title: Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype-phenotype correlations in a large cohort of patients.
abstract: BACKGROUND
  The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype-phenotype correlations and phenotypic variability have yet to be fully clarified.
  
  
  METHODS
  We report genotype-phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation, 3 of whom were not previously reported.
  
  
  RESULTS
  The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations.
  
  
  CONCLUSIONS
  In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour.
authors.affiliation: Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Zollino
authors.affiliation: Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marangi
authors.affiliation: Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ponzi
authors.affiliation: Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Orteschi
authors.affiliation: Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ricciardi
authors.affiliation: Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Lattante
authors.affiliation: Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Murdolo
authors.affiliation: Istituto di Neuropsichiatria Infantile, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Battaglia
authors.affiliation: Istituto di Neuropsichiatria Infantile, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Contaldo
authors.affiliation: Istituto di Neuropsichiatria Infantile, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mercuri
authors.affiliation: Istituto di Neuropsichiatria Infantile, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Stefanini
authors.affiliation: CCA Génétique, Hôpital Necker Enfants Malades, Paris, France.
authors.forename: Roseline
authors.initials: R
authors.lastname: Caumes
authors.affiliation: Centre de référence des anomalies du développement Hôpital Femme-Mère-Enfant Hospices Civils de Lyon, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Edery
authors.affiliation: Centre de référence des anomalies du développement Hôpital Femme-Mère-Enfant Hospices Civils de Lyon, Lyon, France.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Dipartimento Materno-Infantile, Università di Palermo, Palermo, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Piccione
authors.affiliation: Dipartimento Materno-Infantile, Università di Palermo, Palermo, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Corsello
authors.affiliation: Dipartimento di Genetica Medica, Azienda Ospedaliera G.Rummo, Benevento, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Della Monica
authors.affiliation: Dipartimento di Genetica Medica, Azienda Ospedaliera G.Rummo, Benevento, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Scarano
authors.affiliation: Genetica Medica, AO Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Priolo
authors.affiliation: Genetica Medica, Dipartimento Materno-Infantile, Ospedale di Venere, Bari, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Gentile
authors.affiliation: Istituto di Pediatria, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.affiliation: MRC-Holland, Amsterdam, The Netherlands.
authors.forename: Raymon
authors.initials: R
authors.lastname: Vijzelaar
authors.affiliation: Department of Pediatrics, University of Mississippi Medical Center, Jackson, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdulrahman
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Oneda
authors.affiliation: Division of Clinical Genetics, Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.affiliation: Division of Clinical Genetics, Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Sulagna C
authors.initials: SC
authors.lastname: Saitta
authors.affiliation: Division of Clinical Genetics, Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Marni J
authors.initials: MJ
authors.lastname: Falk
authors.affiliation: Division of Clinical Genetics, Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Dubbs
authors.affiliation: Division of Clinical Genetics, Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics; D056726:Genetic Association Studies; D057895:Haploinsufficiency; D006801:Humans; D007223:Infant; D007805:Language Development Disorders / Q000235:genetics; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D012640:Seizures / Q000235:genetics; D012720:Severity of Illness Index; D058496:Smith-Magenis Syndrome / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult
chemical_list: C574033:NSL1 protein, human; D009687:Nuclear Proteins
keywords: 17q21.31 deletion; KANSL1 mutation; clinical heterogeneity; genotype-phenotype correlations