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Joosen AM, Gielen M, Vlietinck R, Westerterp KR. Genetic analysis of physical activity in twins.Am J Clin Nutr 2005 Dec;82(6):1253-1259. SCI 5.692
L. Spruijt, P.Verdyck, W.van Hul, W.Wuyts, C. de Die-Smulders. A novel mutation in the MSX2 gene in a family with foramina parietalia permagna (FPP). Am J Med Genet 2005; 139A(1):45-47. SCI 2.603
Meex SJ, van der Kallen CJ, van Greevenbroek MM, Eurlings PM, El Hasnaoui M, Evelo CT, Lindsey PJ, Luiken JJ, Glatz JF, de Bruin TW. Up-regulation of CD36/FAT in preadipocytes in familial combined hyperlipidemia. FASEB J 2005 Dec;19(14):2063-5. SCI: 7.172
de Die-Smulders CE, Faber CG, Smeets HJ. [From gene to disease; altered RNA processing as a cause of myotonic dystrophy type 1] Ned Tijdschr Geneeskd. 2005 Sep 10;149(37):2043-6. Review. Dutch. Erratum in: Ned Tijdschr Geneeskd. 2005 Oct 8;149(41):2316. SCI 0.586
Jacobs LJ, de Wert G, Geraedts JP, de Coo IF, Smeets HJ. The transmission of OXPHOS disease and methods to prevent this. Hum Reprod Update. 2005 Sep 30. SCI: 3.731
Defoor J, Martens K, Matthijs G, Zielinska D, Schepers D, Philips T, Vlietinck R, Fagard R, Vanhees L.The caregene study: muscle-specific creatine kinase gene and aerobic power in coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2005 Aug;12(4):415-417. SCI 3.000
Paulussen AD, Raes A, Jongbloed RJ, Gilissen RA, Wilde AA, Snyders DJ, Smeets HJ, Aerssens J. HERG mutation predicts short QT based on channel kinetics but causes long QT by heterotetrameric trafficking deficiency. Cardiovasc Res. 2005 Jun 13. SCI 4.575
Gielen M, Pinto-Sietsma SJ, Zeegers MP, Loos RJ, Fagard R, de Leeuw PW, Beunen G, Derom C, Vlietinck R. Birth Weight and Creatinine Clearance in Young Adult Twins: Influence of Genetic, Prenatal, and Maternal Factors. J Am Soc Nephrol. 2005 Jun 8. SCI 6.644
Lambrechts D, Devriendt K, Driscoll DA, Goldmuntz E, Gewillig M, Vlietinck R, Collen D, Carmeliet P. Low expression VEGF haplotype increases the risk for tetralogy of Fallot: a family based association study. J Med Genet. 2005 Jun;42(6):519-22. SCI 4.112
Aerssens J, Paulussen AD. Pharmacogenomics and acquired long QT syndrome. Pharmacogenomics 2005 Apr;6(3):259-70. SCI 4.056
Van Kruiningen HJ, Joossens M, Vermeire S, Joossens S, Debeugny S, Gower-Rousseau C, Cortot A, Colombel JF, Rutgeerts P, Vlietinck R. Environmental Factors in Familial Crohn's Disease in Belgium. Inflamm Bowel Dis. 2005 Apr;11(4):360-365. SCI 3.545
Yarden J, Radojkovic D, De Boeck K, Macek M Jr, Zemkova D, Vavrova V, Vlietinck R, Cassiman JJ, Cuppens H. Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype. Thorax. 2005 Apr;60(4):320-5. SCI 5.040
Gomez-Garcia EB, Ambergen T, Blok MJ, van den Wijngaard A. Patients with an unclassified genetic variant in the BRCA1 or BRCA2 genes show different clinical features from those with a mutation. J Clin Oncol. 2005 Apr 1;23(10):2185-90.
Persu A, Vinck WJ, Khattabi OE, Janssen RG, Paulussen AD, Devuyst O, Vlietinck R, Fagard RH. Influence of the endothelial nitric oxide synthase gene on conventional and ambulatory blood pressure: sib-pair analysis and haplotype study. J Hypertens. 2005 Apr;23(4):759-765. SCI 4.871
Jacobs LJ, de Coo IF, Nijland JG, Galjaard RJ, Los FJ, Schoonderwoerd K, Niermeijer MF, Geraedts JP, Scholte HR, Smeets HJ. Transmission and prenatal diagnosis of the T9176C mitochondrial DNA mutation.
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Rossenbacker T, Mubagwa K, Jongbloed RJ, Vereecke J, Devriendt K, Gewillig M, Carmeliet E, Collen D, Heidbuchel H, Carmeliet P. Novel mutation in the Per-Arnt-Sim domain of KCNH2 causes a malignant form of long-QT syndrome. Circulation. 2005 Mar 1;111(8):961-8. SCI
Pierik M, De Hertogh G, Vermeire S, Van Assche G, Van Eyken P, Joossens S, Claessens G, Vlietinck R, Rutgeerts P, Geboes K. Epithelioid granulomas, pattern recognition receptors, and phenotypes of Crohn's disease. Gut. 2005 Feb;54(2):223-7. SCI 6.601
van den Bosch BJ, van den Burg CM, Schoonderwoerd K, Lindsey PJ, Scholte HR, de Coo RF, van Rooij E, Rockman HA, Doevendans PA, Smeets HJ. Regional absence of mitochondria causing energy depletion in the myocardium of muscle LIM protein knockout mice. Cardiovasc Res. 2005 Feb 1;65(2):411-8. SCI 4.575
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Petit MM, Meulemans SM, Alen P, Ayoubi TA, Jansen E, Van de Ven WJ. The tumor suppressor Scrib interacts with the zyxin-related protein LPP, which shuttles between cell adhesion sites and the nucleus. BMC Cell Biol. 2005 Jan 13;6(1):1. SCI 2.617
Smeets E, Terhal P, Casaer P, Peters A, Midro A, Schollen E, van Roozendaal K, Moog U, Matthijs G, Herbergs J, Smeets H, Curfs L, Schrander-Stumpel C, Fryns JP. Rett syndrome in females with CTS hot spot deletions: a disorder profile. Am J Med Genet A. 2005 Jan 15;132(2):117-20. SCI 3.659
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C. Schrander-Stumpel, L. Spruijt, H. van der Vlught, T. Defloor, L. Curfs, J. Schrander. Kabuki syndrome: clinical data in 20 patients, literature review and further guidelines for preventive management. Am J Med Genet. 2005 Jan 22; 132A(3):234-243. SCI 3.659
A. van Steensel, L. Spruijt, I. van der Burgt, R. Bladergroen, M. Vermeer, P. Steijlen, M. van Geel. A 2-bp deletion in the GJA1 gene is associated with oculo-dento-digital dysplasia with palmoplantar keratoderma. Am J Med Genet. 2005 Jan 15; 132A(2):171-4. SCI 3.659
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SIX3 and ZIC2 mutations in a series of
J. Herbergs1, S. Spierts1, D. Tserpelis1, A. Van Haeringen2, M. Kerstjens3, G. Mancini4, M. Kwee5, J. Hoogeboom4, I. Stolte-Dijkstra3, H. Smeets1; 1Academic Hospital Maastricht, Maastricht, The Netherlands, 2Leiden University Medical Centre, Leiden, The Netherlands, 3Academic Hospital Groningen, Groningen, The Netherlands, 4Erasmus Medical Center, Rotterdam, The Netherlands, 5VU University Medical Center, Amsterdam, The Netherlands. Holoprosencephaly (HPE) is a common severe malformation of the brain that involves abnormal formation and septation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, but the live born prevalence is only 1:16000. The etiology of HPE is extremely heterogeneous and can include both a teratogenic and/or genetic basis. We studied four genes known to be involved in HPE, namely SHH, ZIC2, SIX3 and TGIF by sequence analysis. A series of in total 31 sporadic and familial HPE cases with a variable clinical spectrum has been analysed. We detected 7 pathogenic mutations (23%), 5 out of 28 sporadic cases (18%) and 2 out of 3 familial cases (67%). Three mutations were detected in the SIX3 gene and four mutations in the ZIC2 gene. A ZIC2 mutation in a sporadic case appeared not to be a de novo mutation, but was also found in a healthy mother with no clinical features of the HPE spectrum. This was also seen in a carrier of the mutation in a familial case. In this study the genetic heterogeneity of the disease and the extremely variable phenotypes in HPE families have been confirmed.
Two novel TNNI3 mutations in restrictive
R. Blok1, A. van den Wijngaard1, D. Merckx1, C. Marcelis2, E. Rubio1,3, R. de Coo4, C. de Die1, R. Jongbloed1, B. Smeets1; 1Clinical Genetics, University Hospital Maastricht, Maastricht, The Netherlands, 2Clinical Genetics, Radboud Hospital Nijmegen, Nijmegen, The Netherlands, 3Pediatrics, University Hospital Maastricht, Maastricht, The Netherlands, 4Child Neurology, Erasmus MC, Rotterdam, The Netherlands. Troponine I (TNNI3) is a sarcomeric protein expressed in the human ventricular myocardium. The protein is essential for the coupling between the myosin heavy chain globulair head and actin during contraction of the cardiac fibers. Occasionally mutations in TNNI3 are found in families with hypertrofic cardiomyopathy (HCM). Recently, also some mutations were reported in patients with restrictive cardiomyopathy. Restrictive cardiomyopathy is a rare cardiomyopathic disorder characterized by impaired ventricular filling with reduced volume, ultimately leading to heart failure. Especially in young children the prognosis is poor compared to adults where the clinical course is more variable. In this study we screened two exons of TNNI3 , known to contain the majority of previously identified mutations, in 69 HCM families for mutations by DHPLC. In addition, the complete TNNI3 gene was analyzed by direct sequence analysis in four families with idiopathic restrictive cardiomyopathy. No mutations were identified in the HCM families. However, in two of the four unrelated probands with restrictive cardiomyopathy we found three mutations. In proband 1 we found a novel splice site mutation (IVS7+2delT) and in proband 2 we found a known mutation (R145Q) together with a novel mutation (Arg192Cys). In both families the probands were young girls (age 0.5 and 9 years respectively). The disease manifestation is more severe in proband 1, which might be explained by the difference in the underlying genetic defect. These data indicate that TNNI3 should be analyzed completely when restrictive cardiomyopathy is diagnosed especially in young patients.
An unstable intermediate allele in a family with the
Fragile X syndrome
D. Marcus-Soekarman1, A. v.d. Wijngaard1, J. Herbergs1, L. A. Bok2, L. Curfs1, N. van Slobbe-Knoers3, J. P. Fryns4, C. Schrander-Stumpel1; 1University Hospital, Maastricht, The Netherlands, 2Maxima Medisch Centrum, Veldhoven, The Netherlands, 3Universitair Medisch Centrum St Radboud, Nijmegen, The Netherlands, 4Centrum voor Menselijke Erfelijkheid, Leuven, Belgium. A 1 year and 4 months old toddler presented with a developmental delay. He showed mildly dysmorphic features with length and head circumference above p80. A maternal cousin had a developmental delay that had never been analysed. Investigation of the FMR-gene as part of the work-up for mental retardation showed a full mutation as found in persons with classic Fragile X syndrome. Further analysis in this family showed that female carriers of the syndrome showed so-called intermediate alleles in the FMR-gene. In this family, a normal/intermediate allele became a full mutation in two generations. A review of the literature is given regarding the significance of the size of premutations and their risk to be transmitted to next generations as full blown mutations.
Towards a better definition of unclassified genetic
variants in the BRCA1 and BRCA2 genes: the clinical approach.
E. B. Gomez Garcia1, T. Ambergen2, M. J. Blok1, A. van den Wijngaard1; 1Dept. Clinical Genetics, Maastricht, The Netherlands, 2Dept. Methodology and Statistics, Maastricht, The Netherlands. One third of the nucleotide variants in BRCA1 and half of those in BRCA2 are genetic variants of uncertain significance, also known as unclassified variants (UVs). Pre-symptomatic testing is not possible and genetic counseling can only be based upon the clinical features and family history. Whether patients with an UV have different clinical features than those with a mutation in the BRCA1/2 genes had not been investigated. Using BRCAPRO and Myriad II models, we retrospectively obtained the mutation probabilities in 24 patients with an UV. The UVs included: in BRCA1:Arg841Trp, Asp1739Gly, and IVS19: 5313 -25 A>C, and in BRCA2:Tyr42Cys, Ser384Thr, Lys467Arg, Pro655Arg, His1085Arg, Ser1750Phe, Arg2108His,Thr2337Ile, Ala2717Ser, Glu2856Ala, and Lys2950Asn. Secondly, we compared their clinical features and family history with those from 46 patients with an established pathogenic mutation. The probability to detect a mutation was significantly lower in the group with UVs than in those with mutations (BRCAPRO: M±SD.297±.312 vs. .627±.315 p=.001; Myriad II: M±SD.124±.090 vs. .283±.176, p=.001). Presence of tumors other than invasive breast and ovarian cancer, number of affected relatives and of tumors among relatives correlated with that difference. The last two variables were independent predictive factors of finding either an UV or a mutation. The combined probability data show significant differences between both groups. Individual probabilities (“low” vs. “high”) can be regarded as a help to guide the clinical management of patients with an UV in those genes. However, with the clinical criteria, evaluation of the pathogenicity of an UV should also include biochemical and epidemiological criteria.
High-throughput and comprehensive CHIP-based
resequencing of the mitochondrial DNA in patients with OXPHOS disease.
H. Smeets1,2, M. Gerards1, A. Hendrickx2, R. Van Eijsden1, I. De Coo3, P. Lindsey1. 1) Genetics & Cell Biology/GROW, Maastricht University, Maastricht, Netherlands; 2) Clinical Genetics, Academic Hospital Maastricht, Maastricht, The Netherlands; 3) Neurology, Erasmus University Medical Center Rotterdam, Netherlands. Mitochondrial disorders are often fatal multisystem disorders, associated with abnormalities of oxidative phosphorylation (OXPHOS). Because of its dual genetic control, defects in OXPHOS can be due to mutations in either the mitochondrial (mtDNA) or nuclear DNA. Although OXPHOS disorders have common characteristics as a group, there is considerable clinical variability among patients, even in those having the same genetic defect. Also, clinically indiscernible conditions can be caused by different mutations in a number of genes and it is often not possible to directly identify the genetic defect involved. Therefore, we applied a new CHIP-based platform suitable for rapid resequencing of the mtDNA. Up to now 30 chips have been processed in different experiments. CHIPs were analysed using both the Affymetrix GDAS software and the statistic analysis software R. We found a complete match with classical resequencing in 3 samples. Two samples were mixed to generate artificially heteroplasmy at 11 positions in the mtDNA sequence. Ten were detectable as such and one gave a no-call. Analysis of mixed amounts of different mtDNAs indicated that it should be possible to quantify a mutation load of ≥10% (n=3). Although the platform is not optimal for the detection of small deletions or insertions, we were able to identify two samples with a single nucleotide insertion as a heterozygote call. Screening of 20 patients suspected for mitochondrial disease revealed 171 different mutations: 90 SNPs, 5 known pathogenic mutations and 71 unknown variants (5 of which were heteroplasmic). Our conclusion is that the resequencing CHIPs are a very promising tool for rapid and comprehensive mtDNA-screening. Especially for genomes like the mtDNA, where it is possible to generate the template with a single PCR, and in which the vast majority of the point mutations are nucleotide substitutions, it will become the method of choice.
SIX3 and ZIC2 mutations in a series of
J. Herbergs1, S. Spierts1, D. Tserpelis1, A. Van Haeringen2, M. Kerstjens-Frederikse3, G. Mancini4, M. Kwee5, J. Hoogeboom4, I. Stolte-Dijkstra3, H. Smeets1. 1) Dept Clinical Genetics, Academic Hosp Maastricht, Maastricht, Netherlands; 2) Leiden University Medical Centre, Leiden, The Netherlands; 3) University Medical Center Groningen, The Netherlands,; 4) Erasmus Medical Center, Rotterdam, The Netherlands; 5) VU University Medical Center, Amsterdam, The Netherlands. Holoprosencephaly (HPE) is a common severe malformation of the brain that involves abnormal formation and septation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, but the live born prevalence is only 1:16000. The etiology of HPE is extremely heterogeneous and can include both a teratogenic and/or genetic basis. We studied four genes known to be involved in HPE, namely SHH, ZIC2, SIX3 and TGIF by sequence analysis. A series of in total 31 sporadic and familial HPE cases with a variable clinical spectrum has been analysed. We detected 7 pathogenic mutations (23%), 5 out of 28 sporadic cases (18%) and 2 out of 3 familial cases (67%). Three mutations were detected in the SIX3 gene and four mutations in the ZIC2 gene. A ZIC2 mutation in a sporadic case appeared not to be a de novo mutation, but was also found in a healthy mother with no clinical features of the HPE spectrum. This was also seen in a carrier of the mutation in a familial case. In this study the genetic heterogeneity of the disease and the extremely variable phenotypes in HPE families have been confirmed.
Mutation screening of BRCA1 and BRCA2 in the
Netherlands and Belgium: An overview of 9 years screening and identification of
1700 mutation positive families.
F.B.L. Hogervorst1,2, H. Gille2, A. van der Hout2, G. Vink2, M. Vreeswijk2, P. Devilee2, A. van den Wijngaard2, R. Blok2, D. Bodmer2, M. Ligtenberg2, H. Bruggenwirth2, A. van den Ouweland2, R. van der Luijt2, K. Claes2, G. Michils2, E. Teugels2, S. Wilcocx2. 1) Family Cancer Clinic, Dept Pathology, Netherlands Cancer Inst, Amsterdam, Netherlands; 2) The Dutch/Belgian working group on BRCA mutation screen of the Clinical Genetic centers. In 1995 the DNA-diagnostic laboratories of the Dutch and Belgian Clinical Genetic Centres started DNA testing for BRCA1 and BRCA2. At present, BRCA1 and BRCA2 are completely screened either by a combination of PTT and DGGE/DHPLC or entirely by DGGE/DHPLC/Sequencing. In addition BRCA1 specific testing is performed by Multiplex Ligation-dependent Probe Amplification (MLPA). Up to March 2005, more than 10.000 families have been tested identifying 1700 mutation positive families: 1190 BRCA1 and 510 BRCA2 families. For BRCA1, 171 distinct pathogenic mutations have been identified. The “TOP 10” mutations did account for almost 55% of the families. For BRCA2 173 distinct mutations were identified of which the majority (127) is found in only one or two families. The “TOP 10” mutations account for 42% of the families. For both genes we identified regional and national founders. Recently, BRCA1 mutation screening has been improved by a novel method, called MLPA. This test allows rapid screening for rearrangements in the BRCA1 gene in a high throughput format. In addition to the genomic deletions of exons 13 or 22, more than 15 different deletions and duplications have been found. With the completion of the mutation scanning for both genes many so-called unclassified variants (UV's) have been reported. These are minor changes in the genes for which the relation with the genetic predisposition for breast/ovarian cancer still has to be established. For BRCA1, 148 different UV’s have been identified in 241 families. For BRCA2 this is number is much larger: 247 different UV’s in 481 families. As more than 80% of all different UV’s have been reported only once or twice this clearly is a drawback in the elucidation of the pathogenic status of such variants.