Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Human Molecular Genetics

Volumn 23, Issue 11, 2014, Pages 2888-2900

  Kaiser, Frank J ^a   Ansari, Morad ^b   Braunholz, Diana ^a   Gil Rodríguez, María Concepción ^a,c,d   Decroos, Christophe ^e   Wilde, Jonathan J ^f   Fincher, Christopher T ^f   Kaur, Maninder ^f   Bando, Masashige ^h   Amor, David J ^i,j   Atwal, P S ^l   Bahlo, Melanie ^j,m   Bowman, Christine M ^e   Bradley, Jacquelyn J ^f   Brunner, Han G ⁿ   Clark, Dinah ^f   Campo, Miguel Del ^o,p,q   Di Donato, Nataliya ^r   Diakumis, Peter ^k,m   Dubbs, Holly ^f   Dyment, David A ^s   Eckhold, Juliane ^a   Ernst, Sarah ^f   Ferreira, Jose C ^t   Francey, Lauren J ^f   Gehlken, Ulrike ^a   Guillén Navarro, Encarna ^q,u,v   Gyftodimou, Yolanda ^w   Hall, Bryan D ^x   Hennekam, Raoul ^y   Hudgins, Louanne ^l   Hullings, Melanie ^f   Hunter, Jennifer M ^b   Yntema, Helger ⁿ   Innes, A Micheil ^z   Kline, Antonie D ^aa   Krumina, Zita ^ab   Lee, Hane ^ac   Leppig, Kathleen ^ad   Lynch, Sally Ann ^ae   Mallozzi, Mark B ^f   Mannini, Linda ^af   Mckee, Shane ^ag   Mehta, Sarju G ^ah   Micule, Ieva ^ab   Consortium, Care Rare Canada ^ai   Mohammed, Shehla ^aj   Moran, Ellen ^ak   Mortier, Geert R ^al   Moser, Joe Ann S ^e   Noon, Sarah E ^f   Nozaki, Naohito ^am   Nunes, Luis ^an   Pappas, John G ^ao   Penney, Lynette S ^ap   Pérez Aytés, Antonio ^aq   Petersen, Michael B ^ar   Puisac, Beatriz ^c   Revencu, Nicole ^as   Roeder, Elizabeth ^at   Saitta, Sulagna ^f,au,av   Scheuerle, Angela E ^aw   Schindeler, Karen L ^ax   Siu, Victoria M ^ay   Stark, Zornitza ⁱ   Strom, Samuel P ^ac   Thiese, Heidi ^ad   Vater, Inga ^az   Willems, Patrick ^ba   Williamson, Kathleen ^b   Wilson, Louise C ^bb   Hakonarson, Hakon ^f,g,bc   Quintero Rivera, Fabiola ^ac   Wierzba, Jolanta ^j,bd   Musio, Antonio ^af   Gillessen Kaesbach, Gabriele ^a   Ramos, Feliciano J ^c,d   Jackson, Laird G ^be   Shirahige, Katsuhiko ^h,bf   Pié, Juan ^c,d   Christianson, David W ^e   Krantz, Ian D ^f,bc   Fitzpatrick, David R ^b   Deardorff, Matthew A ^e,bc   more..

^a UNIVERSITY OF LÜBECK   (Germany)

^b UNIVERSITY OF EDINBURGH   (United Kingdom)

^c UNIVERSITY OF ZARAGOZA   (Spain)

^d HOSPITAL CLÍNICO UNIVERSITARIO LOZANO BLESA   (Spain)

^e UNIVERSITY OF PENNSYLVANIA   (United States)

^f Division of Medical Genetics   (United States)

^g CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

^h UNIVERSITY OF TOKYO   (Japan)

ⁱ MURDOCH CHILDREN'S RESEARCH INSTITUTE   (Australia)

^j Victorian Clinical Genetics Services Murdoch Childrens Research Institute ^*  (Poland)

^k UNIVERSITY OF MELBOURNE   (Australia)

^l STANFORD UNIVERSITY   (United States)

^m WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH   (Australia)

ⁿ RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

^o HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

^p UNIVERSITAT POMPEU FABRA   (Spain)

^q INSTITUTO DE SALUD CARLOS III   (Spain)

^r DRESDEN UNIVERSITY OF TECHNOLOGY   (Germany)

^s CHILDREN S HOSPITAL OF EASTERN ONTARIO   (Canada)

^t MEDICAL UNIVERSITY OF WARSAW   (Poland)

^u HOSPITAL UNIVERSITARIO VIRGEN DE LA ARRIXACA   (Spain)

^v CATHOLIC UNIVERSITY OF MURCIA   (Spain)

^w Institute of Child Health   (Greece)

^x UNIVERSITY OF KENTUCKY   (United States)

^y ACADEMIC MEDICAL CENTER   (Netherlands)

^z ALBERTA CHILDREN'S HOSPITAL   (Canada)

^aa GREATER BALTIMORE MEDICAL CENTER   (United States)

^ab CHILDREN'S CLINICAL UNIVERSITY HOSPITAL   (Latvia)

^ac UNIVERSITY OF CALIFORNIA   (United States)

^ad CENTER FOR HEALTH STUDIES   (United States)

^ae OUR LADY S CHILDREN S HOSPITAL   (Ireland)

^af Istituto di Ricerca Genetica eBiomedica   (Italy)

^ag BELFAST CITY HOSPITAL   (United Kingdom)

^ah ADDENBROOKE S HOSPITAL   (United Kingdom)

^ai Care Rare Canada Consortium Department ofGenetics   (Canada)

^aj GUY S HOSPITAL   (United Kingdom)

^ak NYU HOSPITAL FOR JOINT DISEASES   (United States)

^al ANTWERP UNIVERSITY HOSPITAL   (Belgium)

^am MAB Institute Inc   (Japan)

^an NOVA MEDICAL SCHOOL   (Portugal)

^ao NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^ap DALHOUSIE UNIVERSITY   (Canada)

^aq INSTITUTO DE INVESTIGACIÓN SANITARIA DEL HOSPITAL CLÍNICO SAN CARLOS IDISSC   (Spain)

^ar AALBORG UNIVERSITY HOSPITAL   (Denmark)

^as CLINIQUES UNIVERSITAIRES SAINT LUC   (Belgium)

^at BAYLOR COLLEGE OF MEDICINE   (United States)

^au Medical Genetics Research Institute   (United States)

^av CEDARS SINAI MEDICAL CENTER   (United States)

^aw Tesserae Genetics Texas   (United States)

^ax IWK HEALTH CENTRE   (Canada)

^ay UNIVERSITY OF WESTERN ONTARIO   (Canada)

^az UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

^ba Genetic Diagnostics Belgium   (Belgium)

^bb GREAT ORMOND STREET HOSPITAL   (United Kingdom)

^bc UNIVERSITY OF PENNSYLVANIA   (United States)

^bd MEDICAL UNIVERSITY OF GDANSK   (Poland)

^be DREXEL UNIVERSITY COLLEGE OF MEDICINE   (United States)

^bf JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

more..

Author keywords

[No Author keywords available]

Indexed keywords

HISTONE DEACETYLASE 8; HDAC8 PROTEIN, HUMAN; HISTONE DEACETYLASE; REPRESSOR PROTEIN;

ANTERIOR FONTANEL; ARTICLE; CHILD; CLINICAL ARTICLE; CLINICAL FEATURE; CONTROLLED STUDY; COPY NUMBER VARIATION; CRANIOFACIAL MALFORMATION; DE LANGE SYNDROME; DISEASE SEVERITY; ENZYME ACTIVITY; FEMALE; GENE; GENE MUTATION; GENETIC SCREENING; GENOME ANALYSIS; HDAC8 GENE; HETEROZYGOTE; HUMAN; HYPERTELORISM; INFANT; LOSS OF FUNCTION MUTATION; MALE; MISSENSE MUTATION; MUTATIONAL ANALYSIS; NOSE MALFORMATION; NUCLEOTIDE SEQUENCE; PHENOTYPIC VARIATION; PRESCHOOL CHILD; PRIORITY JOURNAL; TOOTH MALFORMATION; WILD TYPE; X CHROMOSOMAL INHERITANCE; X CHROMOSOME INACTIVATION; AMINO ACID SEQUENCE; CHEMISTRY; COHORT ANALYSIS; CONGENITAL MALFORMATION; ENZYMOLOGY; EYE MALFORMATION; FONTANEL; GENETICS; METABOLISM; MOLECULAR GENETICS; PHENOTYPE; SEQUENCE ALIGNMENT;

AMINO ACID SEQUENCE; CHILD; CHILD, PRESCHOOL; COHORT STUDIES; CRANIAL FONTANELLES; DE LANGE SYNDROME; EYE ABNORMALITIES; FEMALE; GENES, X-LINKED; HISTONE DEACETYLASES; HUMANS; HYPERTELORISM; INFANT; MALE; MOLECULAR SEQUENCE DATA; MUTATION, MISSENSE; PHENOTYPE; REPRESSOR PROTEINS; SEQUENCE ALIGNMENT;

EID: 84900037229     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddu002     Document Type: Article

References (54)

1. Bhuiyan, Z., Klein, M., Hammond, P., Mannens, M.M., Van Haeringen, A., Van Berckelaer-Onnes, I. and Hennekam, R.C. (2005) Genotype-phenotype correlations of 39 patients with Cornelia de Lange syndrome: the Dutch experience. J. Med. Genet., 43, 568-575.
2. Gillis, L.A., McCallum, J., Kaur, M., DeScipio, C., Yaeger, D., Mariani, A., Kline, A.D., Li, H.H., Devoto, M., Jackson, L.G. et al. (2004) NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. Am. J. Hum. Genet., 75, 610-623.
3. Krantz, I.D., McCallum, J., DeScipio, C., Kaur, M., Gillis, L.A., Yaeger, D., JGBRofsky, L., Wasserman, N., Bottani, A., Morris, C.A. et al. (2004) Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat. Genet., 36, 631-635.
4. Tonkin, E.T., Wang, T.J., Lisgo, S., Bamshad, M.J. and Strachan, T. (2004) NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat. Genet., 36, 636-641.
5. Yan, J., Saifi, G.M., Wierzba, T.H., Withers, M., Bien-Willner, G.A., Limon, J., Stankiewicz, P., Lupski, J.R. and Wierzba, J. (2006) Mutational and genotype-phenotype correlation analyses in 28 Polish patients with Cornelia de Lange syndrome. Am. J. Med. Genet. A, 140, 1531-1541.
6. Selicorni, A., Russo, S., Gervasini, C., Castronovo, P., Milani, D., Cavalleri, F., Bentivegna, A., Masciadri, M., Domi, A., Divizia, M.T. et al. (2007) Clinical score of 62 Italian patients with Cornelia de Lange syndrome and correlations with the presence and type of NIPBL mutation. Clin. Genet., 72, 98-108.
7. Pie, J., Gil-Rodriguez, M.C., Ciero, M., Lopez-Vinas, E., Ribate, M.P., Arnedo, M., Deardorff, M.A., Puisac, B., Legarreta, J., de Karam, J.C. et al. (2010) Mutations and variants in the cohesion factor genes NIPBL, SMC1A, and SMC3 in a cohort of 30 unrelated patients with Cornelia de Lange syndrome. Am. J. Med. Genet. A, 152A, 924-929.
8. Huisman, S.A., Redeker, E.J., Maas, S.M., Mannens, M.M. and Hennekam, R.C. (2013) High rate of mosaicism in individuals with Cornelia de Lange syndrome. J. Med. Genet., 50, 339-344.
9. Rollins, R.A., Morcillo, P. and Dorsett, D. (1999) Nipped-B, a Drosophila homologue of chromosomal adherins, participates in activation by remote enhancers in the cut and Ultrabithorax genes. Genetics, 152, 577-593.
10. Ciosk, R., Shirayama, M., Shevchenko, A., Tanaka, T., Toth, A. and Nasmyth, K. (2000) Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins. Mol. Cell, 5, 243-254.
11. Gillespie, P.J. and Hirano, T. (2004) Scc2 couples replication licensing to sister chromatid cohesion in Xenopus egg extracts. Curr. Biol., 14, 1598-1603.
12. Takahashi, T.S., Yiu, P., Chou, M.F., Gygi, S. and Walter, J.C. (2004) Recruitment of Xenopus Scc2 and cohesin to chromatin requires the pre-replication complex. Nat. Cell. Biol., 6, 991-996.
13. Nasmyth, K. and Haering, C.H. (2009) Cohesin: its roles and mechanisms. Annu. Rev. Genet., 43, 525-558.
14. Rohatgi, S., Clark, D., Kline, A.D., Jackson, L.G., Pie, J., Siu, V., Ramos, F.J., Krantz, I.D. and Deardorff, M.A. (2010) Facial diagnosis of mild and variant CdLS: insights from a dysmorphologist survey. Am. J. Med. Genet. A, 152A, 1641-1653.
15. Musio, A., Selicorni, A., Focarelli, M.L., Gervasini, C., Milani, D., Russo, S., Vezzoni, P. and Larizza, L. (2006) X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat. Genet., 38, 528-530.
16. Deardorff, M.A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A.D. et al. (2007) Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Am. J. Hum. Genet., 80, 485-494.
17. Deardorff, M.A., Wilde, J.J., Albrecht, M., Dickinson, E., Tennstedt, S., Braunholz, D., Monnich, M., Yan, Y., Xu, W., Gil-Rodriguez, M.C. et al. (2012)RAD21mutations cause ahumancohesinopathy.Am.J.Hum.Genet., 90, 1014-1027.
18. Zhang, J., Shi, X., Li, Y., Kim, B.J., Jia, J., Huang, Z., Yang, T., Fu, X., Jung, S.Y., Wang, Y. et al. (2008) Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and yeast. Mol. Cell, 31, 143-151.
19. Rolef Ben-Shahar, T., Heeger, S., Lehane, C., East, P., Flynn, H., Skehel, M. and Uhlmann, F. (2008) Eco1-dependent cohesin acetylation during establishment of sister chromatid cohesion. Science, 321, 563-566.
20. Unal, E., Heidinger-Pauli, J.M., Kim, W., Guacci, V., Onn, I., Gygi, S.P. and Koshland, D.E. (2008) A molecular determinant for the establishment of sister chromatid cohesion. Science, 321, 566-569.
21. Sutani, T., Kawaguchi, T., Kanno, R., Itoh, T. and Shirahige, K. (2009) Budding yeast Wpl1(Rad61)-Pds5 complex counteracts sister chromatid cohesion-establishing reaction. Curr. Biol., 19, 492-497.
22. Beckouet, F., Hu, B., Roig, M.B., Sutani, T., Komata, M., Uluocak, P., Katis, V.L., Shirahige, K. and Nasmyth, K. (2010) An Smc3 acetylation cycle is essential for establishment of sister chromatid cohesion. Mol. Cell, 39, 689-699.
23. Xiong, B., Lu, S. and Gerton, J.L. (2010) Hos1 is a lysine deacetylase for the Smc3 subunit of cohesin. Curr. Biol., 20, 1660-1665.
24. Borges, V., Lehane, C., Lopez-Serra, L., Flynn, H., Skehel, M., Rolef Ben-Shahar, T. and Uhlmann, F. (2010) Hos1 deacetylates Smc3 to close the cohesin acetylation cycle. Mol. Cell, 39, 677-688.
25. Deardorff, M.A., Bando, M., Nakato, R., Watrin, E., Itoh, T., Minamino, M., Saitoh, K., Komata, M., Katou, Y., Clark, D. et al. (2012)HDAC8mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature, 489, 313-317.
26. Harakalova, M., van den Boogaard, M.J., Sinke, R., van Lieshout, S., van Tuil, M.C., Duran, K., Renkens, I., Terhal, P.A., de Kovel, C., Nijman, I.J. et al. (2012) X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face. J. Med. Genet., 49, 539-543.
27. Vannini, A., Volpari, C., Gallinari, P., Jones, P., Mattu, M., Carfi, A., De Francesco, R., Steinkuhler, C. and Di Marco, S. (2007) Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex. EMBO Rep., 8, 879-884.
28. Wang,D.F., Helquist, P., Wiech, N.L. and Wiest, O. (2005)Towardselective histone deacetylase inhibitor design: homology modeling, docking studies, and molecular dynamics simulations of human class I histone deacetylases. J. Med. Chem., 48, 6936-6947.
29. Haider, S., Joseph, C.G., Neidle, S., Fierke, C.A. and Fuchter, M.J. (2011)On the function of the internal cavity of histone deacetylase protein 8: R37 is a crucial residue for catalysis. Bioorg. Med. Chem. Lett., 21, 2129-2132.
30. Dowling, D.P., Gantt, S.L., Gattis, S.G., Fierke, C.A. and Christianson,D.W. (2008) Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors. Biochemistry, 47, 13554-13563.
31. Wegener, D., Hildmann, C., Riester, D. and Schwienhorst, A. (2003) Improved fluorogenic histone deacetylase assay for high-throughput-screening applications. Anal. Biochem., 321, 202-208.
32. Lombardi, P.M., Cole, K.E., Dowling, D.P. and Christianson, D.W. (2011) Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes. Curr. Opin. Struct. Biol., 21, 735-743.
33. Somoza, J.R., Skene, R.J., Katz, B.A., Mol, C., Ho, J.D., Jennings, A.J., Luong, C., Arvai, A., Buggy, J.J., Chi, E. et al. (2004) Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure, 12, 1325-1334.
34. Cole, K.E., Dowling, D.P., Boone, M.A., Phillips, A.J. and Christianson, D.W. (2011) Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases. J. Am. Chem. Soc., 133, 12474-12477.
35. Allen, R.C., Zoghbi, H.Y., Moseley, A.B., Rosenblatt, H.M. and Belmont, J.W. (1992) Methylation of HpaII and HhaI sites near the polymorphicCAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am. J. Hum. Genet., 51, 1229-1239.
36. Kuczmarski, R.J., Ogden, C.L., Guo, S.S., Grummer-Strawn, L.M., Flegal, K.M., Mei, Z., Wei, R., Curtin, L.R., Roche, A.F. and Johnson, C.L. (2002) 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat. 11, 1-190.
37. Kline, A.D., Barr, M. and Jackson, L.G. (1993) Growth manifestations in the Brachmann-de Lange syndrome. Am. J. Med. Genet., 47, 1042-1049.
38. Haberland, M., Mokalled, M.H., Montgomery, R.L. and Olson, E.N. (2009) Epigenetic control of skull morphogenesis by histone deacetylase 8. Genes Dev., 23, 1625-1630.
39. Kawauchi, S., Calof, A.L., Santos, R., Lopez-Burks, M.E., Young, C.M., Hoang, M.P., Chua, A., Lao, T., Lechner, M.S., Daniel, J.A. et al. (2009) Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/2) mouse, a model of Cornelia de Lange syndrome. PLoS Genet., 5, e1000650.
40. Xu, H., Balakrishnan, K., Malaterre, J., Beasley, M., Yan, Y., Essers, J., Appeldoorn, E., Tomaszewski, J.M., Vazquez, M., Verschoor, S. et al. (2010) Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice. PLoS ONE, 5, e12112.
41. Remeseiro, S., Cuadrado, A., Carretero, M., Martinez, P., Drosopoulos, W.C., Canamero, M., Schildkraut, C.L., Blasco, M.A. and Losada, A. (2012) Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres. EMBO J., 31, 2076-2089.
42. Kline, A.D., Krantz, I.D., Sommer, A., Kliewer, M., Jackson, L.G., FitzPatrick, D.R., Levin, A.V. and Selicorni, A. (2007) Cornelia de Lange syndrome: clinical review, diagnostic and scoring systems, and anticipatory guidance. Am. J. Med. Genet. A, 143, 1287-1296.
43. Deardorff, M.A., Clark, D.M. and Krantz, I.D. (2011), In GeneReviews at GeneTests: Medical Genetics Information Resource (Database Online). University of Washington, Seattle, in press.
44. Strom, T. (2006), ExonPrimer (database online).
45. Shaikh, T.H., Gai, X., Perin, J.C., Glessner, J.T., Xie, H., Murphy, K., O'Hara, R., Casalunovo, T., Conlin, L.K., D'Arcy, M. et al. (2009) High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications. Genome Res., 19, 1682-1690.
46. Wang, K., Li, M., Hadley, D., Liu, R., Glessner, J., Grant, S.F., Hakonarson, H. and Bucan, M. (2007) PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res., 17, 1665-1674.
47. Peiffer, D.A., Le, J.M., Steemers, F.J., Chang, W., Jenniges, T., Garcia, F., Haden, K., Li, J., Shaw, C.A., Belmont, J. et al. (2006) High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping. Genome Res., 16, 1136-1148.
48. Krumm, N., Sudmant, P.H., Ko, A., O'Roak, B.J., Malig, M., Coe, B.P., Project, N.E.S., Quinlan, A.R., Nickerson, D.A. and Eichler, E.E. (2012) Copy number variation detection and genotyping from exome sequence data. Genome Res., 22, 1525-1532.
49. Eddy, S.R. (1995) Multiple alignment using hidden Markov models. Proc. Int. Conf. Intell. Syst. Mol. Biol., 3, 114-120.
50. Wang, Y., Geer, L.Y., Chappey, C., Kans, J.A. and Bryant, S.H. (2000) Cn3D: sequence and structure views for Entrez. Trends Biochem. Sci., 25, 300-302.
51. Jessberger, R. (2002) The many functions of SMC proteins in chromosome dynamics. Nat. Rev. Mol. Cell. Biol., 3, 767-778.
52. Gill, S.C. and von Hippel, P.H. (1989) Calculation of protein extinction coefficients from amino acid sequence data. Anal. Biochem., 182, 319-326.
53. Wang, X., Sutton, V.R., Omar Peraza-Llanes, J., Yu, Z., Rosetta, R., Kou, Y.C., Eble, T.N., Patel, A., Thaller, C., Fang, P. et al. (2007) Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat. Genet., 39, 836-838.
54. Amos-Landgraf, J.M., Cottle, A., Plenge, R.M., Friez, M., Schwartz, C.E., Longshore, J. and Willard, H.F. (2006) X chromosome-inactivation patterns of 1,005 phenotypically unaffected females.Am. J. Hum.Genet., 79, 493-499.