. , Suivi des patients actuels et inclusion de nouveaux patients

. , Un gène nécessaire au développement-la survie par le mosaïcisme

.. .. Conseil-génétique,

, Une nouvelle voie de signalisation impliquée dans les syndromes en mosaïque, p.57

. .. Perspectives-thérapeutiques,

.. .. Limites-de-la-stratégie,

.. .. Conclusion-générale, , p.61

. .. Bibliographie,

. .. Annexes,

.. .. Permis-d'imprimer,

V. P. Sybert, J. Invest. Dermatol, vol.103, pp.141-143, 1994.

M. Ruggieri and L. J. Pavone, Child Neurol, vol.15, pp.635-644, 2000.

P. Pavone, A. D. Praticò, M. Ruggieri, and R. Falsaperla, Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol, vol.36, pp.1173-1180, 2015.

S. Besenbacher, Nat. Commun, vol.6, p.5969, 2015.

J. C. Canman, Science, vol.322, pp.1543-1546, 2008.

S. Narumiya, J. Biochem. (Tokyo), vol.120, pp.215-228, 1996.

K. Y. Wu, Nature, vol.436, pp.1020-1024, 2005.

A. Hall, Science, vol.279, pp.509-514, 1998.

I. R. Vetter and A. Wittinghofer, Science, vol.294, pp.1299-1304, 2001.

Z. K. Pan, J. Immunol. Baltim. Md, vol.160, pp.3038-3045, 1950.

X. Zhao, Cancer Res, vol.69, pp.483-491, 2009.

M. Maekawa, Science, vol.285, pp.895-898, 1999.

G. M. Mirzaa, JAMA Neurol, vol.73, pp.836-845, 2016.

J. H. Lee, Nat. Genet, vol.44, pp.941-945, 2012.

M. A. Van-steensel, . Pediatr, and . Genet, , vol.4, pp.144-153, 2015.

M. Lek, Nature, vol.536, pp.285-291, 2016.

V. A. Blomen, Science, vol.350, pp.1092-1096, 2015.

T. Wang, Science, vol.350, pp.1096-1101, 2015.

R. Happle, J. Am. Acad. Dermatol, vol.16, pp.899-906, 1987.

L. C. Fernández, M. Torres, and F. X. Real, Nat. Rev. Cancer, vol.16, pp.43-55, 2016.

R. Happle, Arch. Dermatol, vol.129, pp.1460-1470, 1993.

J. Thevenon, Am. J. Hum. Genet, vol.95, pp.113-120, 2014.

J. Rivière, Nat. Genet, vol.44, pp.934-940, 2012.

G. M. Cooper, Nat. Methods, vol.7, pp.250-251, 2010.

M. Kircher, Nat. Genet, vol.46, pp.310-315, 2014.

. Supplementary-references-1 and A. Vanderver, Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations, Am. J. Med. Genet. A, vol.164, pp.627-633, 2014.

Z. Li, Regulation of PTEN by Rho small GTPases, Nat. Cell Biol, vol.7, pp.399-404, 2005.

J. T. Robinson, Integrative genomics viewer, Nat. Biotechnol, vol.29, pp.24-26, 2011.

A. Mckenna, The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data, Genome Res, vol.20, pp.1297-1303, 2010.

S. A. Forbes, COSMIC: exploring the world's knowledge of somatic mutations in human cancer, Nucleic Acids Res, vol.43, pp.805-811, 2015.

M. Lek, Analysis of protein-coding genetic variation in 60,706 humans, Nature, vol.536, pp.285-291, 2016.

G. M. Cooper, Single-nucleotide evolutionary constraint scores highlight disease-causing mutations, Nat. Methods, vol.7, pp.250-251, 2010.

M. Kircher, A general framework for estimating the relative pathogenicity of human genetic variants

. Genet, , vol.46, pp.310-315, 2014.

Y. Nagata, Variegated RHOA mutations in adult T-cell leukemia/lymphoma, Blood, vol.127, pp.596-604, 2016.

M. Sakata-yanagimoto, Somatic RHOA mutation in angioimmunoblastic T cell lymphoma, Nat. Genet, vol.46, pp.171-175, 2014.

M. Kakiuchi, Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma

. Genet, , vol.46, pp.583-587, 2014.

K. Wang, Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer, Nat. Genet, vol.46, pp.573-582, 2014.

M. O'hayre, Inactivating mutations in GNA13 and RHOA in Burkitt's lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the G?13/RhoA axis in B cells, Oncogene, vol.35, pp.3771-3780, 2016.

M. Rohde, Recurrent RHOA mutations in pediatric Burkitt lymphoma treated according to the NHL-BFM protocols, Genes. Chromosomes Cancer, vol.53, pp.911-916, 2014.

I. Partie, Conclusion et perspectives Bibliographie 1. Lynch M. Rate, molecular spectrum, and consequences of human mutation, Proc Natl Acad Sci U S A. 19 janv, vol.107, issue.3, pp.961-969, 2010.

H. Youssoufian and R. E. Pyeritz, Mechanisms and consequences of somatic mosaicism in humans, Nat Rev Genet, vol.3, issue.10, pp.748-58, 2002.

R. Happle, Mosaicism in human skin. Understanding the patterns and mechanisms

, Arch Dermatol. nov, vol.129, issue.11, pp.1460-70, 1993.

M. J. Lindhurst, J. C. Sapp, J. K. Teer, J. J. Johnston, E. M. Finn et al.,

J. Rivière, G. M. Mirzaa, O. 'roak, B. J. Beddaoui, M. Alcantara et al.,

, De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes, Nat Genet. août, vol.44, issue.8, pp.934-974, 2012.

K. C. Kurek, V. L. Luks, U. M. Ayturk, A. I. Alomari, S. J. Fishman et al.,

, Somatic Mosaic Activating Mutations in PIK3CA Cause CLOVES Syndrome, Am J Hum Genet. juin, vol.90, issue.6, pp.1108-1123, 2012.

L. Groesser, E. Herschberger, A. Ruetten, C. Ruivenkamp, E. Lopriore et al.,

, Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome, Nat Genet. juillet, vol.44, issue.7, pp.783-790, 2012.

A. C. Thomas, Z. Zeng, J. Rivière, O. Shaughnessy, R. et al.,

, Mosaic Activating Mutations in GNA11 and GNAQ Are Associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis, J Invest Dermatol. avril, vol.136, issue.4, pp.770-778, 2016.

G. M. Mirzaa, C. D. Campbell, N. Solovieff, C. Goold, L. A. Jansen et al.,

, Association of MTOR Mutations With Developmental Brain Disorders, Including

. Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism, JAMA Neurol. 1 juill, vol.73, issue.7, pp.836-881, 2016.

V. P. Sybert, Hypomelanosis of Ito: A Description, Not a Diagnosis, J Invest Dermatol

A. Poduri, G. D. Evrony, X. Cai, and C. A. Walsh, Somatic Mutation, Genomic Variation, and

, Neurological Disease. Science. 5 juill, vol.341, issue.6141, p.1237758, 2013.

D. Abuelo, Clinical significance of chimerism, Am J Med Genet C Semin Med Genet. mai, vol.151, issue.2, pp.148-51, 2009.

M. Lynch, Evolution of the mutation rate, Trends Genet TIG. août, vol.26, issue.8, p.345, 2010.

L. A. Forsberg, D. Gisselsson, and J. P. Dumanski, Mosaicism in health and disease-clones picking up speed, Nat Rev Genet. février, vol.18, issue.2, pp.128-170, 2017.

E. Vanneste, T. Voet, L. Caignec, C. Ampe, M. Konings et al.,

T. H. Taylor, S. A. Gitlin, J. L. Patrick, J. L. Crain, J. M. Wilson et al., The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans

, Hum Reprod Update. août, vol.20, issue.4, pp.571-81, 2014.

W. J. Dreyer and J. M. Roman, Immunology and embryogenesis: the chromosomal editing hypothesis, Adv Exp Med Biol, vol.181, pp.87-97, 1984.

M. A. Lodato, M. B. Woodworth, S. Lee, G. D. Evrony, B. K. Mehta et al.,

, Somatic mutation in single human neurons tracks developmental and transcriptional history, Science, vol.350, issue.6256, p.94, 2015.

M. J. Mcconnell, M. R. Lindberg, K. J. Brennand, J. C. Piper, and T. Voet,

J. K. Baillie, M. W. Barnett, K. R. Upton, D. J. Gerhardt, T. A. Richmond et al.,

A. Blaschko, Die Nervenverteilung in der Haut in ihrer Beziehung zu den

, Erkrankungen der Haut. In Breslau: Wien ; Leipzig : W. Braumèuller, 1901.

R. Happle, Mosaicism in Human Skin-Understanding Nevi, Nevoid Skin Disorders, and Cutaneous Neoplasia, 2014.

. Disponible,

A. Maruani, R. Khallouf, M. Machet, and L. G. , Diffuse linear and whorled nevoid hypermelanosis in a newborn, J Pediatr. janv, vol.160, issue.1, p.171, 2012.

A. Sorlin, A. Maruani, M. Aubriot-lorton, P. Kuentz, Y. Duffourd et al.,

, Mosaicism for a KITLG mutation in linear and whorled nevoid hypermelanosis, J Invest Dermatol. 28 févr, 2017.

R. Jackson, The lines of Blaschko: a review and reconsideration, Br J Dermatol, vol.95, issue.4, pp.349-60, 1976.

R. Happle, Genetic significance of Blaschko's lines, Z Hautkr. 15 sept, vol.52, issue.18, pp.935-979, 1977.

R. Happle, The categories of cutaneous mosaicism: A proposed classification, Am J

, Med Genet A. févr, vol.170, issue.2, pp.452-461, 2016.

L. G. Biesecker and N. B. Spinner, A genomic view of mosaicism and human disease, Nat Rev Genet. mai, vol.14, issue.5, pp.307-327, 2013.

J. N. Myers, L. Davis, D. Sheehan, and A. S. Kulharya, Mosaic tetrasomy 13q and phylloid hypomelanosis: a case report and review of the literature, Pediatr Dermatol. avr, vol.32, issue.2, pp.263-269, 2015.

M. Ruggieri, M. Roggini, I. Kennerknecht, A. Polizzi, A. Distefano et al.,

, Acta Paediatr Oslo Nor, vol.100, issue.1, pp.121-128, 1992.

R. Happle, Cutaneous manifestation of lethal genes, Hum Genet. mars, vol.72, issue.3, p.280, 1986.

L. S. Weinstein, A. Shenker, P. V. Gejman, M. J. Merino, E. Friedman et al.,

, Activating Mutations of the Stimulatory G Protein in the McCune-Albright Syndrome

, Engl J Med. décembre, vol.325, issue.24, pp.1688-95, 1991.

M. Gajecka, Unrevealed mosaicism in the next-generation sequencing era, Mol Genet Genomics, vol.291, pp.513-543, 2016.

P. Kuentz, J. St-onge, Y. Duffourd, J. Courcet, V. Carmignac et al.,

, Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing, Genet Med, 2017.

. Disponible, M. D. Shirley, H. Tang, C. J. Gallione, J. D. Baugher et al.,

, Weber Syndrome and Port-Wine Stains Caused by Somatic Mutation in GNAQ, N Engl J Med. mai, vol.368, issue.21, pp.1971-1980, 2013.

M. Van-steensel, Neurocutaneous Manifestations of Genetic Mosaicism, J Pediatr Genet. sept, vol.4, issue.3, pp.144-53, 2015.

N. Nathan, K. M. Keppler-noreuil, L. G. Biesecker, J. Moss, and T. N. Darling, Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway, Dermatol Clin. janv, vol.35, issue.1, pp.51-60, 2017.

C. Hafner and L. Groesser, Mosaic RASopathies, Cell Cycle. 1 janv, vol.12, issue.1, pp.43-50, 2013.

M. Ruggieri and A. D. Praticò, Mosaic Neurocutaneous Disorders and Their Causes

, Pediatr Neurol. déc, vol.22, issue.4, pp.207-240, 2015.

M. Ito, Studies on melanin XI. Incontinentia pigmenti achrominans. A singular case of nevus depigmentosus systematicus bilateralis, Tohoku J Exp Med, vol.55, pp.57-66, 1952.

R. Ruiz-maldonado, S. Toussaint, L. Tamayo, A. Laterza, and V. Del-castillo,

. Hypomelanosis and . Ito, Diagnostic Criteria and Report of 41 Cases, Pediatr Dermatol. 1 mars, vol.9, issue.1, pp.1-10, 1992.

D. Donnai, A. P. Read, C. Mckeown, and T. Andrews, Hypomelanosis of Ito: a manifestation of mosaicism or chimerism, J Med Genet. 1 déc, vol.25, issue.12, pp.809-827, 1988.

S. M. Taibjee, D. C. Bennett, and C. Moss, Abnormal pigmentation in hypomelanosis of Ito and pigmentary mosaicism: the role of pigmentary genes, Br J Dermatol. août, vol.151, issue.2, pp.269-82, 2004.

H. Li and R. Durbin, Fast and accurate short read alignment with Burrows-Wheeler transform, Bioinformatics. 15 juill, vol.25, issue.14, pp.1754-60, 2009.

A. Mckenna, M. Hanna, E. Banks, A. Sivachenko, K. Cibulskis et al.,

, Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data, Genome Res. 9 janv, vol.20, issue.9, pp.1297-303, 2010.

K. J. Karczewski, B. Weisburd, B. Thomas, M. Solomonson, D. M. Ruderfer et al., The ExAC browser: displaying reference data information from over 60 000 exomes, Nucleic Acids Res, vol.45, issue.D1, pp.840-845, 2017.

M. Lek, K. J. Karczewski, E. V. Minikel, K. E. Samocha, E. Banks et al., Analysis of protein-coding genetic variation in 60,706 humans, Nature. août, vol.536, issue.7616, pp.285-91, 2016.

M. Kircher, D. M. Witten, P. Jain, O. 'roak, B. J. Cooper et al.,

R. Grantham, Amino Acid Difference Formula to Help Explain Protein Evolution

, Science. 6 sept, vol.185, issue.4154, pp.862-866, 1974.

G. M. Cooper, E. A. Stone, G. Asimenos, E. D. Green, S. Batzoglou et al.,

I. Adzhubei, D. M. Jordan, and S. R. Sunyaev, Predicting functional effect of human missense mutations using PolyPhen-2, Curr Protoc Hum Genet. janv, p.20, 2013.

P. Kumar, S. Henikoff, and P. C. Ng, Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm, Nat Protoc. juin, vol.4, issue.7, pp.1073-81, 2009.

M. Ruggieri and L. Pavone, Topical Review: Hypomelanosis of Ito: Clinical Syndrome or Just Phenotype?, J Child Neurol, vol.15, issue.10, pp.635-679, 2000.

T. G. Schulze and F. J. Mcmahon, Defining the Phenotype in Human Genetic Studies: Forward Genetics and Reverse Phenotyping, Hum Hered, vol.58, issue.3-4, pp.131-139, 2004.

M. Inoue, M. Fukuda, E. Ishii, and K. Sayama, Linear Leukoplakia and Central Nervous System Lesions: A Clinical Clue to the Diagnosis of Hypomelanosis of Ito, J Pediatr. sept, vol.167, issue.3, pp.771-771, 2015.

. Souza-pvs-de, R. Pinto-wbv-de, F. G. Calente, S. Burlin, J. L. Pedroso et al.,

, Hypomelanosis of Ito presenting with adult-onset dementia and marked enlarged VirchowRobin spaces, Arq Neuropsiquiatr. avr, vol.73, issue.4, pp.366-374, 2015.

J. L. Orgaz, C. Herraiz, and V. Sanz-moreno, Rho GTPases modulate malignant

A. Hall, Rho GTPases and the Actin Cytoskeleton, Science. 23 janv, vol.279, issue.5350, pp.509-523, 1998.

K. Burridge and C. Guilluy, Focal adhesions, stress fibers and mechanical tension, Exp Cell Res. 10 avr, vol.343, issue.1, pp.14-20, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01831589

Z. K. Pan, R. D. Ye, S. C. Christiansen, M. A. Jagels, G. M. Bokoch et al.,

, Rho GTPase in Bradykinin-Stimulated Nuclear Factor-?B Activation and IL-1? Gene Expression in Cultured Human Epithelial Cells, J Immunol. 15 mars, vol.160, issue.6, pp.3038-3083, 1998.

X. Zhao, L. Lu, N. Pokhriyal, H. Ma, L. Duan et al., Overexpression of RhoA Induces Preneoplastic Transformation of Primary Mammary Epithelial Cells, Cancer Res. 15 janv, vol.69, issue.2, pp.483-91, 2009.

S. Petrovski, Q. Wang, E. L. Heinzen, A. S. Allen, and D. B. Goldstein, Genic Intolerance to Functional Variation and the Interpretation of Personal Genomes, PLOS Genet. août, vol.9, issue.8, p.1003709, 2013.

V. A. Blomen, P. Májek, L. T. Jae, J. W. Bigenzahn, J. Nieuwenhuis et al.,

T. Wang, K. Birsoy, N. W. Hughes, K. M. Krupczak, Y. Post et al.,

T. Hart, M. Chandrashekhar, M. Aregger, Z. Steinhart, K. R. Brown et al.,

, High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities, Cell. décembre, vol.163, issue.6, pp.1515-1541, 2015.

S. Zhang, X. Zhou, R. A. Lang, and F. Guo, RhoA of the Rho Family Small GTPases Is Essential for B Lymphocyte Development, PLOS ONE. 16 mars, vol.7, issue.3, p.33773, 2012.

R. Acuna-hidalgo, T. Bo, M. P. Kwint, M. Van-de-vorst, M. Pinelli et al.,

. Post-zygotic, Point Mutations Are an Underrecognized Source of De Novo Genomic Variation, Am J Hum Genet. 2 juill, vol.97, issue.1, pp.67-74, 2015.

M. Fromer and S. M. Purcell, Using XHMM software to detect copy number variation in whole-exome sequencing data, Curr Protoc Hum Genet Editor Board Jonathan Haines Al. 24 avr, vol.81, 2014.

H. Holstege, W. Pfeiffer, D. Sie, M. Hulsman, T. J. Nicholas et al.,

, Genome Res. mai, vol.24, issue.5, pp.733-775, 2014.

M. J. Landrum, J. M. Lee, M. Benson, G. Brown, C. Chao et al., ClinVar: public archive of interpretations of clinically relevant variants, Nucleic Acids Res. 4 janv, vol.44, issue.D1, pp.862-870, 2016.

S. A. Forbes, D. Beare, P. Gunasekaran, K. Leung, N. Bindal et al.,

, COSMIC: exploring the world's knowledge of somatic mutations in human cancer, Nucleic Acids Res. 28 janv, vol.43, issue.D1, pp.805-816, 2015.