂthon and that of Nagaraja et al,7,11 this spontaneous or induced breakage of chromosomes was interval is about 16.2 cM. We performed mutation analysis noticed after DEB exposure. for two candidate genes in this interval; the ZNF183 and IAP 3 genes and did not find a disease causing mutation in these Molecular studies genes. Twenty-four markers spanning the X chromosome at regular intervals were tested. With two point linkage analysis a maximum lod score of 1.93 for DXS8067 and DXS1001 at Discussion zero recombination frequency was obtained. This result is We report a family with a radial ray deficiency, presence of confirmed by multipoint analysis (Figure 3). thumbs and associated anomalies. In our view, our patients Haplotypes were constructed for the entire chromosome. have a previously unreported phenotype. Our differential The patients share an identical haplotype from DXS990 to diagnosis included autosomal recessive TAR syndrome, DXS1193. A double recombinant would be present for Fanconi anaemia (FA), X-linked recessive VACTERL-H individual II-5 in case DXS1212 is positioned centromeric syndrome, and a phenotype described by Gibson et al.5 of DXS1001 as indicated by the Marshfield data. Our data TAR syndrome can be rejected when thrombocytopenia is indicate that DXS1212 is located telomeric of DXS1001. This excluded.12 FA is an unlikely diagnosis in the absence of Figure 3 Multipoint lodscores for twenty tested X-chromosomal markers. X-axis: the distance in cM. The most telomeric marker tested DXS996 was used as a point of reference (0), and the one on the right is DXS1193. The highest lodscores are obtained in the region in between DXS8055 and DXS1212. European Journal of Human Genetics X-linked radial ray deficiency R-JH Galjaard et al 657 chromosome breakage after DEB exposure.13 There are 12 The gene defect could also be involved in differentiation or cases published with X-linked VACTERL-H; 10 cases growth of the radius. Disturbance of the chondrofication summarised by Lomas et al.,3 and two cases by Froster et process could result in a fibrous radius;17,18 disturbance of the al.4 In Table 2 we summarise these cases, the two cases with ossification process in a cartilagenous one.19 Alternatively, X-linked radial aplasia,5 and the cases presented in this the gene defect could also be involved in disturbance of study. Our index patient has been evaluated for all defects apoptotic cell death eliminating mesenchymal cells which summarised by Lomas et al.3 He shares only radial aplasia would normally be the precursors of the radius resulting in and a cardiac anomaly with the cases described with X- the absence of the radius. It has been suggested that the linked VACTERL-H cases. Moreover, his life expectancy is radius and the ulna are derived from one mesenchymal different from that in these patients. The cases described by condensation separated by apoptotic cell death in the opaque Gibson et al.,5 only share radial aplasia with our patients. patch.20,21 Considering the pathogenic mechanisms de- Therefore, we do not think our patients have the same scribed above we searched for a likely candidate gene or phenotype. transcript in our critical region with a possible function in The phenotype of our patients can be caused by a defect of pattern formation, cell differentiation, or apoptosis. Genes a single gene or several closely linked genes. Alternatively, coding for zinc finger (ZF) containing proteins are known to large variability in the phenotype might be caused by either be often involved in pattern formation. We searched the modifier genes located elsewhere on the genome or OMIM database and found the RING finger containing IAP environmental factors. A literature search for patients with (Inhibitor of apoptosis protein) 3 gene to be a likely a radial ray deficiency and a chromosomal anomaly candidate. IAP 3 is mapped to Xq25 by in situ hybridisation.22 involving our defined critical region revealed no cases, which It is expressed in all fetal and adult tissues except peripheral limits the search for a gene causing the phenotype to a blood leucocytes.23 candidate gene approach. Since absence of the radii is the We also searched the Human Gene Map (http:// most consistently present anomaly in our patients we www.ncbi.nlm.nih.gov/genemap) and found the ZNF183 hypothesise that the responsible gene must be involved in gene of the RING finger gene family. This gene is patterning, differentiation, or apoptosis during human ubiquitously expressed and its function is unknown.24 We embryonic limb development. In our patients the gene did not find a mutation in these genes in our patients. We are defect could have its major effect on the mesenchymal currently searching for additional families as an approach to condensation process of the anterior (radial) part of the upper identify the responsible gene, which could be a starting point limb, comparable with the effects of the mutant TBX5 for functional studies in order to obtain better insight in the gene.14,15 Haploinsufficiency of this gene causes mainly pathogenesis of the disorder. anterior limb malformations in patients with Holt-Oram syndrome, whereas haploinsufficiency of the TBX3 gene causes mainly posterior limb malformations in patients with Acknowledgments the ulnar-mammary syndrome.14,16 We thank the family for their cooperation. R Koppenol and T de Vries Lentsch are acknowledged for their work on the illustrations. We thank Prof Dr H Galjaard and the foundation of Clinical Genetics Rotterdam for their support. Table 2 Summary of anomalies in cases with VACTERL-H and X-linked radial aplasia a b c d e f Anomalies 1 2 3 4 5 6 References 1 Froster UG, Baird PA: Upper limb deficiencies and associated Hydrocephalus 4/4 2/2 4/4 2/2 1/1 0/3 malformations: a population-based study. Am J Med Genet 1992; Radial anomalies 4/4 2/2 4/4 2/2 2/2 4/4 44:767±781. Anal atresia 2/2 2/2 3/4 1/2 1/2 0/4 2 Tentamy SA, McKusick VA: Radial defects; in The genetics of Genital anomalies 2/2 1/1 2/3 ? 1/2 0/4 hand malformations. Alan R Liss, Inc., for the National Renal anomalies 2/2 2/2 2/2 1/2 ? 0/2 Foundation-March of Dimes, New York, BD:OAS 1978, 14: T.E.F./Atresia 1/1 1/2 1/3 1/2 ? 0/1 44 ± 48. Vertebral anomalies 1/1 ? 0/1 1/2 ? 0/1 3 LomasFE,DahlstromJE,FordJH:VACTERLwithhydrocepha- Cardiac anomalies ? ? 1/3 1/2 ? 2/2 lus: family with X-linked VACTERL-H. Am J Med Genet 1998; 76: Lung anomalies ? ? 0/3 1/2 ? 0/1 74 ± 78. Gut anomalies 1/1 1/1 0/3 1/2 ? ? 4 Froster UG, Wallner SJ, Reusche E, Schwinger E, Rehder H: Accessory spleens 1/1 0/1 0/3 ? ? 0/2 VACTERL with hydrocephalus and branchial arch defects: Microphthalmia 1/1 0/1 0/3 2/2 ? 0/3 prenatal, clinical, and autopsy findings in two brothers. Am J Cleft palate 1/1 2/2 0/3 1/2 ? 0/4 Med Genet 1996; 62:169±172. Ear anomalies 2/2 ? 0/3 2/2 ? 0/4 5 Gibson CC, Genest DR, Bieber FR, Holmes LB: X-linked Died 4/4 2/2 4/4 2/2 ? 1/4 phenotype of absent radius and anogenital anomalies. Am J Authors: 1a, Lomas et al.3: family 1, four cases; 2b, family 2 cases; Med Genet 1993; 45:743±744. 3c, family 3, four cases; 4d, Froster et al.4: two cases; 5e, Gibson et 6 Miller SA, Dykes DD, Polesky HF: A simple salting out procedure al.5: two cases; 6f, present paper: four cases. Anomalies indicated for extracting DNA from human nucleated cells. Nucleic Acids when known; ? means not known in any case of the family. Res 1988; 16: 1215. European Journal of Human Genetics X-linked radial ray deficiency R-JH Galjaard et al 658 7DibC,Faure S, Fizames C et al:TheGeÂneÂthon human genetic 17 Heikel HVA: Aplasia and hypoplasia of the radius. Acta Orthop linkage map. Nature 1996; 380: A124 ± 129. Scand Suppl 1959; 39:9±150. 8 Reed PW, Davies JL, Copeman JB et al: Chromosome-specific 18 Flatt AE: Radial clubhand; in The care of congenital hand microsatellite sets for fluorescence-based, semi-automated anomalies. Quality Medical Publishing Inc, St. Louis, Missouri genome mapping. Nat Genet 1994; 7: 390 ± 395. 1994, 2nd ed, pp 366 ± 341. 9 WeberJL,MayPE:AbudantclassofhumanDNApolymorphisms 19 Duncan GJ, Omer GE, Garcia JF, Latimer E: Magnetic resonance which can be typed using polymerase chain reaction. Am J Hum imaging to visualize the internal anatomy in the Baller-Gerold Genet 1989; 44: 388 ± 396. syndrome. JHandSurg1993; 18A:588±592. 10 Lathrop GM, Lalouel JM: Easy calculations of lodscores and 20 Hinchliffe JR, Ede DA: Limb development in the polydactylous genetic risks on a small computer. Am J Hum Genet 1984; 36: talpid3 mutant of the fowl. JEmbryolExpMorp1967; 17:385± 460 ± 465. 404. 11 Nagaraja R, McMillan S, Kere J et al: X chromosome map at 75-kb 21 Dawd DS, Hinchliffe JR: Cell death in the ``opaque patch'' in the STS resolution, revealing extremes of recombination and GC central mesenchyme of the developing chick limb: a cytologi- content. Gen Res 1997; 7:210±222. cal, cytochemical and electron microscopic analysis. JEmbryol 12 Hall J. Thrombocytopenia and absent radius (TAR) syndrome. J Exp Morp 1971; 3:401±424. Med Genet 1987; 24:79±83. 22 Rajcan-Separovic E, Liston P, Lefebvre C, Korneluk RG: Assign- 13 Giampietro PH, Adler-Brecher B, Verlander PC, Pavlakis SG, ment of human inhibitor of apoptosis protein (IAP) genes xiap, Davis JG, Auerbach AD: The need for more accurate and timely hiap-1, and hiap-2 to chromosomes Xq25 and 11q22-23 by diagnosis in Fanconi anemia: a report from the International fluorescence in situ hybridization. Genomics 1996; 37: 404 ± 406. Fanconi Anemia Registry. Pediatrics 1993; 91 no 6: 1116 ± 1120. 23 Liston P, Roy N, Tamai K et al: Suppression of apoptosis in 14 Yi Li Q, Newbury-Ecob RA, Terrett JA et al:Holt-Oramsyndrome mammalian cells by NAIP and a related ramily of IAP genes. is caused by mutations in TBX5, a member of the Brachyury (T) Nature 1996; 379:349±353. gene family. Nat Genet 1997; 15:21±29. 24 Frattini A, Faranda S, Bagnasco L et al: Identification of a new 15 Basson CT, Bachinsky DR, Lin RC et al: Mutations in human member (ZNF183) of the Ring finger gene family in Xq24-25. limb and cardiac malformation in Holt-Oram syndrome. Nat Gene 1997; 192: 291 ± 298. Genet 1997; 15:30±35. 16 Bamshad M, Lin R, Law DJ, et al: Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet 1997; 16:311±315. European Journal of Human Genetics &KDSWHU $QHZORFXVIRUSRVWD[LDOSRO\GDFW\O\W\SH$%RQ FKURPRVRPHTT *DOMDDUG5-+6PLWV$377XHUOLQJV-+$0%DLV$*%HUWROL$YHOOD$0 %UHHGYHOG*-GH*UDDII(2RVWUD%$+HXWLQN3(XU-+XP*HQHW European Journal of Human Genetics (2003) 11, 409–415 & 2003 Nature Publishing Group All rights reserved 1018-4813/03 $25.00 www.nature.com/ejhg ARTICLE A new locus for postaxial polydactyly type A/B on chromosome 7q21–q34 Robert-Jan H Galjaard*,1, Arie PT Smits2, Joep HAM Tuerlings2, Aagje G Bais1, Aida M Bertoli Avella1, Guido Breedveld1, Esther de Graaff1, Ben A Oostra1 and Peter Heutink1 1Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands; 2Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands Postaxial polydactyly (PAP) is the occurrence of one or more extra ulnar or fibular digits or parts of it. In PAP-A, the extra digit is fully developed and articulates with the fifth or an additional metacarpal/ metatarsal, while it is rudimentary in PAP-B. Isolated PAP usually segregates as an autosomal dominant trait, with variable expression. Three loci are known for PAP in humans. PAPA1 (including PAP-A/B in one patient) on 7p13 caused by mutations in the GLI3 gene, PAPA2 on 13q21–q32 in a Turkish kindred with PAP-A only, and a third one (PAPA3) in a Chinese family with PAP-A/B on 19p13.1–13.2. We identified a fourth locus in a large Dutch six-generation family with 31 individuals including 11 affecteds. Their phenotype varied from either PAP-A, or PAP-B to PAP-A/B with or without the co-occurence of partial cutaneous syndactyly. We performed a whole-genome search and found linkage between PAP and markers on chromosome 7q. The highest LOD score was 3.34 obtained at D7S1799 and D7S500 with multipoint analysis. European Journal of Human Genetics (2003) 11, 409–415. doi:10.1038/sj.ejhg.5200982 Keywords: postaxial polydactyly; linkage; fourth locus; chromosome 7q21–q34 Introduction syndrome, or of a multiple congenital anomaly case.3 The Postaxial polydactyly (PAP) is the occurrence of one or syndromic cases have a heterogeneous aetiology, for more extra ulnar or fibular digits or parts of it.1 The instance trisomy 13. Partial cutaneous syndactyly between incidence varies from 1/3300 to 1/630 and from 1/300 to toes 2–3, 4–5, and other, is a frequent finding in 1/100 livebirths in Caucasian- and African-Americans, individuals with PAP.3 respectively.2 The phenotype of PAP is usually subdivided Isolated PAP usually segregates as an autosomal domi- into types A and B. In type A, the extra digit is fully nant trait, with variable penetrance and expression. developed and articulates with the fifth or an additional Penetrance rates of 0.68 and 0.43 have been estimated for metacarpal/metatarsal. In type B, it is rudimentary types A and B, respectively,4 although higher estimates and mostly presents as a skin tag (pedunculated have been published.5 postminimus).1 Currently, there are three loci for isolated PAP in PAP is either seen as an isolated malformation or humans. PAPA1 (MIM 174200) has been described in three associated with other defects. Associated defects can be families with PAP-A/B with a disease-causing mutation in restricted to the limbs. If not, they can be part of a the human transcription regulator GLI3 gene on 7p13.6.6–8 PAPA2 (MIM 602085) on 13q21–q32 has been reported in a Turkish kindred with PAP-A only.9 PAPA3 has recently *Correspondence: R-JH Galjaard, Department of Clinical Genetics, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The been published in a Chinese family with PAP-A/B on Netherlands. Tel: +31 1040 87214; Fax: +31 1040 87200; 19p13.1–13.2.10 E-mail: [email protected] We present a fourth locus in a family with PAP-A/B and Received 15 November 2002; revised 31 January 2003; accepted 4 February 2003 partial cutaneous syndactyly on 7q21–q34. In our family A new locus for PAP on chromosome 7q21–34 R-JH Galjaard et al 410 there are patients with three types of PAP (type A, B or A/B) phenotype is strikingly consistent in four preceding with or without syndactyly. generations of VI-1 (Figure 3A). Linkage analysis for PAP A genome search was carried out with 24 individuals of our Materials and methods family including 11 affecteds with PAP. Evidence of linkage A large six-generation family with PAP and/or syndactyly was found with a marker on chromosome 7q35 (data not was ascertained (Figure 1). After informed consent was shown). Additional markers around D7S1799 were tested given, 31 individuals were clinically examined and blood to identify the smallest region in which the gene involved samples were taken from them. Genomic DNA was isolated has to reside. With two-point linkage analysis the highest from peripheral blood lymphocytes as described before.11 LOD score obtained was 3.18 for marker D7S1799 at y ¼ 0 From four affected individuals, deceased at the time of (Table 2). Using multipoint analysis, LOD scores above 3.20 examination, anamnestic data were available (Table 1). were found for markers D7S1799–D7S495, so evidence for Initially, a genome search was started with 24 individuals linkage is spread over a large genomic region (Figure 4). of our family including all 11 affecteds with PAP (Figure 1). LOD scores were calculated using the MLINK and LINK- 12 Haplotype analysis MAP programs of the LINKAGE package version 5.1. The Only affecteds with PAP and individual VI-6, with bilateral following model was used: PAP as an autosomal dominant partial cutaneous syndactyly of IDS 2, share the same condition with a penetrance of 0.9, a gene frequency of haplotype for markers between D7S1799 and D7S495 0.0003, a phenocopy rate of 0.05, and equal recombination (Figure 1). In addition, they share their haplotype for rates between males and females. In this model only markers GATA63F08 and D7S2513 with the clinically individuals with PAP, including V-6, were considered to be normal individuals IV-19 and V-18, and individual VI-9 affected (Table 1). Allele frequencies were calculated from having only syndactyly (Figure 1). The maximum size of independent individuals of this family. In total, 26 the genomic regions located on chromosome 7q21–q34, additional polymorphic markers of chromosome 7 were between D7S1799 and D7S495, and GATA63F08 and selected from the Center of Medical Genetics, Marshfield D7S2513 is about 50 and 3.7 cM, respectively. Medical Research Foundation (htpp://research. Marshfield- No other locus associated with the PAP phenotype was clinic.org/genetics/). The most recently published high- identified in this family using the DNA pooling and shared resolution recombination map of the human genome of segment analysis (data not shown). Kong et al (htpp://genetics.nature.com) was also used. For marker GATA63F08, locus number D7S2202 has recently been assigned. The results of haplotype analysis in this Discussion family prompted us to determine if another locus could be We describe a large family with PAP-A/B and/or syndactyly. associated with the PAP- and the syndactyly phenotype. This family is interesting because of the presence of three A whole-genome screen was performed on all affecteds types of PAP with or without syndactyly. In addition, a except for V-6, five nonaffected and five control indivi- single individual with PAP-B (V-6) does not share the duals. Microsatellite markers from the Weber Human haplotype shared by the other affecteds with PAP-A/B. Screening Set V5 (n ¼ 363) were tested, DNA pooling and There is a longstanding debate in the literature if the shared segment analysis were performed essentially as PAP-A and PAP-B phenotypes are genetically hetero- described before.13 DNA quantity and quality were care- geneous. Differences between PAP-A and PAP-B concerning fully matched to ensure equal amplification. incidence, penetrance and side preference have been used to argue that the phenotypic distinction between them is also genetically determined.1,2,4,14 Until now, only families Results with individuals with the PAP-A or PAP-A/B phenotype Clinical findings have been used for genotyping; none of them includes the The clinical findings of 17 affected individuals with PAP PAP-B only phenotype. In our family individual V-6 with and/or syndactyly of our family are presented in Table 1. PAP-B only does not share the haplotype with other They do not have additional anomalies. PAP-A is the affecteds with PAP-A or PAP-A/B (Figure 1). In addition, predominant polydactyly phenotype. The expression of both of his alleles are transmitted to his offspring, who are both the PAP and syndactyly phenotypes is highly variable clinically normal. This indicates his phenotype is probably in our family, especially for descendants of III-7 and IV-5, caused by a genetic defect elsewhere on the genome, or less as examplified in Figure 2. This variability concerns likely, by a nongenetic factor. This is corroborated by the differences in involvement of upper/lower limbs, left/right finding that no other locus, associated with PAP-A/B, was side, type A and/or B regarding PAP, and the interdigital found in this family after we performed a whole-genome space(s) (IDS) and extent of syndactyly. However, the PAP search. In order to strengthen our findings we also tested European Journal of Human Genetics e ou o A ncrmsm 7q21–34 chromosome on Galjaard PAP R-JH for locus new A tal et uoenJunlo ua Genetics Human of Journal European Figure 1 Pedigree diagram of a subset of a family with PAP. Pedigree symbols: black ¼ PAP-A/B with or without cutaneous syndactyly. Black right upper quadrant ¼ PAP-B only. Black right lower quadrant ¼ cutaneous syndactyly digit 2–3 feet only. Haplotypes for eight chromosome 7 markers for 31 individuals. Shared haplotype for markers D7S1799–D7S495 between affecteds with PAP/syndactyly, except for V-6 (phenocopy) and VI-6 (nonpenetrance). 411 A new locus for PAP on chromosome 7q21–34 R-JH Galjaard et al 412 Table 1 Clinical findings of affecteds with PAP/syndactyly Patient No. PAP type PAP type Syndactyly Syndactyly PAP type PAP type Syndactyly Syndactyly left hand right hand left hand right hand left foot right foot left foot right foot I-1* P P ? ? P P ? ? II-2* A A ? ? A A ? ? III-1* N A IDS 4–5 N A A N N III-13* N N ? ? P P ? ? IV-2 A A N N A A N N IV-5 A A N N N N N IDS 4–5 IV-11 N N N N A A N IDS 5–6 IV-13 N A N IDS 4–5 A N IDS 4–6 N V-1AANNAANN V-6BBNNNNNN V-8AANNAANN V-10 A A N N A A N IDS 5–6 V-15 A B N IDS 2–3 A A N N VI-1 A A N N A A N N VI-6 N N N N N N IDS 2–3 IDS 2–3 VI-8 B B N N A A IDS 2–3 IDS 2–3 VI-9 N N N N N N IDS 2–3 IDS 2–3 *=anamnestic data, P=present, N=normal, ?=unknown, A=PAP-A, B=PAP-B, IDS=interdigital space. Figure 2 (a, b) Left and right hand, respectively, of VI-8 with PAP-B. (c) From left to right: feet of VI-6 with cutaneous syndactyly digits 2–3 only, normal feet of VI-7, feet with PAP-A/syndactyly digits 2–3 of VI-8. 10 other small families with PAP, but none of them was Syndactyly is the most frequent associated anomaly in linked to this 7q region. These findings are indicative of individuals with PAP.3 In syndactyly type II or synpoly- further genetic heterogeneity of PAP, except for the locus dactyly (SPD, MIM186000), the characteristic phenotype is harbouring the GLI3 gene. In our family, the PAP-A/B syndactyly between fingers 3–4, and toes 4–5 with or phenotype is genetically homogeneous as described before, without an extra finger/toe in the syndactylous web.15 but the PAP-A/B and PAP-B only phenotypes are genetically Polydactyly does not occur without syndactyly. SPD is heterogeneous. caused by a polyalanine tract expansion in the HOXD13 European Journal of Human Genetics A new locus for PAP on chromosome 7q21–34 R-JH Galjaard et al 413 Figure 3 (a) Feet of V-1 and VI-1 with PAP-A. (b) Right foot of IV-11 with PAP-A and complete cutaneous syndactyly digits 5–6. (c) Feet of VI-9 with cutaneous syndactyly digits 2–3 only. Table 2 Two-point linkage analysis between PAP/B and chromosome 7 markers at different recombination fractions Recombination fraction y Markers 0 0.01 0.05 0.1 0.2 0.3 0.4 D7S820 1.97 1.69 1.02 0.57 0.13 0.03 0.04 D7S1799 3.18 3.15 3.00 2.76 2.15 1.43 0.65 D7S525 2.44 2.43 2.33 2.15 1.66 1.06 0.44 D7S504 1.26 1.24 1.17 1.05 0.75 0.41 0.14 D7S500 2.64 2.59 2.38 2.11 1.54 0.94 0.39 D7S495 1.08 1.07 1.02 0.94 0.72 0.48 0.24 GATA63F08 2.00 1.96 1.81 1.60 1.13 0.65 0.24 D7S513 0.45 0.44 0.39 0.34 0.23 0.14 0.07 D7S661 0.84 0.51 0.09 0.06 0.11 0.05 0.01 gene on chromosome 2q31. This phenotype can be VI-9) with only cutaneous syndactyly IDS 2–3 of both feet differentiated from that in patients of our family. Their (Figures 2c and 3c). All patients with PAP-A/B, share the phenotype include an extra digit 5 without syndactyly, or same haplotype between markers GATA63F08 and with syndactyly between fingers/toes not typically present D7S2513 (Figure 1). This includes the clinically normal in patients with SPD (Table 1). Isolated syndactyly IDS 2–3 mother (V-18) and maternal grandfather (IV-19) of the of the feet has an incidence of 1.17/10 000 individuals.3 We individual with bilateral syndactyly IDS 2–3 of his feet looked if PAP and syndactyly could be genetically homo or (VI-9). There are two possible explanations for these heterogeneous in our family. PAP and syndactyly are observed phenotypes/genotypes. present in seven individuals (Table 1). Four individuals First, the region shared by all of them harbours the have PAP type A or A/B. There are two individuals (VI-6, gene(s) causing the PAP and the syndactyly phenotype, so European Journal of Human Genetics A new locus for PAP on chromosome 7q21–34 R-JH Galjaard et al 414 that GLI3 mutations cause PAP-A. In individuals with PAP- A/B, these mutations and environmental or stochastic factors could cause the PAP-B phenotype. In our view, it is difficult to envisage a major impact of the same environ- mental factor on patterning causing PAPA/B in V-15 and VI-8 in different generations excluding a genetic suscept- ibility for such a factor, although a stochastic factor could cause the phenotypic expression of PAP-A/B in V-15 and VI-8. We identified the fourth locus containing one or more genes involved in the PAP and syndactyly phenotype. This is based on our results of the genome scan, the linkage and haplotype analyses. The maximum size of the critical region between D7S820 and GATA63F08 is about 50 cM. Figure 4 Results of multipoint linkage analysis between PAP- This chromosome 7 region excludes genes previously A/B and chromosome 7 markers. Triangles indicate markers known to be involved in the polydactyly phenotype like used also in the two-point linkage analysis. From left to right: the sonic hedgehog- and GLI3 genes. We looked for D7S820, D7S1799, D7S525, D7S504, D7S500, D7S495, GATA63F08, D7S2513, D7S661. candidate genes and we found many genes with unknown functions which could be potential candidates, genes coding for zinc-finger containing proteins from which members are known to be involved in patterning in the PAP and syndactyly phenotypes are genetically homo- embryonic development, and two members of the Wnt geneous and the region would be about 3.7 cM. If so, four gene family. Wnt7a, located elsewhere, is shown to be individuals with PAP-A/B only are nonpenetrant for involved in dorsal–ventral patterning in the developing syndactyly. In addition, VI-6 and VI-9 with syndactyly limb.21 Wnt2 (MIM147870) and two variants of Wnt16 only do not show penetrance for the polydactyly pheno- (MIM606267) are located on 7q31. There are no data type. Moreover, the mother, the maternal grandfather and available on expression in limb since this is relatively rarely the great-grandfather of VI-9 are nonpenetrant for both looked for. Besides, we found a Wnt receptor frizzled PAP and syndactyly. The PAP phenotype is highly pene- homolog1 Drosophila (FZD1), mapped on 7q21. Frizzled1 trant in offspring of II-1 and II-2. Nonpenetrance of this (fz1) has distinct D–V domains of expression in mesench- phenotype in three successive generations in offspring of yme of developing footpads.22 Given the large number of II-5 and II-6 is an unlikely occurrence. candidate genes and the fact that none of these is an Besides, the syndactyly phenotype of VI-6 could be a obvious candidate, we did not perform mutation analysis variable expression of the syndactyly phenotype in this in our family. At this point we are pursuing other families branch of the family, with a different locus than that with PAP linked to this region in order to be able to narrow harbouring the gene mutation causing syndactyly of VI-9, down the region containing the gene associated with PAP taking the relatively high incidence of syndactyly IDS 2–3 and syndactyly in this family. of feet in the normal population into account. Alternatively and more likely, the PAP and syndactyly phenotypes are genetically heterogeneous in our family. In that case, the critical region is defined by the haplotype Acknowledgements We acknowledge the family for their cooperation, R Koppenol for his shared by patients with PAP-A/B only (Figure 1). If so, VI-6 work on the illustrations. We also acknowledge the Foundation of is the only case of nonpenetrance for the PAP phenotype in Clinical Genetics Rotterdam for their financial support. this family. This is in accordance with rates of penetrance for PAP from other families reported in the litera- ture.4,8,14,16 Penetrance is probably determined by modifier 17 References genes, analogous to the observation of Fawcett et al. They 1 Temtamy SA, McKusick VA: The genetics of hand malformations. described CRABPII knockout mice with an extra bone of New York: Alan R. Liss, 1978, pp 364–372. digit V and found that the penetrance of this phenotype 2 Temtamy SA: Polydactyly, postaxial; in Buyse ML (eds): Birth 17 defects encyclopaedia. Cambridge, MA: Blackwell Scientific, 1990, varies according to their genetic background. pp 1397–1398. We hypothesize that genetic background also affects the 3 Castilla EE, Lugarinho R, da Graca Dutra M, Salgado LJ: phenotypic expression of PAP-A and PAP-A/B. There are Associated anomalies in individuals with polydactyly. Am J Med two affected in our family with PAP-A/B (V-15, VI-8 Genet 1998; 80: 459–465. 4 Castilla EE, Paz J, Mutchinick O, Munoz E, Giorgiutti E, (Figure 2)). PAP types A and B in one individual has been Gelman Z: Polydactyly: a genetic study in South America. Am J described before.8,14,18 – 20 Radhakrishna et al.8 suggested Hum Genet 1973; 25: 405–412. European Journal of Human Genetics A new locus for PAP on chromosome 7q21–34 R-JH Galjaard et al 415 5 Scott-Emuakpor AB, Madueke E-DN: The study of genetic 13 Vaessen N, Heutink P, Houwing-Duistermaat JJ et al: A genome- variation in Nigeria. Hum Hered 1976; 26: 198–202. wide search for linkage-disequilibrium with type 1 diabetes in a 6 Radhakrishna U, Blouin J-L, Mehenni H et al: Mapping one form recent genetically isolated population from the Netherlands. of autosomal dominant postaxial polydactyly type A to Diabetes 2002; 51: 856–859. chromosome 7p15 –q11.23 by linkage analysis. Am J Hum Genet 14 Kucheira K, Kenue RK, Taneja N: An Indian family with postaxial 1997; 60: 597–604. polydactyly in four generations. Clin Genet 1981; 20: 36–39. 7 Radhakrishna U, Wild A, Greschik KH, Antanorakis SE: Mutation 15 Goodman FR: Limb malformations and the human HOX genes. in GLI3 in postaxial polydactyly type A. Nat Genet 1997; 17: Am J Med Genet 2002; 112: 256–265. 269–271. 16 Rayan GN, Frey B: Ulnar polydactyly. Plast Reconstr Surg 2001; 8 Radhakrishna U, Bornholdt D, Scott HS et al: The phenotypic 107: 1455–1457. spectrum of GLI3 morphopathies includes autosomal dominant 17 Fawcett D, Pasceri P, Fraser R, Colbert M, Rossant J, Giguere V: preaxial polydactyly type-IV and postaxial polydactyly type-A/B; Postaxial polydactyly in forelimbs of CRABP-II mutant mice. no phenotype prediction from the position of GLI3 mutations. Development 1995; 121: 671–679. Am J Hum Genet 1999; 65: 645–655. 18 Woolf CM, Myrianthopoulos NC: Polydactyly in American 9 Akarsu AN, Ozbas F, Kostakoglu N: Mapping of the second locus negroes and whites. Am J Hum Genet 1973; 25: 397–404. of postaxial polydactyly type A ( PAP-A2) to chromosome 13q21 – 19 Woolf CM, Woolf R: A genetic study of polydactyly in Utah. Am J q32. Am J Hum Genet 1997; 61 (Suppl): A265. Hum Genet 1970; 22: 75–88. 10 Zhao H, Tian Y, Breedveld G et al: Postaxial polydactyly type A/B 20 Ventruto V, Theo G, Celona A et al: A and B postaxial polydactyly (PAP-A/B) is linked to chromosome 19 p13.1 –13.2 in a Chinese in two members of the same family. Clin Genet 1980; 18: kindred. Eur J Hum Genet 2002; 10: 162–166. 342–347. 11 Miller SA, Dykes DD, Polesky HF: A simple salting out procedure 21 Parr B, McMahon AP. Dorsalizing signal Wnt-7a required for for extracting DNA from human nucleated cells. Nucleic Acids Res normal polarity of D –V and A – P axes of mouse limb. Nature 1988; 16: 1215. 1995; 374: 631–640. 12 Lathrop GM, Laouel JM: Easy calculations of lodscores and 22 Cygan JA, Johnson RL, McMahon AP: Novel regulatory genetic risks on a small computer. Am J Hum Genet 1984; 36: interactions revealed by studies of murine limb pattern in 460–465. Wnt-7a and En-1 mutants. Development 1997; 124: 5021–5032. European Journal of Human Genetics &KDSWHU ,VRODWHGSRVWD[LDOSRO\GDFW\O\W\SH%ZLWKPRVDLFLVPRI DVXEPLFURVFRSLFXQEDODQFHGWUDQVORFDWLRQOHDGLQJWRDQ H[WHQGHGSKHQRW\SHLQRIIVSULQJ *DOMDDUG5-+YDQGHU/LQGH+&(XVVHQ%+-GH9ULHV%%$:RXWHUV&+2RVWUD %$GH*UDDII(+HXWLQN3$P-0HG*HQHW $ American Journal of Medical Genetics 121A:168–173 (2003) Clinical Report Isolated Postaxial Polydactyly Type B With Mosaicism of a Submicroscopic Unbalanced Translocation Leading to an Extended Phenotype in Offspring Robert-Jan H. Galjaard,* Herma C. van der Linde, Bert H.J. Eussen, Bert B.A. de Vries, Cokkie H. Wouters, Ben A. Oostra, Esther de Graaff, and Peter Heutink Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands Postaxial polydactyly (PAP) is characterized INTRODUCTION by the presence of one or more extra ulnar or Postaxial polydactyly (PAP) is characterized by the fibular digits or parts of it. PAP type B pre- presence of one or more extra ulnar or fibular digits or sents frequently as a skin tag on the hand(s). parts of it. The most widely accepted phenotypic clas- It is usually an isolated malformation, but sification distinguish types A and B [Temtamy and in 6.6% it is associated with other congenital McKusick, 1978]. In PAP-A, the extra digit is fully abnormalities, mostly well recognizable syn- developed and articulates with the fifth or an additional dromes. We present a male with PAP-B only metacarpal/metatarsal. In PAP-B, it usually presents as and his daughter with an extended pheno- a skin tag (pedunculated postminimus). type including mental retardation and minor Incidence figures of PAP vary from 1/3300 to 1/630, dysmorphisms. Both share a cytogenetically and from 1/300 to 1/100 livebirths in Caucasian- and balanced t(4;7)(p15.2;q35), present in mosai- African-Americans, respectively [Temtamy, 1990]. This cism in the father. We found microdeletions is mainly due to differences seen in PAP-B [Castilla et al., associated with the breakpoints. The chro- 1973; Woolf and Myrianthopoulos, 1973]. mosomal regions described here have not PAP is usually present as type B of the left hand(s), been previously associated with the PAP-B without associated congenital anomalies [Castilla et al., phenotype. We present the first case of an 1973,1997,1998; Woolf and Myrianthopoulos, 1973; individual with isolated PAP-B and a sub- Scott-Emuakpor and Madueke, 1976]. microscopic chromosome abnormality. It segregates as an autosomal dominant trait, with ß 2003 Wiley-Liss, Inc. variable expression and penetrance [Castilla et al., KEY WORDS: postaxial polydactyly; men- 1973; Scott-Emuakpor and Madueke, 1976]. It is tal retardation; transloca- genetically very heterogeneous, with four genetic loci tion (4;7); microdeletion; for isolated PAP in humans [Akarsu et al., 1997; mosaicism; chromosome Radhakrishna et al., 1997; Zhao et al., 2002; Galjaard 4p15.3; chromosome 7q35-36.1 et al. unpublished communication], and several other loci for PAP as part of syndromal cases. Moreover, PAP with multiple congenital abnormalities is asso- ciated with numerical chromosome abnormalities, mainly trisomy 13, structural abnormalities includ- ing duplications and deletions, and an inversion/ Bert B.A. de Vries’s present address is Department of Human microdeletion. Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands. We present a male individual with isolated PAP-B *Correspondence to: Robert-Jan H. Galjaard, Department of of the hands and his daughter with PAP-B and asso- Clinical Genetics, Erasmus Medical Center, PO Box 1738, 3000 ciated abnormalities. He is mosaic for a cytogenetically DR Rotterdam, The Netherlands. balanced translocation that is present in all cells in E-mail: [email protected] his daughter. We found microdeletions of chromosome Received 14 November 2002; Accepted 13 February 2003 regions near the breakpoints not previously known to be DOI 10.1002/ajmg.a.20165 involved in the PAP-B phenotype. ß 2003 Wiley-Liss, Inc. PAP-B in (Non)Mosaic t(4;7)/Microdeletion 169 PATIENTS AND METHODS The family was ascertained by evaluation of mental retardation and dysmorphisms of a female index patient. She and her family were clinically evaluated and blood samples were taken after informed consent. An EBV-transformed cell line was made from the index patient and her father. GTG-banded metaphases were used for karyotyping. FISH was done essentially as described before [Pinkel et al., 1986; Eussen et al., 2000] on metaphase spreads of skin fibroblasts. DNA was isolated as described by a simple salting out procedure [Miller et al., 1988]. YAC’s and BAC/PAC clones were obtained from the CEPH and RPCI-4,5,11 libraries at BAC/PAC Resources (htpp:// www.chori.org/BACPAC). Data on these YAC/BAC/ PAC’s were obtained via Whitehead Institute (www. genome.wi.mit.edu), and the Chromosome 7 database (www.genet.sickkids.on.ca). Clinical data on PAP and physical maps were obtained from OMIM and NCBI’s Human map viewer via (www.ncbi.nlm.nih.gov), respec- tively. Celera’s database was used for physical maps (http://publication.celera.com). Data on chromosome abnormalities in individuals with PAP were obtained from POSSUM version 5.5 (The Murdoch Institute for Research into Birth Defects, Melbourne, Australia). RESULTS Fig. 1. PAP-B of the left hand of the index patient at the age of 13 years. Clinical Findings in Patients The index patient was born after a normal pregnancy and delivery. At birth her length was 53 cm (90th centile), she weighted 3750 g (75th centile) and her head circumference (HC) was 32.5 cm (10th centile). She had postaxial polydactyly type B (PAP-B) of the left hand (Fig. 1). She was clinically evaluated intermittently from the age of 2.5 months because of microcephaly present untill the age of 13 years, developmental retardation, and hypotonia. At the age of 4.3 years she had a verbal IQ of 58 and non-verbal IQ of 62–72. She was dysmorpholo- gically evaluated at the ages of 8 and 13 years. The following anomalies were noted: strabismus, upward slanting of the palpebral fissures, slightly bifid nose with anteverted nares and long columella, prominent upper frontal teeth, a high arched palate, low-set ears with flattened crux superior and a rightsided preauricular pit, widely spaced nipples (Figs. 2 and 3), and cubiti valgi. The liver was 3 cm, the spleen 2 cm palpable. Moreover, a coloboma of the papil was seen on ophtha- lmological examination. Screening for metabolic dis- orders gave normal results. Physical examination of the father was normal, except for bilateral PAP-B of the hands which were removed after birth. His wife and their other daughter have a normal phenotype, but the latter attends a school for children with learning difficulties. The family history is uneventful. Cytogenetics and FISH Cytogenetics. The karyotype of the index patient Fig. 2. Face of the index patient at 13 years showing upward slanting is 46,XX,t(4;7)(p15.2;q35) in blood lymphocytes and palpebral fissures, strabismus, slightly bifid nose, and long columella. 170 Galjaard et al. Fig. 3. Flattened crux superior of the ears of the index patient and rightsided preauricular pit (A,C). skin fibroblasts. The karyotype of her father is chromosome 4 (Fig. 5). All or most of it is deleted on the 46,XY,t(4;7)(p15.2;q35)[35]/46,XY[15] in blood lympho- der(4). The BAC adjacent to this is RP11-12E5 which cytes and 46,XY,t(4;7)(p15.2;q35)[48]/46,XY[2] in skin showed a signal on both the normal chromosome 4 and fibroblasts; so the translocation is present in 35/50 and the der(4) (Fig. 5). Therefore, all or most of it is present in 48/50 metaphases in blood lymphocytes and skin on the der(4). The breakpoint is either in the chromo- fibroblasts, respectively. The karyotypes of his wife and some region inbetween these BAC’s or in one of the their other daughter are 46,XX. BAC’s themselves. FISH. FISH with YAC’s, BAC’s, and PAC’s from Breakpoint 7q35. PAC RP5-1137M13 of chromo- chromosome 4p14-16 and 7q35-36 was performed for some 7q35 showed a signal on both the normal chromo- fine mapping of the translocation breakpoints. The some 7 and the der(7) (Figs. 4B and 5). The overlapping results, summarized in Table I, lead to the following PAC RP5-958B11 showed a single signal on the normal conclusions: chromosome 7, so all or most of it is deleted (Fig. 5). The Translocation. breakpoint is in or adjacent to this overlap. The translocation in fibroblasts of Breakpoint 7q36.1. the index patient is shown using a whole chromosome PAC RP4-753H13 of chromo- paint with chromosome 4 in red and chromosome 7 in some 7q36.1 showed a single signal on the normal green (Fig. 4A). Part of the short arm of one of the chromosome 7, so all or most of it is deleted on the der(7) chromosomes 4 (4pter-4p15.32) is translocated to the (Fig. 5). The adjacent BAC RP11-728K20 showed a long arm of one of the chromosomes 7, broken in 7q35. signal on both the normal chromosome 7 and the der(4) This chromosome is the der(7) (Fig. 5). (Fig. 5). The breakpoint is either in the chromosome Part of the long arm of one of the chromosomes 7 region in between these BAC and PAC or in the BAC/ (7q36.1-qter) is translocated to the short arm of one of PAC itself. the chromosomes 4p15.31, the der(4) (Fig. 5). Since there are loci known on chromosome 7q36 for Breakpoint 4p15.32. hand abnormalities including polydactyly [Heutink FISH with BAC C0481P14 of et al., 1994; Tsukurov et al., 1994], fine mapping of chromosome 4p15.32 showed a signal on 4p15.32 of the the breakpoints of chromosome 7 was performed. BAC normal chromosome 4, and on the der(7) (Fig. 5). The RP11-163I18 contains the centromeric chromosome 7 overlapping BAC RP11-173B23 showed only a signal on breakpoint (7q35) harbouring the CASPR2 gene. Poly- 4p15.32 of the normal chromosome 4. Therefore, all, or morphic markers were designed and tested to determine most of it is deleted on the der(4). The breakpoint is in or the number of alleles present in the index patient. A adjacent to the overlap of both BAC’s (Fig. 5). marker 10 kb upstream of exon 24 of the CASPR2 Breakpoint 4p15.31. BAC RP11-10P19 of chromo- gene on RP11-163I18 was heterozygous, indicating some 4p15.31 showed a single signal on the normal the presence of two alleles (data not shown). Therefore, PAP-B in (Non)Mosaic t(4;7)/Microdeletion 171 TABLE I. FISH Analysis With Chromosome 4p15 and 7q35-36 YAC/BAC/PAC’s on Metaphase Chromosomes of a t(4;7)(p 15.2;q35) Carrier Chromosome Signal on Signal on Signal on Chromosome Signal on Signal on Signal on 4p14-16 normal 4p der(7) der(4) 7q35–36 normal 7q der(7) der(4) Cosmid/YAC YAC L228A7 þþ C647f12 þþ 657-E4 þþ C846e8 þþ 739D7 þ þHSCE7E162 þþ HSCE7E124 þ BAC/PAC HSCE7E487 þ C873c3 þ þ 116D01 þþ RP11-685B15 þþ BAC/PAC RP11-274B16 þþ C0483I23 þþ RP4-800L12 þþ RP11-576E20 þþ RP5-1137M13 þþ C0481P14 þþ RP11-163I18 þþ RP11-173B23 þ - RP5-958B11 þ C0315N08 þ RP5-1151M05 þ C0162P16 þ RP4-800G07 þ RP11-724A24 þ RP4-751H13 þ RP11-683L20 þ RP11-728K20 þ þ RP11-84N19 þ RP11-543G3 þ þ RP11-96B10 þ RP4-584D14 þ þ RP11-85L2 þ RP11-632K21 þ þ RP11-339D20 þ RP5-1051J4 þ þ RP11-10P19 þ RP11-12E5 þ þ RP11-578A19 þ þ 269N16 þ þ RP11-735L15 þ þ 276O17 þ þ þ, Positive specific signal with FISH. the breakpoint is most likely downstream of the stop- blood lymphocytes. It is tempting to speculate that the codon of the CASPR2 gene. absence of normal cells is associated with the extra Microdeletions. Several BAC/PAC’s from chromo- phenotypic abnormalies in the index patient, compared some 4p15.3 and 7q35-36.1 showed a single signal on to her father. The absence of mental retardation in the the normal chromosome only. This is indicative of father is most likely due to absence or a low degree of microdeletions of the derivative (der) chromosomes. mosaicism in cells of his brain. The microdeletion of the der(4) was localized between Theoretically, PAP-B could be caused by a sponta- 4p15.32 (telomeric) and 4p15.31 (centromeric), which is neous mutation of a gene in a locus different from those about 2.8 Mb. Likewise, a deletion of about 2.3 Mb was involved in the translocation/microdeletions in the found on the der(7) between 7q35 (centromeric), and father and his daughter. However, the co-occurrence of 7q36 (telomeric). two rare events is extremely unlikely. Furthermore, as the PAP-B phenotype and the translocation are shared by the father and his daughter we assume they are DISCUSSION associated. We present a patient with developmental delay, minor The phenotypes of our patients could be caused by facial dysmorphisms, PAP-B of the left hand, a history haploinsufficiency of one or more genes located in or of hypotonia and microcephaly. Her father had only adjacent to the microdeletions. To verify this we se- bilateral PAP-B of the hands. Both are translocation arched the literature for patients with deletions of 4p15 carriers with microdeletions on the breakpoints of and 7q35-36. We found a single patient with a deletion 4p15.3 and 7q35-36.1. It illustrates that in rare cases 4p15.3 [Davies et al., 1990], and four with a deletion chromosome studies could be considered in individuals 4p15.2-15.3 [Chitayat et al., 1995]. They share develop- with only PAP. Furthermore, it stresses the importance mental delay (4/5), abnormal helices of the ears (4/5), a of additional studies for submicroscopic abnormalities in high arched palate (3/5), and strabismus (2/5) with our cases with mild or multiple congenital anomalies and index patient. Two patients with an interstitial deletion cytogenetically balanced translocations. of 7q35 have been reported [Frijns et al., 1988; Fagan In the father the translocation is present with differ- et al., 1994], who share developmental delay (2/2), ent levels of mosaicism in blood lymphocytes and skin strabismus (2/2), a high arched palate (1/2), and micro- fibroblasts, indicating a postzygotic mitotic event. The cephaly (1/2) with our index case. From our point of view lower degree of mosaicism in skin fibroblasts is pro- the number of patients is too small to define a deletion- bably due to the lower mitotic turnover compared to 4p15, or -7q35 phenotype. The developmental delay and 172 Galjaard et al. Fig. 5. Schematic illustration of the t(4;7)(p15.2;q35). The BAC/PAC’s nearest to the four breakpoints are indicated; in red those of chromosome 4p15, in green those of 7q35-36. The circles in blue of 4p15 and in green of 7q35-36 are only present on the normal chromosomes and deleted in the derivatives. For the der(4) breakpoint the (predicted) genes LOC206654 and SLIT2 could be fused to each other. of genes, part of genes or regulatory regions. Therefore, we searched for genes in or adjacent to the breakpoints. The 7q35 breakpoint [on the der(7)] is most likely located downstream of the coding region of the CASPR2 gene, so could influence mRNA levels by disrupting the 30 UTR. However, the CASPR2 gene is not a likely candidate, involved in the pathogenesis of the PAP-B phenotype, because it is only expressed in the central-, and peripheral-nervous system, and shown to be in- volved in rapid conduction of the action potential in myelinated axons [Poliak et al., 1999]. Since the physical maps of the chromosome region 4p15.32 are still not reliable enough, we can not point out a gene to which it could be fused. The LOC206654 on chromosome 7q36.1 could be fused to (part of) the SLIT2 gene on 4p15.31 on the der(4) Fig. 4. A: Whole chromosome paint of chromosome 4 (red) and 7 (green) (Fig. 5). There are no relevant additional data on showing a cytogenetically balanced t(4;7)(p15;q35) in metaphase chromo- LOC206654. SLIT2 is known to be involved in migration somes of skin fibroblasts of the index patient. Arrowheads indicate of neuronal precursors, as well as being expressed in breakpoints. B: FISH with chromosome 7q35 PAC’s on metaphase chro- mosomes of skin fibroblasts of the index patient showing two signals of RP11- the developing limb [Holmes et al., 1998; Holmes and 1137M13 (red) on the normal chromosome 7 q35 and der(7), and only one Niswander, 2001; Vargesson et al., 2001], and could signal of RP5-1151M05 (green) on the normal 7q35, indicating a deletion of therefore be considered a candidate gene. We are this PAC on the der(7) (arrowhead). currently investigating if other families with pheno- types including PAP are linked to either 4p15.3 or 7q35- facial dysmorphisms shared by them and our index 36.1. They could be helpful for further attempts to patient is likely to be due to haploinsufficiency of one or identify the gene associated with the PAP-B phenotype more genes in the deleted regions 4p15.3 and/or 7q35- in this family and possibly reveal if the PAP-B phenotype 36.1. is caused by a mutation in the same gene as the asso- Patients with larger deletions including 4p15 and ciated anomalies in our index patient. 7q35, described in the literature, do not show poly- dactyly, so the PAP-B phenotype in our patients is most ACKNOWLEDGMENTS likely not only due to haploinsufficiency of a gene loca- lized in one of the deleted regions. Based on this, we We acknowledge the family for their cooperation, hypothesized that the translocation could lead to fusion Dr. L. C. P. Govaerts, clinical geneticist, for her clinical PAP-B in (Non)Mosaic t(4;7)/Microdeletion 173 work on the index patient, and R. 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