title: Copy number variants and rasopathies: germline KRAS duplication in a patient with syndrome including pigmentation abnormalities.
abstract: RAS/MAPK pathway germline mutations were described in Rasopathies, a class of rare genetic syndromes combining facial abnormalities, heart defects, short stature, skin and genital abnormalities, and mental retardation. The majority of the mutations identified in the Rasopathies are point mutations which increase RAS/MAPK pathway signaling. Duplications encompassing RAS/MAPK pathway genes (PTPN11, RAF1, MEK2, or SHOC2) were more rarely described. Here we report, a syndromic familial case of a 12p duplication encompassing the dosage sensitive gene KRAS, whose phenotype overlapped with rasopathies. The patient was referred because of a history of mild learning disabilities, small size, facial dysmorphy, and pigmentation abnormalities (café-au-lait and achromic spots, and axillar lentigines). This phenotype was reminiscent of rasopathies. No mutation was identified in the most common genes associated with Noonan, cardio-facio-cutaneous, Legius, and Costello syndromes, as well as neurofibromatosis type 1. The patient constitutional DNA exhibited a ~10.5 Mb duplication at 12p, including the KRAS gene. The index case's mother carried the same chromosome abnormality and also showed development delay with short stature, and numerous café-au-lait spots. Duplication of the KRAS gene may participate in the propositus phenotype, in particular of the specific pigmentation abnormalities. Array-CGH or some other assessment of gene/exon CNVs of RAS/MAPK pathway genes should be considered in the evaluation of individuals with rasopathies.
authors.affiliation: Service de Génétique, C.H.U. de Poitiers, Centre de Référence Anomalies du Développement Ouest, Poitiers, France.|EA 3808 Université de Poitiers, Poitiers, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert-Dussardier
authors.affiliation: Service de Génétique et Biologie Moléculaires, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Bâtiment Jean Dausset, 3ème étage, 27 rue du Faubourg Saint Jacques, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Briand-Suleau
authors.affiliation: EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie, Paris, France.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Laurendeau
authors.affiliation: Service de Génétique, C.H.U. de Poitiers, Centre de Référence Anomalies du Développement Ouest, Poitiers, France.|EA 3808 Université de Poitiers, Poitiers, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bilan
authors.affiliation: Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne-Paris-Cité, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.affiliation: Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, INSERM UMR 1141, Université Paris Diderot, Sorbonne-Paris-Cité, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.affiliation: Service de Génétique et Biologie Moléculaires, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Bâtiment Jean Dausset, 3ème étage, 27 rue du Faubourg Saint Jacques, Paris, France.|EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.affiliation: Service de Génétique et Biologie Moléculaires, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Bâtiment Jean Dausset, 3ème étage, 27 rue du Faubourg Saint Jacques, Paris, France.|EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Vidaud
authors.affiliation: Service de Génétique et Biologie Moléculaires, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Bâtiment Jean Dausset, 3ème étage, 27 rue du Faubourg Saint Jacques, Paris, France. eric.pasmant@gmail.com.|EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie, Paris, France. eric.pasmant@gmail.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Pasmant
mesh_terms: D000293:Adolescent; D019080:Cafe-au-Lait Spots / Q000235:genetics; D002648:Child; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D048370:MAP Kinase Kinase 2 / Q000235:genetics; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009634:Noonan Syndrome / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; C112913:SHOC2 protein, human; C482128:MAP2K2 protein, human; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D048370:MAP Kinase Kinase 2; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D016283:Proto-Oncogene Proteins p21(ras)
keywords: 12p duplication; CNV; Café-au-lait spots; KRAS; Rasopathies