The 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, Attila Mokánszki PhD

Technician: Erika Dzsudzsák, László Madar

Almost every disease has genetic component. Although more than 10,000 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) 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. Niemann-Pick C-type. Analysis is done at both the RNA and DNA levels.

6. AMD. Risk determination by analysis of different SNPs and the testing of the efficiency of the therapy in wet-type AMD.

The supervisor of the following research projects is Éva Oláh, MD, PhD, DSc (Department of Pediatrics).

1. 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.

Genetic investigation in male infertility:
Morphological and functional salubrity of sperm cells (maturity, DNA and histone integrity)can be tested by using different kind of dyes. The epigenetic changes (methylathion status) of sperm cells can be studied by array CGH. Aneuploidy testing in cases of abnormal sperm, segregation analysis of carriers with balanced chromosomal translocations are studied in sperm by FISH. Partial and total microdeletions of the AZF region on chromosome Y are detected by sequence tagged site (STS) analysis.

Genetic investigation in female infertility:
Detection of FMR1 triplet expansion with fragment analysis in premature ovarian failure patient.

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.

2. DNA microarray is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability, autism spectrum disorders or multiple congenital anomalies. Microarray analysis can identify candidate regions and genes in patients with unexplained mental retardations and developmental delays and discover novel microdeletion and microduplication syndromes. In cases with structural chromosome aberrations the identification of precise breakpoints and involved genes using microarray will allow the better understanding of pathogenesis and study of genotype-phenotype correlation.

3. Bone disorders: craniosynostosis, achondro- and hypochondroplasia. Molecular testing of the hot-spot regions of FGFR1,2,3 and TWIST genes. Our laboratory is the only center where molecular genetic of craniosynostoses in Hungary is perfomed. Our group is a member of the International Craniosynostosis Consortium.

4. Lissencephaly is one of the neuronal migration disorder. The spectrum of lissencephaly ranges from absent (agyria) or decreased (pachygyria) convolutions to less severe malformations known as subcortical band heterotopia. In our laboratory - as the only center in Hungary - genetic testing of LIS1, DCX and TUBA1A genes are performed.


Representative publications:

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