2009 Vienna - European Society of Human Genetics

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Metabolic disorders sian Federation. We describe clinical data of 9 patients with mutations in the gene, coding the mitochondrial polymerase gamma (POLG). Mutations in the POLG gene are one of the most common causes of mitochondrial disease in children and adults. We investigate 3 adult patients with clinical picture of mitochondrial disease. One patient, a 62-old woman with severe ataxia, external ophtalmoplegia, paresthesia in legs, autoimmune thyroiditis and myopathy. She has W748S mutation in POLG gene. Two patients had A467T and P587L mutations consequently and showed typical symptoms of CPEO. We investigate six children with hepatopathy and myopathy. Four patients from this group had Alpers syndrome: intractable seizures with a focal component, severe neurological deterioration, hepatic failure. Additional symptoms were vomiting, ataxia, hypotonia, high levels of lactate, liver transaminase and high concentration of tyrosine in urine. Mutant POLG alleles were detected in all Alpers syndrome cases (G268A/A467T; W748S/G848S; W748S/L311P; W748S/ T855S). Symptoms of the rest two patients weren’t suitable for classical Alpers syndrome. They both didn’t have epilepsy, but have very severe hypoglycemia with severe hepatic failure and muscle hypotony. We revealed only one mutant POLG allele in each case, A467T and W748S consequently. mRNA analysis didn’t detect exon deletions in POLG gene. The presence of the second mutant allele in the promotor region or locus heterogeneity involving mutations in other “mitochondrial” genes can not be excluded. Clinical phenotypes of POLG-related disorders are characterized by extremely variability of symptoms and this group may be more common than previously thought. P13.03 Evaluation of disease relevant mutations in Anderson Fabry Disease - how to proof the medical consequences? J. Lukas 1 , J. Frahm 1 , S. Weiss 1,2 , A. Wree 3 , R. Köhling 4 , A. Rolfs 2 ; 1 Albrecht-Kossel-Institute for Neuroregeneration, University of Rostock, Rostock, Germany, 2 Centogene GmbH, Rostock, Germany, 3 Department of Anatomy, University of Rostock, Rostock, Germany, 4 Department of Physiology, University of Rostock, Rostock, Germany. Anderson Fabry Disease (AFD) is an X-linked hereditary disorder of sphingolipid metabolism caused by a genetic defect of the lysosomal hydrolase α-galactosidase A (AGLA). So far, more than 300 AGLA missense mutations have been described. However, numerous amino acid exchanges appear to have only mild effects on enzyme activity reduction. Bioinformatic tools cannot reliably predict the effects of these changes and inevitably need to be supported by enzymatic measurements. Therefore, a rapid screening procedure for all AGLA mutations will be invaluable for this purpose. To solve the limitations of all routine methods we developed an in vitro model based on the overexpression of AGLA mutants using a HEK293 cell system. Using fluorescence enzyme activity assays we are able to determine the activity of mutant enzymes compared to the wildtype. This procedure has shown that the following mutations, which are described in the literature or have been found in our screening programs for Fabry have to be interpreted as SNPs and not clinically relevant AGLA mutations: D83N, S102L, S126G, R220Q, R252T. Tools for the systematic in-vitro evaluation of newly detected mutations are also of high value for the evaluation of the consequences of new therapeutic strategies, e.g. using pharmacological chaperones (PCs) such as 1-Deoxygalactonojirimycin (DGJ). One of the challenges is to find the right PC for any particular mutation because a substance might perform well on one mutation while failing on another. The present study includes a solution for screening newly synthesized drugs to discover substances capable of acting like PCs. P13.04 the molecular landscape of genetic B12 metabolism disorders in patients from mediterranean and Latin- American origin B. Pérez, B. Merinero, A. Rincón, A. Jorge-Finnigan, S. Brasil, F. Leal, L. R. Desviat, M. Ugarte; Centro de Biología Molecular. Universidad Autónoma de Madrid, Madrid, Spain. Vitamin B 12 is the cofactor of Methionine synthase (MTR) and Methylmalonyl-CoA Mutase (MCM) that catalyze the remethylation of homo- cysteine and the isomerization of L-methylmalonyl-CoA, respectively. To date defects in ten different genes coding for proteins involved in B 12 transport, synthesis of active cofactors-MetCbl and AdoCbl- and for the two apoenzymes MCM and MTR have been described. We report the molecular analysis of 65 cases with isolated methylmalonic acidemia (MMA) and 32 with methylmalonic acidemia combined with homocystinuria (MMACH) mainly from Mediterranean and Latin- American origin referred to our laboratory. Using cellular, enzymatic and genetic approaches the MMA patients were classified belonging to the cblA (n=13), cblB (n=6), cblD-variant2 (n=3) and mut (n=43) complementation groups, and the MMACH patients belonging to the cblC group (n=32). The mutational spectrum in the mut affected patients includes a high frequency of missense changes (56%). Two deep intronic changes causing intronic sequence exonization were found and in vitro antisense therapy was investigated. In cblB affected patients intronic and exonic nucleotide changes affecting splicing were frequent, and two misfolding missense mutations have been functionally analyzed. Finally, in cblA, cblC and cblD-variant2 complementation groups a high proportion of premature stop codon changes (PTC), including nonsense and frame-shift mutations, has been identified. In cblC type patients the highest frequency described to date of the common change R91fs (89%) has been found. The present work has a diagnostic and therapeutic value in this complex metabolism addressing our investigation towards genetic specific therapies. P13.05 study of apoptosis in genetic B metabolism disorders (cblB 12 and cblc types) A. Jorge-Finnigan1,2 , B. Pérez1,2 , A. Gámez2 , M. Ugarte1,2 , E. Richard1,2 ; 1Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Madrid, Spain, 2Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER- ER), Madrid, Spain. B metabolism disorders are a heterogeneous group of rare genetic 12 metabolic diseases caused by defects on cobalamin adsorption, transport or function. The aim of this study was to analyze apoptosis in several patients´ fibroblasts with defects on two of the genes involved (MMAB and MMACHC) by flow cytometry, as well as to investigate the differential gene expression in pathways that regulate this process by PCR array. Patients´ cell lines showed a higher rate of apoptosis compared to controls. Using the human apoptosis pathway array, we examined the gene expression profiles exhibited by six cblC and two cblB patients´ fibroblasts relative to four control individuals. Of the 84 apoptosis pathway-focused genes in the array, a total of 31 genes were differentially expressed. Up-regulation was observed in 23 genes, while 8 genes appeared to be down-regulated in patients´ fibroblasts. The most highly up-regulated genes belong to BCL2 and TNF receptor and ligand functional gene families. Multiple anti-apoptotic genes, including BAG1, BCL2, BCL2A1, BCL2L1, NAIP, BRAF, MCL1, TNF, CD27 and IGF1R were up-regulated; meanwhile BFAR was down-regulated. PCR array results are currently being confirmed by Western Blot. In addition, we have detected the up-regulation of the intracellular modulators of apoptosis, JNK and p38 MAP kinases, in patients´ cells by immunoblotting. In conclusion, the increased rate of apoptosis in cblB and cblC patients´ fibroblasts might up-regulate the anti-apoptotic molecules representing a compensatory response to a potential disease pathogenic mechanism. P13.06 Novel mutation in the GCH gene causing GtP-6 cyclohydrolase deficiency in two saudi sibs and early detection by serum neopterin N. M. AL-HASHMI1 , M. Al-Owain2 ; 1 2 king fasial special hospital and research center, riyadh, Saudi Arabia, King fasial special hospital and research center, Riyadh, Saudi Arabia. GTP-6 cyclohydrolase (GTPC) deficiency is a rare autosomal recessive disorder of the terahydrobiopterin (BH4) pathway. Only 5 patients reported in the literature. GTPC deficiency characteristic by hyperphenylalaninemia and low concentration of neopterins in urine and blood and neurotransmitter defect. We report tow sibling diagnosed with GTPC deficiency, one late and other early diagnosis. Patient 1 presented at the age of nine years with severe global development delay and frequent twitching of body. The plasma amino acid showed a phenylalanine of 357 umol/l.Which was not consistent with classical
Metabolic disorders PKU. BH4 challenge test showed normalization of phenylalanine indicating BH4 dependent PKU. Serum neopterin level was extremely low at < 2.0 (2.0-10 nmol/L) suggesting that the cause is most likely GTPC deficiency. Patient was started on BH4, l-dopa/carbidopa, 5-hydroxytyptophan, and folic acid without appreciable improvement.. Patient 2 is the brother who at age of 3 months and in view of positive family history of GTPC deficiency, serum neopterin level was found to be low at A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in
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Volume 17 Supplement 2 May 2009 www
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European Society of Human Genetics
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Table of Contents spoken Presentati
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Plenary Lectures PL2.2 massive para
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Concurrent Symposia s01.1 Genome va
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Concurrent Symposia Monogenic diabe
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Concurrent Symposia invariable in t
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Concurrent Symposia s11.2 clinical,
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Concurrent Symposia s13.2 A novel g
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Concurrent Sessions c01.1 mRNA-seq
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Concurrent Sessions velopmental del
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Concurrent Sessions development of
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Concurrent Sessions c04.6 Duplicati
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Concurrent Sessions genes to be rec
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Concurrent Sessions c07.5 Prenatal
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Concurrent Sessions with familial h
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Concurrent Sessions University of W
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Concurrent Sessions with this, we f
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Concurrent Sessions had immotile ci
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Concurrent Sessions abnormal glycos
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Concurrent Sessions showers’ and
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Concurrent Sessions partial gene de
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Concurrent Sessions leads to distre
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Genetic counseling Genetics educati
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Clinical genetics and Dysmorphology
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Cytogenetics P03. cytogenetics Recu
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Cytogenetics use of metaphase analy
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Cytogenetics 2: mother’s age < fa
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Cytogenetics P03.028 HLA B27 allele
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Cytogenetics karyotype revealed a p
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Cytogenetics drome is estimated at
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Cytogenetics P03.057 Pathological c
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Cytogenetics grandmother and 2 mate
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Cytogenetics method used to detect
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Cytogenetics P03.082 High-resolutio
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Cytogenetics All detected anomalies
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Cytogenetics somy for chromosome 2.
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Cytogenetics cially in chromosome 4
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Cytogenetics (59.390.122 to 62.021.
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Cytogenetics For further characteri
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Cytogenetics 9p duplication. This c
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Cytogenetics regions with mental /d
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Cytogenetics donation program of po
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Cytogenetics P03.165 interpretation
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Cytogenetics P03.174 Deletion of th
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Cytogenetics P03.183 An atypical 7q
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Cytogenetics spermia, 11 oligosperm
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Reproductive genetics and social fa
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Reproductive genetics mosomal chang
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Reproductive genetics two cohorts w
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Reproductive genetics the 147 SC ch
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Prenatal and perinatal genetics P05
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Prenatal and perinatal genetics and
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Prenatal and perinatal genetics fro
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Prenatal and perinatal genetics dev
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Prenatal and perinatal genetics in
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Prenatal and perinatal genetics obj
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Prenatal and perinatal genetics P05
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Cancer genetics P06.005 tiling reso
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Cancer genetics tient group in whic
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Cancer genetics chronic inflammatio
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Cancer genetics licular thyroid can
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Cancer genetics also studied. In 31
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Cancer genetics tile polyposis. We
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Cancer genetics Upon recombinant ex
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Cancer genetics variant allele was
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Cancer genetics from patients with
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Cancer genetics tion (PAX5 and GATA
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Cancer genetics scribed underexpres
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Cancer genetics of the ZIC gene fam
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Cancer genetics Materials and metho
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Cancer genetics the past and it is
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Cancer genetics P06.130 spectrum an
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Cancer genetics P06.139 the role of
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Cancer genetics and MSH2 germline m
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Cancer genetics P06.155 New roles f
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Cancer genetics screening was perfo
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Cancer genetics val (DFI) than pati
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Cancer genetics is hTERC gene ampli
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Cancer genetics on chromosome regio
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Cancer genetics preferentially dupl
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Cancer cytogenetics mutations in co
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Cancer cytogenetics P07.08 molecula
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Statistical genetics, includes Mapp
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Complex traits and polygenic disord
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Evolutionary and population genetic
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Genomics, Genomic technology and Ep
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Page 301 and 302: Genomics, Genomic technology and Ep
Page 313 and 314: Molecular basis of Mendelian disord
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Page 385 and 386: Genetic analysis, linkage ans assoc
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Author Index Allanson, J.: P02.140
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Author Index 0 Barbacioru, C.: C01.
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Author Index 0 Bonneau, D.: C16.2,
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Author Index 0 Chakravarti, A.: C13
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Author Index 0 Dan, D.: P01.39, P14
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Author Index 0 Duskova, J.: P06.012
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Author Index Franke, A.: P09.056 Fr
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Author Index Grasso, R.: P02.025 Gr
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Author Index Holder-Espinasse, M.:
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Author Index Jurkiewicz, E.: C14.5
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Author Index Kooper, A. J. A.: P05.
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Author Index Li, K. J.: P11.086 Li,
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Author Index Martinet, D.: P03.095
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Author Index Moorman, A. F. M.: P16
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Author Index P10.57, P10.82 Oguzkan
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Author Index P09.054, P09.085, P09.
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Author Index P16.01 Renieri, A.: P0
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Author Index Santorelli, F.: P08.55
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Author Index Sinke, R. J.: P02.020
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Author Index Taheri, M.: P04.33, P0
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Author Index Valentino, P.: P02.064
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Author Index Wiemer-Kruel, A.: P14.
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Keyword Index 1 10q22 deletions: P0
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Keyword Index autosomal dominant re
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Keyword Index CLA: P06.073 CLCN1 ge
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Keyword Index DMD: P16.40, P16.41,
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Keyword Index gene networks: S12.2
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Keyword Index hydrocephaly: P05.11
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Keyword Index malignant hyperthermi
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Keyword Index NAT2: P12.118 natridi
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Keyword Index Polymalformations: P0
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Keyword Index Sardinia: C09.6 Sardi
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Keyword Index TNFalpha: P08.61, P09
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2009 Vienna - European Society of Human Genetics

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