title: 15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: a series of 52 patients.
abstract: Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, 'de novo' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.
authors.affiliation: Institut de génétique médicale, Hôpital Jeanne de Flandre, CHRU Lille, France. Electronic address: clemence.vanlerberghe@chru-lille.fr.
authors.forename: Clémence
authors.initials: C
authors.lastname: Vanlerberghe
authors.affiliation: Service de génétique clinique, Hôpital Jeanne de Flandre, CHRU Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Petit
authors.affiliation: Service de cytogénétique et d'embryologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Malan
authors.affiliation: Service de génétique clinique, Hôpital Jeanne de Flandre, CHRU Lille, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vincent-Delorme
authors.affiliation: Institut de génétique médicale, Hôpital Jeanne de Flandre, CHRU Lille, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bouquillon
authors.affiliation: Service de génétique clinique, Hôpital Jeanne de Flandre, CHRU Lille, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Boute
authors.affiliation: Service de génétique clinique, Hôpital Jeanne de Flandre, CHRU Lille, France; Department of Clinical Genetics, Guy's Hospital, London, UK.
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder-Espinasse
authors.affiliation: Centre de cytogénétique, Hôpital Saint Vincent de Paul, Lille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Delobel
authors.affiliation: Centre de cytogénétique, Hôpital Saint Vincent de Paul, Lille, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Duban
authors.affiliation: Service de neuropédiatrie, Hôpital Jeanne de Flandre, CHRU Lille, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Vallee
authors.affiliation: Service de neuropédiatrie, Hôpital Jeanne de Flandre, CHRU Lille, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Cuisset
authors.affiliation: Service de neuropédiatrie, Hôpital Jeanne de Flandre, CHRU Lille, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Lemaitre
authors.affiliation: Service d'endocrinologie, Hôpital Claude Huriez, CHRU Lille, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vantyghem
authors.affiliation: Service d'endocrinologie, Hôpital Claude Huriez, CHRU Lille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Pigeyre
authors.affiliation: Service de neuropédiatrie, Hôpital de Sambre - Avesnois, Maubeuge, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lanco-Dosen
authors.affiliation: Service de génétique clinique, CHU Caen, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Plessis
authors.affiliation: Service de génétique clinique, CHU Caen, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gerard
authors.affiliation: Service de génétique clinique, CHU Caen, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Decamp
authors.affiliation: Service de génétique clinique, CHU Amiens, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Mathieu
authors.affiliation: Service de génétique clinique, CHU Amiens, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Morin
authors.affiliation: Service de génétique clinique, CHU Amiens, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jedraszak
authors.affiliation: Laboratoire de Génétique cellulaire et moléculaire, Pôle Biologie Santé, CHU Poitiers, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bilan
authors.affiliation: Service de génétique clinique, La Milétrie, CHU Poitiers, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert-Dussardier
authors.affiliation: Service de cytogénétique, CHI Poissy, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Fauvert
authors.affiliation: Unité de génétique médicale, CHI Poissy, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Roume
authors.affiliation: Unité de génétique médicale, Hôpital Necker-Enfants malades, AP-HP, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: Unité de génétique médicale, Hôpital Necker-Enfants malades, AP-HP, Paris, France.
authors.forename: Roseline
authors.initials: R
authors.lastname: Caumes
authors.affiliation: Service de génétique médicale, CHRU Montpellier, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Puechberty
authors.affiliation: Service de génétique médicale, CHRU Montpellier, France.
authors.forename: David
authors.initials: D
authors.lastname: Genevieve
authors.affiliation: Service de génétique médicale, CHRU Montpellier, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sarda
authors.affiliation: Service de génétique médicale, CHRU Montpellier, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Pinson
authors.affiliation: Service de génétique médicale, CHRU Montpellier, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Blanchet
authors.affiliation: Service de cytogénétique, CHU Rouen, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lemeur
authors.affiliation: Institute of Human Genetics, Jodhpur Village Road, Gujarat, India.
authors.forename: Frenny
authors.initials: F
authors.lastname: Sheth
authors.affiliation: Service de génétique clinique, Hôpital Jeanne de Flandre, CHRU Lille, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manouvrier-Hanu
authors.affiliation: Institut de génétique médicale, Hôpital Jeanne de Flandre, CHRU Lille, France.
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics; D027682:Cation Transport Proteins; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006331:Heart Diseases / Q000151:congenital / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D001523:Mental Disorders / Q000175:diagnosis / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D013064:Speech Disorders / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C109916:CYFIP1 protein, human; D027682:Cation Transport Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C478824:NIPA1 protein, human; C478825:NIPA2 protein, human; C444455:TUBGCP5 protein, human
keywords: 15q11.2 microdeletion; BP1–BP2; CYFIP1; Congenital heart disease; NIPA1; NIPA2; TUBGCP5