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 C.L. Harteveld, Dr I. Ginjaar, Dr S.G. Kant, Dr S. Lesnik Oberstein, Dr M. Losekoot, Drs A. van Haeringen, Drs Y. Hilhorst-Hofstee

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, Marfan syndrome, and disorders of hemoglobin. In this program we focus on known genes. 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. 

Position in international context

The Laboratory for Diagnostic Genome Analysis (LDGA) offers DNA diagnosis for more than 100 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 constantly innovates DNA techniques for diagnostic purposes, recent examples being: Multiplex Ligation dependent Probe Amplification (MLPA), melting curve analysis, the use of SNP-microarrays instead of a microscope the detection of chromosomal aberrations, and whole exome sequencing. 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.

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.

Content / highlights / achievements

  • Detailed neuro-imaging of patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarction and Leukoencephalopathy (CADASIL)
  • First experiments toward a new therapy for CADASIL using exon skipping (unpublished)
  • Detailed studies of families with Duchenne Muscular Dystrophy (DMD) reveal that many female family members at risk of being a carrier have not been tested
  • Detailed studies of Marfan patients and their families reveal autosomal recessive inheritance of syndrome
  • Detailed clinical study of the 16p11.2 microdeletion
  • Participation in the successful worldwide first human DMD exon-skip clinical trial together with the Department of Human Genetics.
  • Comparison of regulation of gene expression by p300 and CBP.
  • Identification of a new gene involved in chromatin remodeling as a frequent cause of mental retardation (unpublished)

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,  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. A system for monitoring progression of neurodegenerative disease in order to be able to assess the effect of interventions will have to be developed.

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.