Clinical Genetics 1

Genetics of disease, diagnosis and treatment

Principal investigators

Prof.Dr M.H. Breuning, Prof.Dr E. Bakker, Prof.Dr. A. Tibben, , Dr J.T. den Dunnen, Dr  E. Bijlsma, Dr C. Ruivenkamp, Dr K.B. Hansson, Dr I. Ginjaar, Dr S.G. Kant, Dr S. Lesnik Oberstein, Dr M. Losekoot, drs A. van Haeringen, Dr P. Giordano

Aim and focus

The common focus of this program is on applying modern molecular technology to the diagnosis, clinical research and genetic counseling of the following disorders: mental retardation, growth disorders, neurodegenerative- and muscular disease, and disorders of hemoglobin. In this program we focus on known genes. By studying large numbers of clinically well characterized patients, and collect all relevant information in gene variant databases (LSDB’s) we want to aid diagnostics and look for genotype-phenotype correlations. This will facilitate the distinction between pathogenic and non-pathogenic variants, and will improve early diagnosis and genetic counselling. The ultimate aim is to understand how mutations in genes lead to disease in order to design and test targeted interventions.

The psychological impact of early genetic diagnosis on counselees and patients is studied in families showing segregation of neurodegenerative disease and cancer predisposition (see also 5A2)

Position in international context

Specific areas of the program are amongst internationally recognized cutting-edge research. The well defined collections of patients and DNA samples are an excellent source for exchange of samples with many other groups, both nationally and internationally.

The Laboratory for Diagnostic Genome Analysis (LDGA) offers DNA diagnosis for more than 80 genes, for some of which it receives many requests from abroad. Our laboratory is a national referral center for disorders of hemoglobin synthesis and offers mutation analysis for a large variety of neurodegenerative and muscular diseases, growth disorders, including those with slow as well as accelerated growth. The laboratory leads the way with the innovation and implementation of DNA techniques for diagnostic purposes, recent examples being: Multiplex Ligation dependent Probe Amplification (MLPA), melting curve analysis, and the use of SNP-microarrays instead of a microscope the detection of chromosomal aberrations. The laboratory plays an active role in several large European projects, the European Molecular Genetics Quality Network (EMQN)(FP5), Eurogentest (FP6), and several FP7 projects, Gen2Phen, NMDchip, Techgene.

Content / highlights / achievements

• Discovery of the gene involved in Peters’ Plus syndrome
• Development of SNP-based (Pharmacogenomics) optimization of hydroxyurea therapy which allows thalassemia patients to become transfusion-free.
• Participation in the successful worldwide first human DMD exon-skip clinical trial together with the Department of Human Genetics.
• Discovery of p300 mutations underlying Rubinstein-Taybi Syndrome, following our earlier finding of CBP mutations, defining RTS as chromatin (re)modeling disease.
• Development of Leiden Open (source) Variation Database (LOVD)
•  Establishment of >50 Locus Specific DataBases (LSDB’s)

Future themes

How to correctly interpret the enormous variety of DNA sequences in the context of diagnostic questions ? The new diagnostic techniques, DNA sequencing, MLPA, and copy number analysis using microarrays, reveal many variants that may be either causal to the patients problem, may be contributing, or may be completely neutral, not involved with disease at all. To tackle this problem, all the detected gene variants will be reported in gene specific databases. Detailed clinical data on patients and their family will be stored in an electronic database in order to facilitate cross-sectional as well as follow up studies.

Therapeutic and/or preventive interventions will become available for several inherited disorders. In order to assess such interventions properly, cohorts of patients need to be well defined clinically as well as genetically.

Cohesion within LUMC and Leiden University

The Department, together with the Department of Human Genetics, constitutes the Center for Human and Clinical Genetics. Studies on mental retardation are performed in close collaboration with the Departments of Pediatrics and Neurology. Studies of neuromuscular and neurogenetic (episodic) diseases, such as Duchenne’s muscular dystrophy, Huntington’s chorea, Migraine and CADASIL, are performed in collaboration with the departments of Neurology, Radiology (neuroimaging), Neurophysiology, and Pathology. The collaboration with the Departments of Pediatrics and of Endocrinology is particularly close for studies on growth disorders.

Key publications

van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A, Bremmer-Bout M, den Dunnen JT, Koop K, van der Kooi AJ, Goemans NM, de Kimpe SJ, Ekhart PF, Venneker EH, Platenburg GJ, Verschuuren JJ, van Ommen GJ. Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med. 2007; 357:2677-86.
IF 51.3

Harteveld CL, Voskamp A, Phylipsen M, Akkermans N, den Dunnen JT, White SJ, Giordano PC. Nine unknown rearrangements in 16p13.3 and 11p15.4 causing alpha- and beta-thalassaemia characterised by high resolution multiplex ligation-dependent probe amplification. J Med Genet 2005; 42: 922-31.
IF 5.5

Lesnik Oberstein SA, Kriek M, White SJ, Kalf ME, Szuhai K, den Dunnen JT, Breuning MH, Hennekam RC. Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase. Am J Hum Genet 2006; 79: 562-6.
IF 12,61

van Moorsel CH, van Wijngaarden EE, Fokkema IF, den Dunnen JT, Roos D, van Zwieten R, Giordano PC, Harteveld CL. beta-Globin mutation detection by tagged single-base extension and hybridization to universal glass and flow-through microarrays. Eur J Hum Genet 2004; 12: 567-73.
IF 4.0

Roelfsema JH, White SJ, Ariyürek Y, Bartholdi D, Niedrist D, Papadia F,  Bacino CA, den Dunnen JT, van Ommen GJB, Breuning MH, Hennekam RC, Peters DJM. Genetic heterogeneity in Rubinstein-Taybi Syndrome: mutations in both the CBP and EP300 genes cause disease. Am J Hum Genet 2005; 76: 572-80.
IF 12.6

Walenkamp MJ, van der Kamp HJ, Pereira AM, Kant SG, van Duyvenvoorde HA, Kruithof MF, Breuning MH, Romijn JA, Karperien M, Wit JM. A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor. J Clin Endocrinol Metab 2006; 91: 3062-70.
IF 5.5

Franssen MTM, Korevaar JC, Leschot NJ, Bossuyt PMM, Knegt AC, Gerssen-Schoorl KBJ, Wouters CH, Hansson KBM, Hochstenbach R, Madan K, van der Veen F, Goddijn M: Selective chromosome analysis in couples with two or more miscarriages: case-control study. British Medical Journal 2005; 331(7509):137-139.     
IF 9.7     

White SJ, Uitte de Willige S, Verbove D, Politano L, Ginjaar I, Breuning MH, den Dunnen JT. Sarco-glycanopathies and the risk of undetected deletion alleles in diagnosis. Hum Mutat 2005; 26: 938-45.
IF 6.2

Lemmers RJLF, van der Wielen MJR, Bakker E, Padberg GW, Frants RR, van der Maarel SM: Somatic mosaicism in FSHD often goes undetected. Annals of Neurology 2004;    55(6):845-850.     
IF 8.8                 

Yavarian M, Karimi M, Bakker E, Harteveld CL, Giordano PC. Response to hydroxyurea treatment in Iranian transfusion-dependent beta-thalassemia patients. Haematologica 2004; 89: 1172-8.
IF 5.5