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:

  • Korade Z, Kim HY, Tallman KA, Liu W, Koczok K, Balogh I, Xu L, Mirnics K, Porter NA. The Effect of Small Molecules on Sterol Homeostasis: Measuring 7-Dehydrocholesterol in Dhcr7-Deficient Neuro2a Cells and Human Fibroblasts. Journal of  Medicinal Chemistry (2016) 59(3):1102-1115
  • Nagy B Jr, Nagy B, Fila L, Clarke LA, Gönczy F, Bede O, Nagy D, Újhelyi R, Szabó Á, Anghelyi A, Major M, Bene Z, Fejes Z, Antal-Szalmás P, Bhattoa HP, Balla G, Kappelmayer J, Amaral MD, Macek M Jr, Balogh I. Human epididymis protein 4 (HE4): a novel serum inflammatory biomarker in cystic fibrosis. Chest Journal (2016) 150(3):661-672
  • Mizzi C, Dalabira E, Kumuthini J, Dzimiri N, Balogh I, Başak N, Böhm R, Borg J, Borgiani P, Bozina N, Bruckmueller H, Burzynska B, Carracedo A, Cascorbi I, Deltas C, Dolzan V, Fenech A, Grech G, Kasiulevicius V, Kádaši Ľ, Kučinskas V, Khusnutdinova E, Loukas YL, Macek M Jr, Makukh H, Mathijssen R, Mitropoulos K, Mitropoulou C, Novelli G, Papantoni I, Pavlovic S, Saglio G, Setric J, Stojiljkovic M, Stubbs AP, Squassina A, Torres M, Turnovec M, van Schaik RH, Voskarides K, Wakil SM, Werk A, Del Zompo M, Zukic B, Katsila T, Lee MT, Motsinger-Rief A, Mc Leod HL, van der Spek PJ, Patrinos GP. A European Spectrum of Pharmacogenomic Biomarkers: Implications for Clinical Pharmacogenomics. PLoS One (2016) 11(9):e0162866
  • Balogh I, Koczok K, Szabo GP, Torok O, Hadzsiev K, Csabi G, Balogh L, Dzsudzsak E, Ajzner E, Szabo L, Csakvary V, Olah AV. Mutational spectrum of Smith-Lemli-Opitz syndrome patients in hungary. Mol Syndromol. 2012, 3:215-222
  • Gaal Z, Klupa T, Kantor I, Mlynarski W, Albert L, Tolloczko J, Balogh I, Czajkowski K, Malecki MT. Sulfonylurea use during entire pregnancy in diabetes because of KCNJ11 mutation: a report of two cases. Diabetes Care. 2012, 35: e40
  • Losonczy G, Vajas A, Takacs L, Dzsudzsak E, Fekete A, Marhoffer E, Kardos L, Ajzner E, Hurtado B, de Frutos PG, Berta A, Balogh I. Effect of the Gas6 c.834+7G>A polymorphism and the interaction of known risk factors on AMD pathogenesis in Hungarian patients. PLoS One. 2012, 7: e50181
  • Szakszon K, Felszeghy E, Csizy I, Jozsa T, Kaposzta R, Balogh E, Olah E, Balogh I, Berenyi E, Knegt AC, Ilyes I. Endocrine and anatomical findings in a case of Solitary Median Maxillary Central Incisor Syndrome. Eur J Med Genet. 2012, 55: 109-111
  • Mokánszki A, Ujfalusi A, Balogh E, Sümegi A, Antal-Szalmás P, Kassai Bazsáné Zs, Molnár Zs, Varga A, Sápy T, Jakab A, Oláh É. Meiotic segregation study of a novel t(3;6)(q21;q23) in an infertile man using fluorescence in situ hybridization (FISH). Syst Biol Reprod Med. 2012, 58(3): 160-164
  • Mokánszki A, Molnár Z, Ujfalusi A, Balogh E, Bazsáné ZK, Varga A, Jakab A, Oláh E. Correlation study between sperm concentration, hyaluronic acid-binding capacity and sperm aneuploidy in Hungarian patients. Reprod Biomed Online. 2012, 25(6): 620-626
  • Mokánszki A, Körhegyi I, Szabó N, Bereg E, Gergev G, Balogh E, Bessenyei B, Sümegi A, Morris-Rosendahl DJ, Sztriha L, Oláh E. Lissencephaly and band heterotopia: LIS1, TUBA1A, and DCX mutations in Hungary. J Child Neurol. 2012, 27(12):1534-40
  • Szabó GP, Knegt AC, Ujfalusi A, Balogh E, Szabó T, Oláh É. Subtelomeric 6.7 Mb trisomy 10p and 5.6 Mb monosomy 21q detected by FISH and array-CGH in three related patients. Am J Med Genet A. 2012, 158A(4): 869-76
  • Oláh AV, Asztalos L, Kovács ÁM, Ivády G, Varga J: Relation between mycophenolic acid level and kidney function during combined immunosuppressive therapy. Clin Chem Lab Med. 2011; 49(11): 1849-53
  • Molnár Zs, Mokánszki A, Benyó M, Kassai Zs, Oláh É, Jakab A: Sperm fertilization potential and chromosomal anomalies in testicular cancer before chemotherapy. Human Reproduction 2011, 26 p. i253
  • Szakszon K, Berényi E, Jakab A, Bessenyei B, Balogh E, Köbling T, Szilvássy J,Knegt AC, Oláh E. Blepharophimosis mental retardation syndrome Say-Barber/Biesecker/Young-Simpson type – new findings with neuroimaging. Am J Med Genet A. 2011, 155A(3): 634-7
  • Demuth I, Dutrannoy V, Marques W Jr, Neitzel H, Schindler D, Dimova PS, Chrzanowska KH, Bojinova V, Gregorek H, Graul-Neumann LM, von Moers A, Schulze I,Nicke M, Bora E, Cankaya T, Oláh É, Kiss C, Bessenyei B, Szakszon K,Gruber-Sedlmayr U, Kroisel PM, Sodia S, Goecke TO, Dörk T, Digweed M, Sperling K,de Sá J, Lourenco CM, Varon R. New mutations in the ATM gene and clinical data of 25 AT patients. Neurogenetics. 2011, 12(4): 273-82
  • Losonczy G, Fekete A, Voko Z, Takacs L, Kaldi I, Ajzner E, Kasza M, Vajas A, Berta A, Balogh I. Analysis of complement factor H Y402H, LOC387715, HTRA1 polymorphisms and ApoE alleles with susceptibility to age-related macular degeneration in Hungarian patients. Acta Ophthalmol. 2011; 89: 255-262
  • Ivady G, Madar L, Nagy B, Gönczi F, Ajzner É, Dzsudzsak E, Dvořáková L, Gombos É, Kappelmayer J, Macek M Jr., Balogh I. Distribution of CFTR mutations in Eastern Hungarians: Relevance to genetic testing and to the introduction of newborn screening for cystic fibrosis. J Cyst Fibros. 2011, 10: 217-20
  • GP Szabó, AV Oláh, L Kozák, E Balogh, A Nagy, I Blahakova, É Oláh: A patient with Smith-Lemli-Opitz Syndrome: novel mutation of the DHCR7 gene and effects of therapy with simvastatin and cholesterol supplement. Eur J Pediatr. 2010, 169:121-3
  • Hallay, J Oláh AV, Fülesdi B, Kocsor M, Végh T, Kovács G, Takács I, Sápy P, Nagy D, Telessy IG: Comparison of the effect of different lipid therapy as part of total parenteral nutrition on short term hepatobiliary response in patients underwent gastrointestinal surgery. Hepato-Gastroenterology 2010, 57: 1069-1073
  • Nelle H, Schreyer I, Ewers E, Mrasek K, Kosyakova N, Merkas M, Hamid AB, Fahsold R, Ujfalusi A, Anderson J, Rubtsov N, Küchler A, von Eggeling F, Hentschel J,Weise A, Liehr T. Presence of harmless small supernumerary marker chromosomes hampers molecular genetic diagnosis: a case report. Mol Med Rep. 2010, 3(4): 571-4
  • Ajzner E, Balogh I, Szabo T, et al. Severe coagulation factor V deficiency caused by 2 novel frameshift mutations: 2952delT in exon 13 and 5493insG in exon 16 of factor 5 gene. Blood. 2002, 99: 702-705
  • Balogh I, Szoke G, Karpati L, et al. Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia. Blood. 2000, 96: 2479-2486