Inherited Diseases Research Group

Group leader: István Balogh, PhD, DSc

Members: Beáta Bessenyei PhD; Máté Bíró PhD student; Katalin Koczok MD, PhD; Anikó Koszorusné Ujfalusi MD, PhD; Kovács Eszter MD-PhD student; László Madar PhD; Orsolya Nagy PhD; Safoura Ghalamkari MSc

Technician: Csilla Bálega-Molnár

Background: 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 (detection of common mutations, 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. Disturbances of glucose metabolism. Molecular analysis of MODY, neonatal diabetes and hyperinsulinism genes are performed (HNF1A, HNF4A, GCK, KCNJ11, etc.). In some cases, advanced genetic methodology (whole exome (WES) and genome sequencing (WGS)), recombinant protein testing are used for pathogenicity testing.

3. 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 in silico analysis of the disease-causing alterations at the population level.

4. Genetic testing of primary immunodeficiency diseases. The method used here is WES. Prenatal testing to help reproductive decisions 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.

5. 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.

6. 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.

7. 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.

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

9. Genetic epilepsy research. In this case the group tests the consequence of the genetic mutations detcted in patients' samples. The research is focusing on the assessing of the pathogenicity of the variants by cloning, mutagenesis, recombinant protein production, stability and cellular localization testing and functional analysis. Part of the work is done in collaboration.

Research techniques applied: We use the entire spectrum of genetic methodologies including gDNA and cDNA sequencing at the gene, gene panel, exome and genome levels. In addition, structural alterations are also tested by MLPA and aCGH. In some selected areas, we use cloning, recombinant protein production, cell biological assays as well.

List of the most relevant publications:

1. Deák, A., Koczok, K., Bessenyei, B., Szűcs, Z., Madar, L., Csorba, G., Orosz, O., Laki, I., Halász, A., Marsal, G., Balogh, I.: A magyar Cystás Fibrosis Regiszter genetikai revíziója. Orv. hetil. 163 (51), 2052-2059, 2022.

2. Szűcs, Z., Pinti, É., Haltrich, I., Pálné, S., Nagy, T., Barta, E., Méhes, G., Bidiga, L., Török, O., Ujfalusi, A., Koczok, K., Balogh, I.: An Ultra-Rare Manifestation of an X-Linked Recessive Disorder: duchenne Muscular Dystrophy in a Female Patient. Int. J. Mol. Sci. 23 (21), 1-15, 2022.

3. Andó, S., Koczok, K., Bessenyei, B., Balogh, I., Ujfalusi, A.: Cytogenetic Investigation of Infertile Patients in Hungary: a 10-Year Retrospective Study. Genes. 13 (11), 1-13, 2022.

4. Madar, L., Juhász, L., Szűcs, Z., Kerkovits, L., Harangi, M., Balogh, I.: Establishing the Mutational Spectrum of Hungarian Patients with Familial Hypercholesterolemia. Genes. 13 (1), 1-13, 2022.

5. Gaál, Z., Szűcs, Z., Kántor, I., Luczay, A., Tóth, -., Benn, O., Felszeghy, E., Karádi, Z., Madar, L., Balogh, I.: A Comprehensive Analysis of Hungarian MODY Patients-Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes. Life (Basel). 11 (755), 1-13, 2021.

6. Gaál, Z., Szűcs, Z., Kántor, I., Luczay, A., Tóth, -., Benn, O., Felszeghy, E., Karádi, Z., Madar, L., Balogh, I.: A Comprehensive Analysis of Hungarian MODY Patients-Part II: glucokinase MODY Is the Most Prevalent Subtype Responsible for about 70% of Confirmed Cases. Life (Basel). 11 (8), 1-20, 2021.

7. Koczok, K., Horváth, L., Korade, Z., Mezei, Z., P. Szabó, G., Porter, N., Kovács, E., Mirnics, K., Balogh, I.: Biochemical and Clinical Effects of Vitamin E Supplementation in Hungarian Smith-Lemli-Opitz Syndrome Patients.  Biomolecules. 11 (8), 1-11, 2021.

8. Szűcs, Z., Fitala, R., Nyuzó, Á., Fodor, K., Czemmel, É., Vrancsik, N., Bessenyei, M., Szabó, T., Szakszon, K., Balogh, I.: Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary. Genes. 12 (9), 1-13, 2021.

9. Nagy, O., Szakszon, K., Biró, B., Mogyorósy, G., Nagy, D., Nagy, B., Balogh, I., Ujfalusi, A.: Copy number variants detection by microarray and multiplex ligation-dependent probe amplification in congenital heart diseases. J. Biotechnol. 299 86-95, 2019.

10. Madar, L., Szakszon, K., Pfliegler, G., P. Szabó, G., Brúgós, B., Ronen, N., Papp, J., Zahuczky, K., Szakos, E., Fekete, G., Oláh, É., Koczok, K., Balogh, I.: FBN1 gene mutations in 26 Hungarian patients with suspected Marfan syndrome or related fibrillinopathies. J. Biotechnol. 301 105-111, 2019.

11. Bessenyei, B., Mokánszki, A., Nagy, O., Szakszon, K., Zimmermann, A., Zombor, M., Horváth, E., Ujfalusi, A., Balogh, I., Sztriha, L.: Genetic investigation of the LIS1, DCX and TUBA1A genes in patients with lissencephaly. Eur. J. Hum. Genet. 27 286, 2019.

12. Gaál, Z., Balogh, I.: Monogenic Forms of Diabetes Mellitus.In: Genetics of Endocrine Diseases and Syndromes. Eds.: Igaz Péter, Patócs Attila, Springer Nature Switzerland, Cham, 385-416, 2019.