Clinical Genetics - Human Molecular Genetics

The main task of our group is the recruitment and clinical characterization of patients and families for the various research groups of the “Human Molecular Genetics” department. As previously costly and laborious molecular genetic investigations get faster and cheaper thanks to technological advances, the recruitment of patients and families with specific phenotypic features increasingly constitutes the bottleneck for all projects in human genetic research.

Autosomal recessive mental retardation

In a large collaboration with the Genetic Research Centre in Tehran/Iran (Dr H Najmabadi) we received DNA and clinical data, including photographic documentation, of more than 100 consanguineous families with multiple mentally retarded children. Whereas the majority of these families suffer from unspecific (non-syndromic) mental retardation, several families have additional clinical problems. Many of these syndromes are apparently novel and do not resemble other published MR syndromes. Beside the clinical evaluation (frequently including proposals for specific investigations such as MRI scans, ophthalmologic examinations and others), we screen the regions of homozygosity for promising functional candidate genes according to morphological similarity or (putative) functional links to other syndromes based on several databases.

In a collaborative project with Dr A Rajab, the leading clinical geneticist in Oman, we obtained blood samples from several consanguineous families with syndromic forms of MR. The spectrum of disorders includes a form of albinism, ectodermal dysplasia, a muscle disorder and a large family with MR and epilepsy. We also received material from families with syndromic forms of mental retardation from our partners in Poznan/Poland (Prof A Latos-Bielenska).

X-linked mental retardation

The elucidation of novel genes involved in X-linked mental retardation is a major research focus of our department. Our group continues to recruit families with probable X-linked MR by collaboration with clinical geneticists in Germany and abroad. We also complete clinical data of formerly submitted families and communicate the results of mutation analysis to the respective physicians or families. Apart from families with non-syndromic XLMR, we also investigate families with syndromic forms of mental retardation. Linkage analysis and mutation analysis in these families is being performed in the “Familial Mental Retardation” group (A. Kuss, H.-H. Ropers).

Disease associated chromosome aberrations

Breakpoint analysis of disease-associated balanced chromosome rearrangements combining array CGH (R. Ullmann’s group), FISH and other molecular genetic techniques (V. Kalscheuer’s group) is a fast and efficient strategy to identify novel disease-causing genes. Comprehensive clinical characterisation is a prerequisite for the selection of patients who are suitable for analysis. New questions concerning specific phenotypic details often arise after the identification of a disrupted gene or genes at the breakpoints. The Clinical Genetics group obtains these data through collaboration with referring doctors or by contacting the patients or their families. Another major task of our group is the recruitment of patients with de novo disease associated balanced chromosome rearrangements by maintaining and extending a network of clinical geneticists and other specialists.

Unbalanced chromosome aberrations

Both large, cytogenetically visible unbalanced chromosome aberrations and small, submicroscopic aberrations which are only detectable by the novel very high resolution array CGH technique (R. Ullmann’s group) are an important cause of congenital malformations and mental retardation, and they can point to single genes responsible for a specific phenotype. Our group characterizes these patients clinically and establishes genotype-phenotype correlations.

Late-onset disorders

Apart from disorders that are usually present at birth or in early childhood, we also perform research on balanced chromosome rearrangements in patients with late-onset diseases. This approach has also the potential to elucidate genes involved in the etiology of complex disorders, as has been shown e.g. for schizophrenia or Tourette’s syndrome before. We have performed a questionnaire survey among adult carriers of balanced chromosome rearrangements, which resulted in the identification of several patients and families in whom an association of the chromosome rearrangement with the respective disease was likely. Subsequent breakpoint analysis led to the identification of candidate genes for psoriasis, dyslexia, hyper-IgE syndrome and haematological malignancies.

Cell culture facility

We establish permanent cell lines from peripheral blood lymphocytes by EBV transformation after obtaining informed consent from patients in whom molecular cytogenetic or molecular genetic investigations are planned. Our cell culture lab performs EBV transformation, stores the cell lines and provides ready-to-use DNA, RNA or metaphase chromosome spreads for FISH investigations to the respective research groups.

Genetic counselling

In his function as a member of the Institute of Medical Genetics at the Charité-Universitätsmedizin Berlin, Andreas Tzschach actively participates in genetic counselling clinics and the regular dysmorphology, clinical genetics and cytogenetics meetings.