title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
abstract: 6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.
authors.affiliation: 1] AP-HP, Groupe hospitalier Cochin-Broca-Hôtel Dieu, Laboratoire de Cytogénétique, Paris, France [2] INSERM, U1016 Institut Cochin, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Laïla
authors.initials: L
authors.lastname: El Khattabi
authors.affiliation: 1] AP-HP, Département de Génétique et Service de Biologie du développement, Hôpital Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, DHU PROTECT, Paris, France [2] INSERM, U1141, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guimiot
authors.affiliation: 1] INSERM, U1141, Paris, France [2] AP-HP, Hôpital Jean Verdier, Laboratoire d'Histologie-Embryologie-Cytogénétique-BDR-CECOS, Bondy, France [3] Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.
authors.forename: Eva
authors.initials: E
authors.lastname: Pipiras
authors.affiliation: Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France.
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.affiliation: AP-HP, Département de Génétique et Service de Biologie du développement, Hôpital Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, DHU PROTECT, Paris, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.affiliation: Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bouquillon
authors.affiliation: 1] AP-HP, Département de Génétique et Service de Biologie du développement, Hôpital Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, DHU PROTECT, Paris, France [2] INSERM, U1141, Paris, France.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Delezoide
authors.affiliation: Centre de Génétique Chromosomique, Saint-Vincent de Paul, GHIC, Lille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Delobel
authors.affiliation: Service de Génétique Clinique CLAD-Ouest-CHU Rennes, université Rennes1, Rennes, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Demurger
authors.affiliation: Département de Cytogénétique, Laboratoire Biomnis, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Dessuant
authors.affiliation: AP-HP, Département de Génétique et Service de Biologie du développement, Hôpital Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, DHU PROTECT, Paris, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Drunat
authors.affiliation: Laboratoire de Génétique Moléculaire, CHU Pontchaillou, UMR 6290 CNRS, IGDR, Faculté de Médecine, Université de Rennes 1, Rennes, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Dubourg
authors.affiliation: AP-HP, Département de Génétique et Service de Biologie du développement, Hôpital Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, DHU PROTECT, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Dupont
authors.affiliation: Centre de référence Anomalies du développement et Syndromes Malformatifs de l'Interrégion Est, Hôpital d'Enfants, CHU de Dijon et Université de Bourgogne, Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: 1] Clinical Genetics Department, Guy's Hospital, Great Maze Pond, London, UK [2] Service de Génétique Clinique, Hôpital Jeanne de Flandres, CHRU de Lille, Lille, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder-Espinasse
authors.affiliation: Laboratoire de Cytogénétique et Biologie Cellulaire, CHU Pontchaillou, Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Jaillard
authors.affiliation: Service de Génétique Médicale, Centre Hospitalier Bretagne Atlantique, Vannes, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Journel
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Hôpital Necker-Enfants Malades, INSERM U-1163, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Hôpital Necker-Enfants Malades, INSERM U-1163, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Malan
authors.affiliation: Centre de référence Anomalies du développement et Syndromes Malformatifs de l'Interrégion Est, Hôpital d'Enfants, CHU de Dijon et Université de Bourgogne, Dijon, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Masurel
authors.affiliation: Centre de référence Anomalies du développement et Syndromes Malformatifs de l'Interrégion Est, Hôpital d'Enfants, CHU de Dijon et Université de Bourgogne, Dijon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Marle
authors.affiliation: Laboratoire de Génétique Chromosomique, CHU Timone enfants, AP-HM, Marseille, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Missirian
authors.affiliation: Service de Génétique Clinique, Hôpital Jeanne de Flandres, CHRU de Lille, Lille, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Moerman
authors.affiliation: Laboratoire de Génétique Chromosomique, CHU Timone enfants, AP-HM, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Moncla
authors.affiliation: Service de Génétique Clinique CLAD-Ouest-CHU Rennes, université Rennes1, Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Orazio
authors.identifier: 0000000165833482
authors.initials: O
authors.lastname: Palumbo
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Palumbo
authors.affiliation: Institut Jérôme Lejeune, Paris, France.
authors.forename: Aimé
authors.initials: A
authors.lastname: Ravel
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Hôpital Necker-Enfants Malades, INSERM U-1163, Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Romana
authors.affiliation: AP-HP, Département de Génétique et Service de Biologie du développement, Hôpital Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, DHU PROTECT, Paris, France.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Tabet
authors.affiliation: Laboratoire de Génétique, EA 4002, CHU, Nancy-University, Nancy, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Valduga
authors.affiliation: Service de Pédiatrie, Centre Hospitalier de Dunkerque, Dunkerque, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vermelle
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.affiliation: 1] AP-HP, Groupe hospitalier Cochin-Broca-Hôtel Dieu, Laboratoire de Cytogénétique, Paris, France [2] INSERM, U1016 Institut Cochin, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dupont
authors.affiliation: 1] AP-HP, Département de Génétique et Service de Biologie du développement, Hôpital Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, DHU PROTECT, Paris, France [2] INSERM, U1141, Paris, France.
authors.forename: Alain
authors.identifier: 0000000348190264
authors.initials: A
authors.lastname: Verloes
authors.affiliation: 1] AP-HP, Département de Génétique et Service de Biologie du développement, Hôpital Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, DHU PROTECT, Paris, France [2] INSERM, U1141, Paris, France [3] AP-HP, Hôpital Jean Verdier, Laboratoire d'Histologie-Embryologie-Cytogénétique-BDR-CECOS, Bondy, France [4] Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Benzacken
authors.affiliation: 1] INSERM, U1141, Paris, France [2] AP-HP, Hôpital Jean Verdier, Laboratoire d'Histologie-Embryologie-Cytogénétique-BDR-CECOS, Bondy, France [3] Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.
authors.forename: Andrée
authors.initials: A
authors.lastname: Delahaye
mesh_terms: D037881:Aborted Fetus; D000293:Adolescent; D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000473:pathology; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D011218:Prader-Willi Syndrome / Q000150:complications / Q000235:genetics* / Q000473:pathology; D011247:Pregnancy; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C491094:SIM1 protein, human