BDNF gene polymorphisms and haplotypes in relation to cognitive performance in Polish healthy subjects

Publications

Share / Export Citation / Email / Print / Text size:

Acta Neurobiologiae Experimentalis

Nencki Institute of Experimental Biology

Polish Neuroscience Society

Subject: Behavioral Sciences , Biomedical Sciences & Nutrition , Life Sciences , Medicine , Neurosciences

GET ALERTS

ISSN: 0065-1400
eISSN: 1689-0035

DESCRIPTION

19
Reader(s)
78
Visit(s)
0
Comment(s)
0
Share(s)

SEARCH WITHIN CONTENT

FIND ARTICLE

Volume / Issue / page

Related articles

VOLUME 76 , ISSUE 1 (March 2016) > List of articles

BDNF gene polymorphisms and haplotypes in relation to cognitive performance in Polish healthy subjects

Monika Wiłkość * / Agnieszka Szałkowska / Maria Skibińska / Ludmiła Zając-Lamparska / Małgorzata Maciukiewicz / Aleksander Araszkiewicz

Keywords : brain derived neurotrophic factor, polymorphism, haplotype, cognition

Citation Information : Acta Neurobiologiae Experimentalis. Volume 76, Issue 1, Pages 43-52, DOI: https://doi.org/10.21307/ane-2017-004

License : (CC BY 4.0)

Received Date : 06-October-2015 / Accepted: 01-March-2016 / Published Online: 25-July-2017

ARTICLE

ABSTRACT

The brain derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in the cell survival, axonal and dendritic growth, and synaptic plasticity. BDNF gene polymorphisms, functional Val66Met mainly, were shown to influence human brain structure and cognition.

The aim of the study was to assess the relationship between twelve BDNF gene variants and their haplotypes and cognitive performance measured using the Wisconsin Card Sorting Test (WCST), the Trail Making Test (TMT), the Stroop Test which are to a large extent connected with prefrontal cortex activity. Our sample consisted of 460 healthy participants from Polish population. We detected possible association between five BDNF polymorphisms (rs11030101, rs10835210, rs2049046, rs2030324, rs2883187) and TMT_A. Additionally, one haplotype block made from eleven BDNF variants (rs2883187, rs1401635, rs2049046, rs2030324, rs11030101, rs10835210, rs1013402, rs1401635, rs1013402), as significant linkage disequilibrium appeared. We discovered possible relationships of CACCGCGTACG and CACCGCGTACG haplotypes with TMT_A and TMT_B performance respectively. Our results confirmed the involvement of BDNF in the regulation of psychomotor speed, working memory and executive function in healthy subjects measured by a task engaging visuoperceptual abilities.

Content not available PDF Share

FIGURES & TABLES

REFERENCES

  1. Altar CA, Boylan CB, Jackson C, Hershenson S, Miller J, Wielgand SJ, Lindsay RM, Hyman C (1992) Brain-derived neurotrophic factor augments rotational behavior and nigrostriatal dopamine turnover in vivo. Proc Natl Acad Sci USA 89(23): 11347–11351.
  2. Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT (2010) Data quality control in genetic case-control association studies. Nat Protoc 5(9): 1564–1573.
  3. Badgaiyan RD, Posner M (1998) Mapping the cingulate cortex in response selection and monitoring. Neuroimage 7(3): 255–260.
  4. Badzakova-Trajkov G, Barnett KJ, Waldie KE, Kirk, I.J. (2009). An ERP investigation of the Stroop task: the role of the cingulate in attentional allocation and conflict resolution. Brain Res 1253: 139–148.
  5. Barde YA, Edgar D, Thoenen H (1982) Purification of a new neurotrophic factor from mammalian brain. EMBO J 1(5): 549–553.
  6. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2): 263–265.
  7. Bath KG, Lee FS (2006) Variant BDNF (Val66Met) impact on brain structure and function. Cogn Affect Behav Neurosci 6(1): 79–85.
  8. Brooks SJ, Nilsson EK, Jacobsson JA, Stein DJ, Fredriksson R, Lind L, Schiöth HB (2014) BDNF polymorphisms are linked to poorer working memory performance, reduced cerebellar and hippocampal volumes and differences in prefrontal cortex in a Swedish elderly population. PLoS One 9(1): e82707.
  9. Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta JK (2006) BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 59(9): 812–815.
  10. Cathomas F, Vogler C, Euler-Sigmund JC, de Quervain DJF, Papassoitripolous A (2010) Fine-mapping of the brain derived neurotrophic factor (BDNF) gene supports an association of the Val66Met polymorphism with episodic memory. Int J Neuropsychopharmacol 13(8): 975–980.
  11. Cerasa A, Tongiorgi E, Fera F, Gioia MC, Valentino P, Liguori M, Manna I, Zito G, Passamonti L, Nisticò R, Quattrone A (2010) The effects of BDNF Val66Met polymorphism on brain function in controls and patients with multiple sclerosis: an imaging genetic study. Behav Brain Res 207(2): 377–386.
  12. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempsted LB, Lee FS (2004) Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 24(18): 4401–4411
  13. Chepenik LG, Fredericks C, Papademetris X, Spencer L, Lacadie C, Wang F, Pittman B, Duncan JS, Staib LH, Duman RS, Gelernter J, Blumberg HP (2009) Effects of the brain-derived neurotrophic growth factor val66met variation on hippocampus morphology in bipolar disorder. Neuropsychopharmacology 34(4): 944–951.
  14. Dempster E, Toulopoulou T, McDonald C, Bramon E, Walshe M, Filbey F, Wickham H, Sham PC, Murray RM, Collier DA (2005) Association between BDNF val66 met genotype and episodic memory. Am J Med Genet B Neuropsychiatr Genet 134B(1): 73–75.
  15. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112(2): 257–269.
  16. Figurov A, Pozzo-Miller LD, Olafson P, Wang T, Lu B (1996) Regulation synaptic responses to high-frequency stimulation and LPT by neurotrophins in the hippocampus. Nature 381(6584): 706–709.
  17. Frodl T, Schüle C, Schmitt G, Born C, Baghai T, Zill P, Bottlender R, Rupprecht R, Bondy B, Reiser M, Möller HJ, Meisenzahl EM (2007) Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry 64(4): 410–416.
  18. Goldberg TE, Iudicello J, Russo C, Elvevåg B, Straub R, Egan MF, Weinberger DR (2008) BDNF Val66Met polymorphism significantly affects d’ in verbal recognition memory at short and long delays. Biol Psychol 77(1): 20–24.
  19. Gong P, Zheng A, Chen D, Ge W, Lv C, Zhang K, Gao X, Zhang F (2009) Effect of Val66Met polymorphism on digital working memory and spatial localization in a healthy Chinese Han population. J Mol Neurosci38(3): 250–256.
  20. Hajek T, Kopecek M, Höschl C (2012) Reduced hippocampal volumes in healthy carriers of brain-derived neurotrophic factor Val66Met polymorphism: meta-analysis. World J Biol Psychiatry 13(3): 178–187.
  21. Han C, Bae H, Won SD, Roh S, Kim DJ (2015) The relationship between brain-derived neurotrophic factor and cognitive functions in alcohol-dependent patients: a preliminary study. Ann Gen Psychiatry 14: 30.
  22. Hansell NK, James MR, Duffy DL, Birley AJ, Luciano M, Geffen GM, Wright MJ, Montgomery GW, Martin NG (2007) Effect of the BDNF V166M polymorphism on working memory in healthy adolescents. Genes Brain Behav 6(3): 260–268.
  23. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR (2003) Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23(17): 6690–6694.
  24. Harris SE, Fox H, Wright AF, Hayward C, Starr JM, Whalley LJ, Deary IJ (2006) The brain-derived neurotrophic factor Val66Met polymorphism is associated with age-related change in reasoning skills. Mol Psychiatry 11(5): 505–513.
  25. Harrisberger F, Smieskova R, Schmidt A, Lenz C, Walter A, Wittfeld K, Grabe HJ, Lang UE, Fusar-Poli P, Borgwardt S (2015) BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: A systematic review and meta-analysis. Neurosci Biobehav Rev 55: 107–118.
  26. Harrisberger F, Spalek K, Smieskova R, Schmidt A, Coynel D, Milnik A, Fastenrath M, Freytag V, Gschwind L, Walter A, Vogel T, Bendfeldt K, de Quervain DJ, Papassotiropoulos A, Borgwardt S (2014) The association of the BDNF Val66Met polymorphism and the hippocampal volumes in healthy humans: a joint meta-analysis of published and new data. Neurosci Biobehav Rev 42: 267–278.
  27. Hashimoto R, Moriguchi Y, Yamashita F, Mori T, Nemoto K, Okada T, Hori H, Noguchi H, Kunugi H, Ohnishi T (2008) Dose dependent effect of the Val66Met polymorphism of the brain-derived neurotrophic factor gene on memory-related hippocampal activity. Neurosci Res 61(4): 360–367.
  28. Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtis G (1993) Wisconsin Card Sorting Test manual: Revised and expanded. Psychological Assessment Resources, Odessa, Florida, USA.
  29. Ho BC, Milev P, O’Leary DS, Librant A, Andreasen NC, Wassink TH (2006) Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatry 63(7): 731–740.
  30. Hong CJ, Liou YJ, Tsai SJ (2011) Effects of BDNF polymorphisms on brain function and behavior in health and disease. Brain Res Bull 86(5–6): 287–297.
  31. Houlihan LM, Harris SE, Luciano M, Gow AJ, Starr JM, Visscher PM, Deary IJ (2009) Replication study of candidate genes for cognitive abilities: the Lothian Birth Cohort 1936. Genes Brain Behav 8(2): 238–247.
  32. Huang ZJ, Kirkwood A, Pizzorusso T, Porciatti V, Morales B, Bear MF, Maffei L, Tonegawa S (1999) BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98(6): 739–755.
  33. Kambeitz JP, Bhattacharyya S, Kambeitz-Ilankovic LM, Valli I, Collier DA, McGuire P (2012) Effect of BDNF val(66)met polymorphism on declarative memory and its neural substrate: a meta-analysis. Neurosci Biobehav Rev 36(9): 2165–2177.
  34. Karnik MS, Wang L, Barch DM, Morris JC, Csernansky JG (2010) BDNF polymorphism rs6265 and hippocampal structure and memory performance in healthy control subjects. Psychiatry Res 178(2): 425–429.
  35. Kubo M, Shoshi C, Kitawaki T, Takemoto R, Kinugasa K, Yoshida H, Honda C, Okamoto M (2008) Increase in prefrontal cortex blood flow during the computer version trail making test. Neuropsychobiology 58(3–4): 200–210.
  36. Laing KR, Mitchell D, Wersching H, Czira ME, Berger K, Baune BT (2012) Brain-derived neurotrophic factor (BDNF) gene: a gender-specific role in cognitive function during normal cognitive aging of the MEMO-Study? Age (Dordr) 34(4): 1011–1022.
  37. Leiberock J, Lottspeich F, Hohn A, Hofer M, Hengrer B, Masiakowaki P, Thoenen H, Barde YA (1989) Molecular cloning and expression of brain-derived neurotrophic factor. Nature 341(6238): 149–152.
  38. Levine ES, Dreyfus CF, Black IB, Plummer MR (1995) Brain-derived neurotrophic factor rapidly enhances synaptic trans-mission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci USA 92: 8074–8077.
  39. Lezak MD, Howieson D, Bigler ED, Tranel D (2012) Neuropsychological assessment. Oxford University Press, New York, USA.
  40. Lindsay RM (1995) Neuron saving schemes. Nature 373(6512): 289–290.
  41. Lindvall O, Kokaia Z, Bengzon J, Elmer E, Kokaia M (1994) Neurotrophins and brain insults. Tends Neurosci 17(11): 490–496.
  42. Lipska BK, Khaing ZZ, Weickert CS, Weiberger DR (2001) BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs. Eur J Neurosci 14: 135–144.
  43. Łojek E, Stańczak J (2012) Kolorowy Test Połączeń wersja dla Dorosłych CTT (in Polish). Pracownia Testów Psychologicznych Polskiego Towarzystwa Psychologicznego, Warsaw, Poland.
  44. Lu B, Gottschalk W (2000) Modulation of hippocampal synaptic transmission and plasticity by neurotrophins. Prog Brain Res 128: 231–241.
  45. Maisonpierre PC, Le Beau MM, Espinosa RIII, Ip NY, Belluscio L, de la Monte SM, Squinto S, Furth ME, Yancopoulos GD (1991) Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics 10(3): 558–568.
  46. Mamounas LA, Altar CA, Blue ME, Kaplan DR, Tessarollo L, Lyons WE (2000) BDNF promoters the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J Neurosci 20(2): 771–782.
  47. Mandelman SD, Grigorenko EL (2012) BDNF Val66Met and Cognition: All, None, or Some? A Meta-Analysis of the Genetic Association. Genes Brain Behav 11(2): 127–136.
  48. Marqués-Iturria I, Garolera M, Pueyo R, Segura B, Hernan I, García-García I, Sánchez-Garre C, Vernet-Vernet M, Sender-Palacios MJ, Narberhaus A, Ariza M, Junqué C, Jurado MÁ (2014) The interaction effect between BDNF val66met polymorphism and obesity on executive functions and frontal structure. Am J Med Genet B Neuropsychiatr Genet 165B(3): 245–253.
  49. Matsuo K, Walss-Bass C, Nery FG, Nicoletti MA, Hatch JP, Frey BN, Monkul ES, Zunta-Soares GB, Bowden CL, Escamilla MA, Soares JC (2009) Neuronal correlates of brain-derived neurotrophic factor Val66Met polymorphism and morphometric abnormalities in bipolar disorder. Neuropsychopharmacology 34(8): 1904–1913.
  50. Miller SA, Dykes D, Plesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res16(3): 1215.
  51. Miyajima F, Ollier W, Mayes A, Jackson A, Thacker N, Rabbitt P, Pendleton N, Horan M, Payton A (2008) Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav 7(4): 411–417.
  52. Molendijk ML, Bus BA, Spinhoven P, Kaimatzoglou A, Oude Voshaar RC, Penninx BW, van IJzendoorn MH, Elzinga BM (2012) A systematic review and meta-analysis on the association between BDNF val(66)met and hippocampal volume-a genuine effect or a winners curse?. Am J Med Genet B Neuropsychiatr Genet 159B(6): 731–740.
  53. Montag C, Felten A, Markett S, Fischer L, Winkel K, Cooper A, Reuter M (2014) The role of the BDNF Val66Met polymorphism in individual differences in long-term memory capacity. J Mol Neurosci 54(4): 796–802
  54. Montag C, Weber B, Fliessbach K, Elger C, Reuter M (2009)The BDNF Val66Met polymorphism impacts parahippocampal and amygdala volume in healthy humans: incremental support for a genetic risk factor for depression. Psychol Med 39(11): 1831–1839.
  55. Montag C, Weber B, Jentgens E, Elger C, Reuter M (2010) An epistasis effect of functional variants on the BDNF and DRD2 genes modulates gray matter volume of the anterior cingulate cortex in healthy humans. Neuropsychologia 48(4): 1016–1021
  56. Mueller SC, Aouidad A, Gorodetsky E, Goldman D, Pine DS, Ernst M (2013) Gray matter volume in adolescent anxiety: an impact of the brain-derived neurotrophic factor Val(66)Met polymorphism? J Am Acad Child Adolesc Psychiatry 52(2): 184–195.
  57. Nemoto K, Ohnishi T, Mori T, Moriguchi Y, Hashimoto R, Asada T, Kunugi H (2006) The Val66Met polymorphism of the brain-derived neurotrophic factor gene affects age-related brain morphology. Neurosci Lett 397(1‑2): 25–29.
  58. Notaras M, Hill R, van den Buuse M (2015) The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy. Mol Psychiatry 20(8): 916–930.
  59. Oral E, Canpolat S, Yildirim S, Gulec M, Aliyev E, Aydin N (2012) Cognitive functions and serum levels of brain-derived neurotrophic factor in patients with major depressive disorder. Brain Res Bull 88(5): 454–459.
  60. Oroszi G, Lapteva L, Davis E, Yarboro CH, Weickert T, Roebuck-Spencer T, Bleiberg J, Rosenstein D, Pao M, Lipsky PE, Goldman D, Lipsky RH, Illei GG (2006) The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus. Ann Rheum Dis 65(10): 1330–1335.
  61. Petryshen TL, Sabeti PC, Aldinger KA, Fry B, Fan JB, Schaffner SF, Waggoner SG, Tahl AR, Sklar P (2010) Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry 15(8): 810–815.
  62. Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, Egan MF, Meyer-Lindenberg A, Weinberger DR (2004) The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 24(45): 10099–10102.
  63. Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T (2007) Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics 90: 397–406.
  64. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3): 559–575.
  65. Raz N, Rodrigue KM, Kennedy KM, Land S (2009) Genetic and vascular modifiers of age-sensitive cognitive skills: effects of COMT, BDNF, ApoE, and hypertension. Neuropsychology 23(1): 105–116.
  66. Reitan RM (1955) The relation of the trail making test to organic brain damage. J Consult Psychol 19(5): 393–394.
  67. Rybakowski JK, Borkowska A, Czerski PM, Skibińska M, Hauser J (2003) Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord 5(6): 468–472.
  68. Rybakowski JK, Borkowska A, Skibinska M, Szczepankiewicz A, Kapelski P, Leszczynska-Rodziewicz A, Czerski PM, Hauser J (2006) Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain derived neurotrophic factor gene. Psychiatry Clin Neurosci 60(1): 70–76.
  69. Sánchez-Cubillo I, Periáñez JA, Adrover-Roig D, Rodríguez-Sánchez JM, Ríos‑Lago M, Tirapu J, Barceló F (2009) Construct validity of the Trail Making Test: role of task-switching, working memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsychol Soc 15(3): 438–450.
  70. Shen RY, Altar CA, Chiodo LA (1994) Brain-derived neurotrophic factor increases the electrical activity of pars compacta dopamine neurons in vivo. Proc Natl Acad Sci U S A 91(19): 8920–8924.
  71. Shibuya-Tayoshi S, Sumitani S, Kikuchi K, Tanaka T, Tayoshi S, Ueno S, Ohmori T (2007) Activation of the prefrontal cortex during the Trail‑Making Test detected with multichannel near-infrared spectroscopy. Psychiatry Clin Neurosci 61(6): 616–621.
  72. Strauss E, Sherman E, Spreen O (2006) A compendium of neuropsychological tests. Administrations, norms, and commentary. Oxford University Press, New York, USA.
  73. Stroop JR (1935) Studies of interference in serial verbal reaction. J Exp Psychol 18: 643–662.
  74. Szeszko PR, Lipsky R, Mentschel C, Robinson D, Gunduz-Bruce H, Sevy S, Ashtari M, Napolitano B, Bilder RM, Kane JM, Goldman D, Malhotra AK (2005) Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry 10(7): 631–636.
  75. Tomaszewska M, Markowska A, Borkowska A (2010) Test Stroopa – wartość diagnostyczna w psychiatrii (in Polish). Neuropsychiatria i Neuropsychologia 5(1): 35–41.
  76. Tsai SJ, Gau YTA, Liu ME, Hsieh CH, Liou YJ, Hong CJ (2008) Association study of brain-derived neurotrophic factor and apolipoprotein E polymorphisms and cognitive function in aged males without dementia. Neurosci Lett 433(2): 158–162.
  77. Tsai SJ, Hong CJ, Yu YW, Chen TJ (2004) Association study of a brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and personality trait and intelligence in healthy young females. Neuropsychobiology 49(1): 13–16.
  78. van Wingen G, Rijpkema M, Franke B, van Eijndhoven P, Tendolkar I, Verkes RJ, Buitelaar J, Fernández G (2010) The brain derived neurotrophic factor Val66Met polymorphism affects memory formation and retrieval of biologically salient stimuli. Neuroimage 50(3): 1212–1218.
  79. Ventimiglia R, Mather PE, Jones BE, Lindsay RM (1995) The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vivo. Eur J Neurosci 7(2): 213–222.
  80. White LA, Eaton MJ, Castro MC, Klose KJ, Globus M, Shaw G, Whittemore SR (1994) Distinct regulatory pathways control neurofilament expression and neurotransmitter synthesis in immortalized serotonergic neurons. J Neurosci 14: 6744–6753.
  81. Yang X, Liu P, Sun J, Wang G, Zeng F, Yuan K, Liu J, Dong M, von Deneen KM, Qin W, Tian J (2012) Impact of brain-derived neurotrophic factor Val66Met polymorphism on cortical thickness and voxel-based morphometry in healthy Chinese young adults. PLoS One 7(6): e37777.
  82. Zhang XY, Chen da C, Xiu MH, Haile CN, Luo X, Xu K, Zhang HP, Zuo L, Zhang Z, Zhang X, Kosten TA, Kosten TR (2012) Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. Hum Genet 131(7): 1187–1195.

EXTRA FILES

COMMENTS