Inherited Diseases Group

Principal Investigator: István Balogh, PhD

Members of the group:
Anna V. Oláh, PhD; Gergely Ivády, MD; Katalin Koczok, MD; Anikó Ujfalusi, MD, PhD; Beáta Bessenyei, PhD; Attila Mokánszki, PhD; Beáta Tóth, PhD; Zsuzsanna Molnár, MD, PhD.

Technician: Erika Dzsudzsák, László Madar

Almost every disease has genetic component. Thousands of monogenic diseases are known, and majority of them can be analyzed directly, the number of the newly identified monogenic disorders is growing every week. In addition to these diseases, many multifactorial disorders exist (AMI, VTE, asthma, AMD) with strong genetic component. In these cases, the genetic alteration does not directly disease-causing rather it contributes to the development of the disease. Based on both the literature and on our previous observations it is clear that the prevalence of many mutations is population-specific. The Inherited Disease Research Group investigates the molecular background of genetic diseases. It identifies and tests genetic alterations at molecular, biochemical and epidemiological levels. Given from the nature of these studies, all of its activities are done with close cooperation with clinicians. The following monogenic diseases are analyzed at this moment:

1. Cystic fibrosis. The Department is one of the CF molecular genetic diagnostic centers in Hungary. The methods that are used are sweat NaCl testing and mutation detection (both using detection kits and DNA sequencing of the entire coding region of CFTR and MLPA analysis) in severe CF patients and in selected patients with suspected CF-related disorders.

2. Monogenic diabetes. Molecular analysis of MODY and neonatal diabetes genes are performed (HNF1A, HNF4A, GCK, KCNJ11, etc.) in suspected patients with monogenic diabetes. In some cases, recombinant protein testing are used for pathogenicity testing.

3. Molecular genetic analysis of the recessive form of polycystic kidney disease (ARPKD). This project is a pilot study to test the mutation screening/testing possibilities of large genes. It is a multi-centric collaboration with clinicians and geneticists from Debrecen, Nyíregyháza, Szeged and Budapest. The methods are both Sanger sequencing and next generation sequencing.

4. Analysis of Smith-Lemli-Opitz (SLO) syndrome. Our laboratory is the only analysis site of SLO in Hungary. The first step in the methodology used in this case is the substrate concentration determination using UV-spectrophotometry. The SLO molecular research strategy involves both the identification of the disease-causing variant and the analysis of the functional consequence of the pathogenic alterations using recombinant technology in the case of missense mutations.

5. Other monogenic diseases. Analysis is done at both the RNA and DNA levels and might invole cell-based assays as well.

6. Molecular genetic analysis of hereditary ophtalmological disorders.

Our aim is to identify genetic mutations or alterations in the background of hereditary retinal disorders. At the moment, two projects are running. In the first one a multigenerational family with X-linked high myopia and cone dystrophy was investigated by clinical exom sequencing and comparative genomic hybridization array.

The second project focuses on a complex multifactorial disease, age-related macular degeneration (AMD). Here we perform risk determination by analysis of different SNPs and the testing of the efficiency of the therapy in wet-type AMD.

7. Genetic investigation in male infertility:
Infertility is an emerging public health problem in developed countries, an estimated 10-15% of couples are infertile. Our goal is to identify specific genetic alterations found in couples with infertility and patients with disorders of sexual differentiation.
Partial and total microdeletions of the AZF region on chromosome Y are detected by sequence tagged site (STS) analysis.
Apart from cystic fibrosis, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are also involved in congenital bilateral absence of the vas deferens which results in obstructive azoospermia.
Morphological and functional characteristics of sperm cells (maturity, DNA integrity) can be tested by using different kind of techniques. The epigenetic changes (methylation status, microRNAs) of sperm cells are also under investigation. Aneuploidy testing in cases of abnormal sperm, segregation analysis of carriers with balanced chromosomal translocations are studied in sperm by FISH.

8. Genetic investigation in the disorders of sexual differentiation.
Mutation analysis of the SRY, desert hedgehog (DHH), androgen receptor (AR), 5α-reductase (SRD5A2) and WT1 genes in children with genital abnormalities. In special cases there is an opportunity to perform clinical exome sequencing in order to analyze all the genes responsible for disorders of sexual differentation.

9. Genetic investigation in female infertility.
Detection of FMR1 triplet expansion in case of premature ovarian failure.

10. Genetic testing of primary immunodeficiency diseases.
The methods used here are both DNA sequencing and MLPA. Prenatal testing to help family planning is typical. We also test the consequences of mutations with functional assays and gene expression analysis to allow the better understanding of pathogenesis and study of genotype-phenotype correlations.

11. Genetic investigations in congenital heart disease.
Congenital heart disease (CHD) is genetically heterogeneous, it can be attributed to chromosomal imbalances, single gene defects or epigenetic alterations. Using array comparative genomic hybridization (aCGH) we can increase the detection of causal chromosomal imbalances in individuals with CHD. Identification of candidate regions and genes will allow the better understanding of pathogenesis and study of genotype-phenotype correlation. Recent evidence demonstrated that miRNAs are also involved in development of CHD. Our aim is to characterize the expression pattern of miRNA related to complex, severe CHDs and assess the possible relationship between alteration of miRNA profil and development of CHD.

12. Bone disorders.
Molecular genetic analyses of the FGFR1, FGFR2, FGFR3 and TWIST1 genes are performed in craniosynostosis syndromes (e.g. Apert, Crouzon, Pfeiffer sy.) and chondrodysplasias such as achondroplasia and hypochondroplasia. Our laboratory is the only molecular diagnostic site of craniosynostoses in Hungary.

13. Prader-Willi and Angelman syndromes.
These syndromes can be caused by different genetic mechanisms such as microdeletion, uniparental disomy, imprinting defects or gene mutations. Investigation of these different genetic causes is performed by FISH, MS-MLPA and DNA sequencing methods. Genotype-phenotype correlations are also analyzed in collaboration with clinical geneticists and pediatricians.

Representative publications

Frissítés dátuma: 2019.06.05.