Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment

Genes, Brain and Behavior

Volumn 13, Issue 4, 2014, Pages 418-429

  Nudel, R ^a   Simpson, N H ^a   Baird, G ^b   O'Hare, A ^c   Conti Ramsden, G ^d   Bolton, P F ^e   Hennessy, E R ^f   Ring, S M ^g   Davey Smith, G ^g   Francks, C ^h,i   Paracchini, S ^j   Monaco, A P ^a,k   Fisher, S E ^h,i   Newbury, D F ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b EVELINA LONDON CHILDREN S HOSPITAL   (United Kingdom)

^c UNIVERSITY OF EDINBURGH   (United Kingdom)

^d UNIVERSITY OF MANCHESTER   (United Kingdom)

^e KING'S COLLEGE LONDON   (United Kingdom)

^f UNIVERSITY OF ABERDEEN   (United Kingdom)

^g UNIVERSITY OF BRISTOL   (United Kingdom)

^h MAX PLANCK INSTITUTE FOR PSYCHOLINGUISTICS   (Netherlands)

ⁱ RADBOUD UNIVERSITY   (Netherlands)

^j UNIVERSITY OF ST ANDREWS   (United Kingdom)

^k TUFTS UNIVERSITY   (United States)

more..

Author keywords

ALSPAC; GWAS; Imprinting; Neurodevelopmental disorder; Specific language impairment

Indexed keywords

GENOMIC DNA; PROSTAGLANDIN E RECEPTOR 4; ARHGEF19 PROTEIN, HUMAN; DAB2 PROTEIN, HUMAN; GUANINE NUCLEOTIDE EXCHANGE FACTOR; NOP9 PROTEIN, HUMAN; PTGER4 PROTEIN, HUMAN; RNA BINDING PROTEIN; SIGNAL TRANSDUCING ADAPTOR PROTEIN; TUMOR SUPPRESSOR PROTEIN;

ARTICLE; ATTENTION DEFICIT DISORDER; AUTISM; CHROMOSOME 1; CHROMOSOME 14; CHROMOSOME 14Q; CHROMOSOME 5; CHROMOSOME 5P; CHROMOSOME BAND; CHROMOSOME REARRANGEMENT; GENE AMPLIFICATION; GENE LINKAGE DISEQUILIBRIUM; GENETIC ASSOCIATION; GENETIC LINKAGE; GENETIC TRAIT; HETEROZYGOSITY; HUMAN; HUMAN EXPERIMENT; INTELLECTUAL IMPAIRMENT; LANGUAGE DISABILITY; NUCLEAR FAMILY; PARENT OF ORIGIN; PRIORITY JOURNAL; QUALITY CONTROL; QUANTITATIVE TRAIT LOCUS; SCHIZOPHRENIA; SINGLE NUCLEOTIDE POLYMORPHISM; ADULT; APRAXIA; CHILD; FEMALE; GENETICS; GENOME IMPRINTING; GENOTYPE; HUMAN CHROMOSOME; MALE; METABOLISM;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ADULT; APRAXIAS; CHILD; CHROMOSOMES, HUMAN; FEMALE; GENOME-WIDE ASSOCIATION STUDY; GENOMIC IMPRINTING; GENOTYPE; GUANINE NUCLEOTIDE EXCHANGE FACTORS; HUMANS; MALE; POLYMORPHISM, SINGLE NUCLEOTIDE; QUANTITATIVE TRAIT LOCI; RECEPTORS, PROSTAGLANDIN E, EP4 SUBTYPE; RNA-BINDING PROTEINS; TUMOR SUPPRESSOR PROTEINS;

EID: 84897958382     PISSN: 16011848     EISSN: 1601183X     Source Type: Journal    
DOI: 10.1111/gbb.12127     Document Type: Article

References (83)

1. Abou Jamra, R., Wohlfart, S., Zweier, M., Uebe, S., Priebe, L., Ekici, A., Giesebrecht, S., Abboud, A., Al Khateeb, M.A., Fakher, M., Hamdan, S., Ismael, A., Muhammad, S., Nothen, M.M., Schumacher, J. & Reis, A. (2011) Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity. Eur J Hum Genet 19, 1161-1166.
2. Adzhubei, I.A., Schmidt, S., Peshkin, L., Ramensky, V.E., Gerasimova, A., Bork, P., Kondrashov, A.S. & Sunyaev, S.R. (2010) A method and server for predicting damaging missense mutations. Nat Methods 7, 248-249.
3. Ainsworth, H.F., Unwin, J., Jamison, D.L. & Cordell, H.J. (2011) Investigation of maternal effects, maternal-fetal interactions and parent-of-origin effects (imprinting), using mothers and their offspring. Genet Epidemiol 35, 19-45.
4. Alarcon, M., Abrahams, B.S., Stone, J.L., Duvall, J.A., Perederiy, J.V., Bomar, J.M., Sebat, J., Wigler, M., Martin, C.L., Ledbetter, D.H., Nelson, S.F., Cantor, R.M. & Geschwind, D.H. (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82, 150-159.
5. Anderson, C.A., Pettersson, F.H., Clarke, G.M., Cardon, L.R., Morris, A.P. & Zondervan, K.T. (2010) Data quality control in genetic case-control association studies. Nat Protoc 5, 1564-1573.
6. Anney, R.J., Hawi, Z., Sheehan, K. et al. (2008) Parent of origin effects in attention/deficit hyperactivity disorder (ADHD): analysis of data from the international multicenter ADHD genetics (IMAGE) program. Am J Med Genet B Neuropsychiatr Genet 147B, 1495-1500.
7. Baird, J., Stevenson, J.C. & Williams, D.C. (2000) The evolution of ADHD: a disorder of communication? Q Rev Biol 75, 17-35.
8. Bartlett, C.W., Flax, J.F., Logue, M.W., Vieland, V.J., Bassett, A.S., Tallal, P. & Brzustowicz, L.M. (2002) A major susceptibility locus for specific language impairment is located on 13q21. Am J Hum Genet 71, 45-55.
9. Bartlett, C.W., Flax, J.F., Logue, M.W., Smith, B.J., Vieland, V.J., Tallal, P. & Brzustowicz, L.M. (2004) Examination of potential overlap in autism and language loci on chromosomes 2, 7, and 13 in two independent samples ascertained for specific language impairment. Hum Hered 57, 10-20.
10. Bishop, D.V.M. (1998) Development of the Children's Communication Checklist (CCC): a method for assessing qualitative aspects of communicative impairment in children. J Child Psychol Psychiatry 39, 879-891.
11. Bishop, D.V.M. (2003) Autism and specific language impairment: categorical distinction or continuum? Novartis Found Symp 251, 213-226 discussion 226-234, 281-297.
12. Bishop, D.V.M. (2006) What causes specific language impairment in children? Curr Dir Psychol Sci 15, 217-221.
13. Bishop, D.V.M. (2008) Specific language impairment, dyslexia, and autism: Using genetics to unravel their relationship. In Norbury, C.F., Tomblin, J.B., & Bishop, D.V.M. (eds), Understanding developmental language disorders: from theory to practice. Psychology press. New York, NY, pp. 67-78.
14. Bishop, D.V.M. (2010) Overlaps between autism and language impairment: phenomimicry or shared etiology? Behav Genet 40, 618-629.
15. Bishop, D.V.M. & Baird, G. (2001) Parent and teacher report of pragmatic aspects of communication: use of the children's communication checklist in a clinical setting. Dev Med Child Neurol 43, 809-818.
16. Bishop, D.V. & Norbury, C.F. (2002) Exploring the borderlands of autistic disorder and specific language impairment: a study using standardised diagnostic instruments. J Child Psychol Psychiatry 43, 917-929.
17. Bishop, D.V.M., North, T. & Donlan, C. (1995) Genetic basis of specific language impairment: evidence from a twin study. Dev Med Child Neurol 37, 56-71.
18. Boyd, A., Golding, J., Macleod, J., Lawlor, D.A., Fraser, A., Henderson, J., Molloy, L., Ness, A., Ring, S. & Davey Smith, G. (2013) Cohort profile: the 'children of the 90s'-the index offspring of the Avon Longitudinal Study of Parents and Children. Int J Epidemiol 42, 111-127.
19. Burmeister, M., McInnis, M.G. & Zollner, S. (2008) Psychiatric genetics: progress amid controversy. Nat Rev Genet 9, 527-540.
20. Chamberlain, S.J. & Lalande, M. (2010) Neurodevelopmental disorders involving genomic imprinting at human chromosome 15q11-q13. Neurobiol Dis 39, 13-20.
21. Conti-Ramsden, G., Falcaro, M., Simkin, Z. & Pickles, A. (2007) Familial loading in specific language impairment: patterns of differences across proband characteristics, gender and relative type. Genes Brain Behav 6, 216-228.
22. Eicher, J.D., Powers, N.R., Miller, L.L. et al. (2013) Genome-wide association study of shared components of reading disability and language impairment. Genes Brain Behav 12, 792-801.
23. Elia, J., Gai, X., Xie, H.M. et al. (2010) Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry 15, 637-646.
24. Falcaro, M., Pickles, A., Newbury, D.F., Addis, L., Banfield, E., Fisher, S.E., Monaco, A.P., Simkin, Z. & Conti-Ramsden, G. (2008) Genetic and phenotypic effects of phonological short-term memory and grammatical morphology in specific language impairment. Genes Brain Behav 7, 393-402.
25. Field, L.L., Shumansky, K., Ryan, J., Truong, D., Swiergala, E. & Kaplan, B.J. (2013) Dense-map genome scan for dyslexia supports loci at 4q13, 16p12, 17q22; suggests novel locus at 7q36. Genes Brain Behav 12, 56-69.
26. Fradin, D., Cheslack-Postava, K., Ladd-Acosta, C., Newschaffer, C., Chakravarti, A., Arking, D.E., Feinberg, A. & Fallin, M.D. (2010) Parent-of-origin effects in autism identified through genome-wide linkage analysis of 16, 000 SNPs. PLoS One 5, e12513.
27. Fraser, A., Macdonald-Wallis, C., Tilling, K., Boyd, A., Golding, J., Davey Smith, G., Henderson, J., Macleod, J., Molloy, L., Ness, A., Ring, S., Nelson, S.M. & Lawlor, D.A. (2013) Cohort profile: the avon longitudinal study of parents and children: ALSPAC mothers cohort. Int J Epidemiol 42, 97-110.
28. Gamazon, E.R., Zhang, W., Konkashbaev, A., Duan, S., Kistner, E.O., Nicolae, D.L., Dolan, M.E. & Cox, N.J. (2010) SCAN: SNP and copy number annotation. Bioinformatics 26, 259-262.
29. Glatt, S.J., Stone, W.S., Nossova, N., Liew, C.C., Seidman, L.J. & Tsuang, M.T. (2011) Similarities and differences in peripheral blood gene-expression signatures of individuals with schizophrenia and their first-degree biological relatives. Am J Med Genet B Neuropsychiatr Genet 156B, 869-887.
30. Grigorenko, E.L., Wood, F.B., Meyer, M.S., Pauls, J.E., Hart, L.A. & Pauls, D.L. (2001) Linkage studies suggest a possible locus for developmental dyslexia on chromosome 1p. Am J Med Genet 105, 120-129.
31. Hawi, Z., Segurado, R., Conroy, J., Sheehan, K., Lowe, N., Kirley, A., Shields, D., Fitzgerald, M., Gallagher, L. & Gill, M. (2005) Preferential transmission of paternal alleles at risk genes in attention-deficit/hyperactivity disorder. Am J Hum Genet 77, 958-965.
32. Hawi, Z., Kent, L., Hill, M., Anney, R.J., Brookes, K.J., Barry, E., Franke, B., Banaschewski, T., Buitelaar, J., Ebstein, R., Miranda, A., Oades, R.D., Roeyers, H., Rothenberger, A., Sergeant, J., Sonuga-Barke, E., Steinhausen, H.C., Faraone, S.V., Asherson, P. & Gill, M. (2010) ADHD and DAT1: further evidence of paternal over-transmission of risk alleles and haplotype. Am J Med Genet B Neuropsychiatr Genet 153B, 97-102.
33. Hoggart, C.J., Clark, T.G., De Iorio, M., Whittaker, J.C. & Balding, D.J. (2008) Genome-wide significance for dense SNP and resequencing data. Genet Epidemiol 32, 179-185.
34. Horii, T., Morita, S., Kimura, M. & Hatada, I. (2009) Epigenetic regulation of adipocyte differentiation by a Rho guanine nucleotide exchange factor, WGEF. PLoS One 4, e5809.
35. Howey, R. & Cordell, H.J. (2012) PREMIM and EMIM: tools for estimation of maternal, imprinting and interaction effects using multinomial modelling. BMC Bioinformatics 13, 149.
36. Kapeli, K. & Yeo, G.W. (2012) Genome-wide approaches to dissect the roles of RNA binding proteins in translational control: implications for neurological diseases. Front Neurosci 6, 144.
37. Kim, J.W., Waldman, I.D., Faraone, S.V., Biederman, J., Doyle, A.E., Purcell, S., Arbeitman, L., Fagerness, J., Sklar, P. & Smoller, J.W. (2007) Investigation of parent-of-origin effects in ADHD candidate genes. Am J Med Genet B Neuropsychiatr Genet 144B, 776-780.
38. Kjelgaard, M.M. & Tager-Flusberg, H. (2001) An investigation of language impairment in autism: implications for genetic subgroups. Lang Cogn Process 16, 287-308.
39. Krawczak, M. (2006) Multiple Significance Testing in Genetic Epidemiology. eLS. John Wiley & Sons, Ltd, Chichester.
40. Kutsche, K., Yntema, H., Brandt, A., Jantke, I., Nothwang, H.G., Orth, U., Boavida, M.G., David, D., Chelly, J., Fryns, J.P., Moraine, C., Ropers, H.H., Hamel, B.C., van Bokhoven, H. & Gal, A. (2000) Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nat Genet 26, 247-250.
41. Libioulle, C., Louis, E., Hansoul, S. et al. (2007) Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet 3, e58.
42. Lin, P.I., Vance, J.M., Pericak-Vance, M.A. & Martin, E.R. (2007) No gene is an island: the flip-flop phenomenon. Am J Hum Genet 80, 531-538.
43. Lin, M., Hrabovsky, A., Pedrosa, E., Wang, T., Zheng, D. & Lachman, H.M. (2012) Allele-biased expression in differentiating human neurons: implications for neuropsychiatric disorders. PLoS One 7, e44017.
44. Liu, J., Nyholt, D.R., Magnussen, P., Parano, E., Pavone, P., Geschwind, D., Lord, C., Iversen, P., Hoh, J., Ott, J. & Gilliam, T.C. (2001) A genomewide screen for autism susceptibility loci. Am J Hum Genet 69, 327-340.
45. Luciano, M., Evans, D.M., Hansell, N.K., Medland, S.E., Montgomery, G.W., Martin, N.G., Wright, M.J. & Bates, T.C. (2013) A genome-wide association study for reading and language abilities in two population cohorts. Genes Brain Behav 12, 645-652.
46. Meaburn, E.L., Harlaar, N., Craig, I.W., Schalkwyk, L.C. & Plomin, R. (2008) Quantitative trait locus association scan of early reading disability and ability using pooled DNA and 100K SNP microarrays in a sample of 5760 children. Mol Psychiatry 13, 729-740.
47. Monaco, A.P. (2007) Multivariate linkage analysis of specific language impairment (SLI). Ann Hum Genet 71, 660-673.
48. Morison, I.M., Paton, C.J. & Cleverley, S.D. (2001) The imprinted gene and parent-of-origin effect database. Nucleic Acids Res 29, 275-276.
49. Mott, R., Yuan, W., Kaisaki, P., Gan, X., Cleak, J., Edwards, A., Baud, A. & Flint, J. (2014) The architecture of parent-of-origin effects in mice. Cell 156, 332-342.
50. Newbury, D.F., Winchester, L., Addis, L. et al. (2009) CMIP and ATP2C2 modulate phonological short-term memory in language impairment. Am J Hum Genet 85, 264-272.
51. Newey, S.E., Velamoor, V., Govek, E.E. & Van Aelst, L. (2005) Rho GTPases, dendritic structure, and mental retardation. J Neurobiol 64, 58-74.
52. Ogdie, M.N., Macphie, I.L., Minassian, S.L., Yang, M., Fisher, S.E., Francks, C., Cantor, R.M., McCracken, J.T., McGough, J.J., Nelson, S.F., Monaco, A.P. & Smalley, S.L. (2003) A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. Am J Hum Genet 72, 1268-1279.
53. Ogdie, M.N., Fisher, S.E., Yang, M., Ishii, J., Francks, C., Loo, S.K., Cantor, R.M., McCracken, J.T., McGough, J.J., Smalley, S.L. & Nelson, S.F. (2004) Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11. Am J Hum Genet 75, 661-668.
54. Ogdie, M.N., Bakker, S.C., Fisher, S.E., Francks, C., Yang, M.H., Cantor, R.M., Loo, S.K., van der Meulen, E., Pearson, P., Buitelaar, J., Monaco, A., Nelson, S.F., Sinke, R.J. & Smalley, S.L. (2006) Pooled genome-wide linkage data on 424 ADHD ASPs suggests genetic heterogeneity and a common risk locus at 5p13. Mol Psychiatry 11, 5-8.
55. Pruim, R.J., Welch, R.P., Sanna, S., Teslovich, T.M., Chines, P.S., Gliedt, T.P., Boehnke, M., Abecasis, G.R. & Willer, C.J. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336-2337.
56. Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M.A., Bender, D., Maller, J., Sklar, P., de Bakker, P.I., Daly, M.J. & Sham, P.C. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81, 559-575.
57. Rabin, M., Wen, X.L., Hepburn, M., Lubs, H.A., Feldman, E. & Duara, R. (1993) Suggestive linkage of developmental dyslexia to chromosome 1p34-p36. Lancet 342, 178.
58. Risch, N.J. (2000) Searching for genetic determinants in the new millennium. Nature 405, 847-856.
59. Risch, N. & Merikangas, K. (1996) The future of genetic studies of complex human diseases. Science 273, 1516-1517.
60. Rust, J. (1996) WOLD Wechsler Objective Language Dimensions Manual. The Psychological Corporation, London.
61. Schanen, N.C. (2006) Epigenetics of autism spectrum disorders. Hum Mol Genet 15 (Spec 2), R138-R150.
62. Schmitt, A., Leonardi-Essmann, F., Durrenberger, P.F., Parlapani, E., Schneider-Axmann, T., Spanagel, R., Arzberger, T., Kretzschmar, H., Herrera-Marschitz, M., Gruber, O., Reynolds, R., Falkai, P. & Gebicke-Haerter, P.J. (2011) Regulation of immune-modulatory genes in left superior temporal cortex of schizophrenia patients: a genome-wide microarray study. World J Biol Psychiatry 12, 201-215.
63. Semel, E.M., Wiig, E.H. & Secord, W. (1992) Clinical Evaluation of Language Fundamentals - Revised. Phychological Corporation, San Antonio, TX.
64. Stromswold, K. (1998) Genetics of spoken language disorders. Hum Biol 70, 297-324.
65. Stromswold, K. (2001) The heritability of language: a review and metaanalysis of twin, adoption, and linkage studies. Language 77, 647-723.
66. Tanegashima, K., Zhao, H. & Dawid, I.B. (2008) WGEF activates Rho in the Wnt-PCP pathway and controls convergent extension in Xenopus gastrulation. EMBO J 27, 606-617.
67. The SLI Consortium (2002) A genomewide scan identifies two novel loci involved in specific language impairment. Am J Hum Genet 70, 384-398.
68. The SLI Consortium (2004) Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment. Am J Hum Genet 74, 1225-1238.
69. The UniProt Consortium (2012) Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res 40, D71-D75.
70. The Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14, 000 cases of seven common diseases and 3, 000 shared controls. Nature 447, 661-678.
71. Thomson, E., Rappsilber, J. & Tollervey, D. (2007) Nop9 is an RNA binding protein present in pre-40S ribosomes and required for 18S rRNA synthesis in yeast. RNA 13, 2165-2174.
72. Tomblin, J.B., Records, N.L., Buckwalter, P., Zhang, X., Smith, E. & O'Brien, M. (1997) Prevalence of specific language impairment in kindergarten children. J Speech Lang Hear Res 40, 1245-1260.
73. Tzenova, J., Kaplan, B.J., Petryshen, T.L. & Field, L.L. (2004) Confirmation of a dyslexia susceptibility locus on chromosome 1p34-p36 in a set of 100 Canadian families. Am J Med Genet B Neuropsychiatr Genet 127, 117-124.
74. Van Aelst, L. & D'Souza-Schorey, C. (1997) Rho GTPases and signaling networks. Genes Dev 11, 2295-2322.
75. Vernes, S.C., Newbury, D.F., Abrahams, B.S., Winchester, L., Nicod, J., Groszer, M., Alarcon, M., Oliver, P.L., Davies, K.E., Geschwind, D.H., Monaco, A.P. & Fisher, S.E. (2008) A functional genetic link between distinct developmental language disorders. N Engl J Med 359, 2337-2345.
76. Viding, E., Spinath, F.M., Price, T.S., Bishop, D.V.M., Dale, P.S. & Plomin, R. (2004) Genetic and environmental influence on language impairment in 4-year-old same-sex and opposite-sex twins. J Child Psychol Psychiatry 45, 315-325.
77. Villanueva, P., Newbury, D.F., Jara, L., De Barbieri, Z., Mirza, G., Palomino, H.M., Fernandez, M.A., Cazier, J.B., Monaco, A.P. & Palomino, H. (2011) Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population. Eur J Hum Genet 19, 687-695.
78. Wang, Y., Suzuki, H., Yokoo, T., Tada-Iida, K., Kihara, R., Miura, M., Watanabe, K., Sone, H., Shimano, H., Toyoshima, H. & Yamada, N. (2004) WGEF is a novel RhoGEF expressed in intestine, liver, heart, and kidney. Biochem Biophys Res Commun 324, 1053-1058.
79. Wang, K.S., Liu, X., Zhang, Q., Aragam, N. & Pan, Y. (2012) Parent-of-origin effects of FAS and PDLIM1 in attention-deficit/hyperactivity disorder. J Psychiatry Neurosci 37, 46-52.
80. Weinberg, C.R., Wilcox, A.J. & Lie, R.T. (1998) A log-linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am J Hum Genet 62, 969-978.
81. Wigginton, J.E. & Abecasis, G.R. (2005) PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics 21, 3445-3447.
82. Wilkinson, L.S., Davies, W. & Isles, A.R. (2007) Genomic imprinting effects on brain development and function. Nat Rev Neurosci 8, 832-843.
83. Yan, J., Zhang, F., Brundage, E., Scheuerle, A., Lanpher, B., Erickson, R.P., Powis, Z., Robinson, H.B., Trapane, P.L., Stachiw-Hietpas, D., Keppler-Noreuil, K.M., Lalani, S.R., Sahoo, T., Chinault, A.C., Patel, A., Cheung, S.W. & Lupski, J.R. (2009) Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange. J Med Genet 46, 626-634.