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Evidence for Genetic Heterogeneity in the Carbohydrate-Deficient Glycoprotein Syndrome Type I (CDG1)

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Evidence for Genetic Heterogeneity in the Carbohydrate-Deficient Glycoprotein Syndrome Type I (CDG1)
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  SHORT COMMUNICATIONEvidence for Genetic Heterogeneity in the Carbohydrate-DeficientGlycoprotein Syndrome Type I (CDG1) G ERT  M ATTHIJS , * ,1 E RIC  L EGIUS , *  E LS S CHOLLEN , *  P ETRA  V ANDENBERK , *  J AAK  J AEKEN , † R ITA  B ARONE , ‡  A GATA  F IUMARA , ‡  G EPKE  V ISSER , §  M ARIE  L AMBERT , Ø AND  J EAN -J ACQUES C ASSIMAN * * Center for Human Genetics, University of Leuven, Leuven, Belgium;   † Department of Pediatrics, University Hospital, Leuven,Belgium;   ‡ Clinica Pediatrica, University of Catania, Catania, Italy;   § Department of Pediatrics, Academisch Ziekenhuis Groningen,Groningen, the Netherlands; and   Ø Service de Ge´ne´tique Me´dicale, Hoˆpital Sainte-Justine, Montre´al, Canada  Received December 1, 1995; accepted May 1, 1996 Polymorphic CA repeats (2) in the interval between We have analyzed a series of polymorphic markers  D16S405 and D16S406 were amplified from genomic on chromosome 16p13 in 17 families with carbohy-  DNA from lymphocytes or fibroblasts. The samples drate-deficient glycoprotein syndrome type I (CDG1).  were run on an ALF Automated Sequencer (Phar- First, linkage to the region between D16S406 and macia), and the alleles were sized using the Fragment D16S500isconfirmed.Thetelomericborderofthecan- Manager software (Pharmacia) with Pharmacia’s 50– didate region is now definitively placed proximal to 500 size standards as a reference. D16S406 by crossovers observed in 2 families. Second, The linkage programs MLINK and ILINK (FAST- in 1 family with 2 affected siblings, the disease is not LINK versions) (5) and the HOMOG program (7) were linked to chromosome 16p. Genetic heterogeneity has used for analysis of the data. The haplotypes were fur- notbeenpreviouslyreportedforCDG1,andthisobser- ther analyzed by family-based association (8, 11). The vation has implications for prenatal diagnosis. Third, sample fulfills the criteria for the analysis by this allelic associations suggest that the disease locus is method: a recessive single locus disease, a mixed popu- localized close to D16S414/D16S497. This places the re- lation, and a  u  near zero. The associations were tested gion of interest centromeric of its published localiza- in 2 by 2 contingency tables ( x 2 ) corrected for multiple tion.   1996 Academic Press, Inc. comparisons. The data were alsoanalyzed by the likeli-hood ( l ) method described recently by Terwilliger (10).RecombinationeventsproximaltoD16S406infamilyCarbohydrate-deficient glycoprotein syndrome type1 (Fig. 1a) and family 6 (not shown) and distal toI (CDG1 or Jaeken disease, OMIM 212065) is an au-D16S500 in family 4 (not shown) confine the candidatetosomal recessive disease with perinatal presentation.region to the region between these two markers. DataIt is a disabling, multisystem disease with severe ner-from linkage analysis in 11 families are given in Tablevous system defects, mental retardation, and a high1. These data confirm the linkage to 16p13. In one fam-mortality in childhood. In adults, the disease is largelyily with two affected siblings, data were not innonprogressive. The syndrome is characterized by aagreement with linkage to chromosome 16p13 (familydeficiencyofthecarbohydratemoietyofN-linkedglyco-11; Fig. 1b). When the families were tested for hetero-proteins. The diagnosis is based on isoelectric focusing geneity usingthe HOMOG program (7),the conditionalof transferrin, showing an increase of the asialo- andprobability that the disease in this family is segregat-disialotransferrins and a decrease of normal tetra- anding with the markers on chromosome 16p is zero. How-pentasialotransferrins in CDG1 (3, 4).ever, the family is too small for the heterogeneity testCDG1 has recently been mapped by Martinsson andto reach significance. The phenotype in family 11 iscollaborators (6) to chromosome 16p, to a 13-cM inter-clinicallyindistinguishablefromCDG1,exceptthattheval between markers D16S406 and S16S500.affected girl showed spontaneous puberty, which is notWe have analyzed this region in 17 families of Bel-normally the case in female CDG1 patients (9). Thegian, Dutch, French, German, Canadian, and Italiantransferrin assay showed the typical pattern seen inorigins. Eleven families with multiple siblings wereCDG1 (not shown). This observation is thus suggestiveavailable for linkage. A total of 14 families were usedof, but does not formally prove, genetic heterogeneityfor family-based associations.of CDG1. The family is of French–Canadian srcin andis the only non-European sample in the study. This 1 To whom correspondence should be addressed at Center for Hu- nonallelic variant of the syndrome must be rare, as man Genetics, University of Leuven, Gasthuisberg O&N6, He- Martinsson  et al.  (6) described homogeneity in their 25 restraat 49, B-3000 Leuven, Belgium. Telephone: 32-16-346070. Fax:32-16-345997. E-mail: gert.matthijs@med.kuleuven.ac.be.  families. However, since most families are small, the 597  GENOMICS  35,  597–599 (1996)  ARTICLE NO . 0404 0888-7543/96 $18.00Copyright  1996 by Academic Press, Inc. All rights of reproduction in any form reserved.  SHORT COMMUNICATION 598 FIG. 1.  Microsatellite analysis in two families with a clinical diagnosis of CDG1. In family 1 (  A  ), the segregation of the disease iscompatible with the location on chromosome 16p, between markers D16S406 and D16S500. A detailed analysis of the maternal diseaseallele in the patients reveals a common haplotype for markers D16S414, D16S497, and D16S519. In family 11 ( B ), the marker data arenot compatible with linkage to chromosome 16. power to detect heterogeneity is low. The observation CDG1 and on 2(2) non-CDG1 chromosomes. Thus, 10of28CDG1chromosomeshavethesame151/162haplo-severely complicates prenatal diagnosis based on ge-netic markers. type versus 2 for non-CDG1 chromosomes ( x 2 Å  6.79,  P  Å  0.1; not significant after correction for multipleHaplotype analysis in a family with affected secondcousins (Fig. 1a) suggests that the disease might be testing (12 observed haplotypes)). Moreover, it is pres-ent in families from different geographical origins.located in the proximal part of the candidate region,proximal to D16S407 and D16S404 and distal to With the likelihood method,  l  reached 0.27 ( x 2 Å 2.84,df  Å 1,  P Å 0.045 in this one-sided test (9)) at D16S497.D16S500. The two second cousins share an identicalhaplotype for the markers D16S414, D16S497, and These data contrast with the linkage disequilibrium atD16S406, observed by Martinsson  et al.  (6).D16S519 on their maternal chromosome 16. Theirmothers are not related but originate from the same Thus, upon comparison with previously reporteddata, three new features are apparent. First, we pro-small region in Belgium. The probability that theyshare these alleles by chance is less than 1 in 2500 vide evidence for a crossover between D16S406 andD16S404 in two families, which places the region of (based on the CEPH frequencies of the alleles). An association of the disease with a rare D16S414 interest definitely centromeric to D16S406. The haplo-typedatainfamily1aresuggestiveforalocationproxi-allele (151; 0.36 frequency in CDG vs 0.11 in non-CDGchromosomes) and with alleles of the closely linked mal to D16S407, reducing the region by 2 cM. The lackof polymorphic markers between D16S519 andmarkers D16S497 (162; 0.36 vs 0.07) and D16S519(147; 0.28 vs 0.11) was observed (see Table 2). The D16S500 (8 cM) precludes a more precise localizationof the centromeric end. Second, the strong associationextended haplotype 151/162/(147) is present on 10(6) TABLE 1Two-Point lod Scores for Linkage between CDG1 and Chromosome 16p13 Markers Recombination fraction ( u )Locus 0.001 0.010 0.050 0.100 0.200 0.300 0.400  Z max  u max D16S502  0 2.112  0 0.359 0.654 0.813 0.624 0.343 0.124 0.81 0.103D16S406  0 2.910  0 0.046 1.478 1.685 1.302 0.742 0.280 1.68 0.095D16S404 1.280 2.199 2.519 2.319 1.612 0.888 0.327 2.51 0.044D16S407 4.284 4.179 3.712 3.132 2.030 1.087 0.395 4.29 0.001D16S414 3.712 3.601 3.121 2.548 1.535 0.757 0.245 3.97 0.001D16S497 4.010 3.874 3.288 2.613 1.493 0.686 0.188 4.01 0.001D16S519 2.753 3.615 3.706 3.271 2.204 1.212 0.451 3.77 0.029D16S500  0 3.190  0 0.310 1.253 1.501 1.179 0.667 0.248 1.28 0.102D16S405  0 1.649 0.246 1.193 1.267 0.953 0.566 0.233 1.28 0.084  SHORT COMMUNICATION  599 TABLE 2 Association Data CDG c Non-CDG c ObservedMarker Allele a CEPH b chromosomes chromosomes  x 2 alleles d  P -valueD16S406 190 0.22 12 6 2.95 9 0.77D16S414 151 0.02 10 3 4.91 7 0.19155 0.56 2 8 4.38 7 0.25D16S497 162 0.20 10 2 6.79 8 0.072150 0.18 1 5 2.99 8 0.67D16S519 147 NA 8 3 2.83 10 0.93D16S500 199 0.23 3 9 3.82 10 0.51191 0.07 0 5 5.49 10 0.20 a For each marker, only those alleles with a distorted distribution between CDG1 and non-CDG1 chromosomes are shown. b  Allele frequencies from CEPH (obtained through GDB). NA, not available in GDB. c Total number of chromosomes analyzed for the family-based associations: 28 (14 unrelated patients with parents). d The  P -values have been adjusted for multiple testing.  n  is the number of alleles observed in this series.S. A.,Lowenstein,M.G.,Sutherland,R.D.,Mundt,M.O.,Knill, with a rarer allele at D16S414 and the prevalence of a E. H., Bruno, W. J., Macken, C. A., Torney, D. C., Wu, J.-R., specific haplotype at D16S414, D16S497, and D16S519 Griffith, J., Sutherland, G. R., Deaven, L. L., Callen, D. F., and on CDG1 chromosomes also move the region of interest Moyzis, R. K. (1995). An integrated physical map of human towardthecenterofthepreviouslypublishedcandidate  chromosome 16.  Nature  377(Suppl.):  335–365. region. Third, the CDG1 phenotype is probably un-  2. Gyapay, G., Morisette, J., Vignal, A., Dib, C., Fizames, C., Mil-lasseau, P., Marc, S., Bernardi, G., Lathrop, M., and Weissen- linked to chromosome 16 in one family in this series. bach, J. (1994). The 1993–1994 Ge´ne´thon human genetic link- Most likely, the CDG1 gene is located between age map.  Nature Genet.  7:  246–339. D16S407 and D16S519, both of which are located on 3. Jaeken, J., and Carchon, H. (1993). The carbohydrate-deficient the current physical map for chromosome 16 (1). glycoprotein syndromes: An overview.  J. Inher. Metab. Dis.  16: D16S414 and D16S497 are closely spaced (probably 813–820. within 500 kb) and located centrally within this region. 4. Jaeken, J., Carchon, H., and Stibler, H. (1993). The carbohy- Based on the number of different haplotypes associ-  drate-deficient glycoprotein syndromes: Pre-Golgi and Golgidisorders?  Glycobiology  3:  423–428. ated with the disease (data not shown), we suggest 5. Lathrop, G. M., and Lalouel, J. M. (1984). Easy calculations of  that the CDG1 gene will show several mutations that lod scores and genetic risks on small computers.  Am. J. Hum. originatedondifferentancestralchromosomes.Atleast Genet.  36:  460–465. one of these mutations, associated with the 151/162 6. Martinsson, T., Bjursell, C., Stibler, H., Kristiansson, B., sequence for markers D16S414/D16S497, is found Skovby, F., Jaeken, J., Blennow, G., Stro¨mme, P., Hanefeld, F., throughout Europe.  and Wahlstro¨m J. (1994). Linkage of a locus for carbohydrate-deficient glycoprotein syndrome type I (CDG1) to chromosome16p, and linkage disequilibrium to microsatellite marker ACKNOWLEDGMENTS D16S406.  Hum. Mol. Genet.  3:  2037–2042.7. Ott, J. (1991). ‘‘Analysis of Human Genetic Linkage,’’ 2nd ed.,We thank Drs. J. Artigas, A. David, H. Ogier, S. Schweitzer, T.Johns Hopkins Univ. Press, Baltimore, MD.Simeray, D. Skladal, and M. S. van der Knaap for their clinicalcontributionsandDr.P.Raeymaekersforassistancewiththecompu- 8. Schaid,D.J.,andSommer,S.S.(1994).Comparisonofstatisticstational analysis of the associations. Gert Matthijs is a postdoctoral for candidate-gene association studies using cases and parents.researcher of the National Foundation for Scientific Research  Am. J. Hum. Genet.  55:  402–409.(NFWO), Belgium. These investigations have been supported by the9. Stibler, H., Blennow, G., Kristiansson, B., Lindehammer, H.,Interuniversitary Network for Fundamental Research (1991–1996)and Hagberg, B. (1994). Carbohydrate-deficient glycoproteinsponsored by the Belgian government.syndrome: Clinical expression in adults with a new metabolicdisease.  J. Neurol. Neurosurg. Psychiatry.  57:  552–556.10. Terwilliger, J. D. (1995). A powerful method for the analysis REFERENCES of linkage disequilibrium between trait loci and one or morepolymorphic marker loci.  Am. J. Hum. Genet.  56:  777–787.1. Doggett, N. A., Goodwin, L. A., Tesmer, J. G., Meincke, L. J.,Bruce, D. C., Clark, L. M., Altherr, M. R., Ford, A. A., Chi, 11. Thomson,G.(1995).Mappingdiseasegenes:Family-basedasso-ciation studies.  Am. J. 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