title: Molecular and clinical analyses of 16q24.1 duplications involving FOXF1 identify an evolutionarily unstable large minisatellite.
abstract: BACKGROUND
  Point mutations or genomic deletions of FOXF1 result in a lethal developmental lung disease Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. However, the clinical consequences of the constitutively increased dosage of FOXF1 are unknown.
  
  
  METHODS
  Copy-number variations and their parental origin were identified using a combination of array CGH, long-range PCR, DNA sequencing, and microsatellite analyses. Minisatellite sequences across different species were compared using a gready clustering algorithm and genome-wide analysis of the distribution of minisatellite sequences was performed using R statistical software.
  
  
  RESULTS
  We report four unrelated families with 16q24.1 duplications encompassing entire FOXF1. In a 4-year-old boy with speech delay and a café-au-lait macule, we identified an ~15 kb 16q24.1 duplication inherited from the reportedly healthy father, in addition to a de novo ~1.09 Mb mosaic 17q11.2 NF1 deletion. In a 13-year-old patient with autism and mood disorder, we found an ~0.3 Mb duplication harboring FOXF1 and an ~0.5 Mb 16q23.3 duplication, both inherited from the father with bipolar disorder. In a 47-year old patient with pyloric stenosis, mesenterium commune, and aplasia of the appendix, we identified an ~0.4 Mb duplication in 16q24.1 encompassing 16 genes including FOXF1. The patient transmitted the duplication to her daughter, who presented with similar symptoms. In a fourth patient with speech and motor delay, and borderline intellectual disability, we identified an ~1.7 Mb FOXF1 duplication adjacent to a large minisatellite. This duplication has a complex structure and arose de novo on the maternal chromosome, likely as a result of a DNA replication error initiated by the adjacent large tandem repeat. Using bioinformatic and array CGH analyses of the minisatellite, we found a large variation of its size in several different species and individuals, demonstrating both its evolutionarily instability and population polymorphism.
  
  
  CONCLUSIONS
  Our data indicate that constitutional duplication of FOXF1 in humans is not associated with any pediatric lung abnormalities. We propose that patients with gut malrotation, pyloric or duodenal stenosis, and gall bladder agenesis should be tested for FOXF1 alterations. We suggest that instability of minisatellites greater than 1 kb can lead to structural variation due to DNA replication errors.
authors.affiliation: Interdepartmental Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. dharmadh@bcm.edu.|Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. dharmadh@bcm.edu.
authors.forename: Avinash V
authors.initials: AV
authors.lastname: Dharmadhikari
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. Tomasz.Gambin@bcm.edu.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. pszafran@bcm.edu.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szafranski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. Wenjian.Cao@bcm.edu.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. Frank.Probst@bcm.edu.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Probst
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. wjin@bcm.edu.
authors.forename: Weihong
authors.initials: W
authors.lastname: Jin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. pfang@bcm.edu.
authors.forename: Ping
authors.initials: P
authors.lastname: Fang
authors.affiliation: Institute of Informatics, University of Warsaw, Warsaw, Poland. k.gogolewski@mimuw.edu.pl.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Gogolewski
authors.affiliation: Institute of Informatics, University of Warsaw, Warsaw, Poland. aniag@mimuw.edu.pl.|Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland. aniag@mimuw.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Gambin
authors.affiliation: Specially for Children, Dell's Children's Medical Center, Austin, TX, USA. JKGeorge-Abraham@seton.org.
authors.forename: Jaya K
authors.initials: JK
authors.lastname: George-Abraham
authors.affiliation: Departments of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Sailaja.Golla@UTSouthwestern.edu.
authors.forename: Sailaja
authors.initials: S
authors.lastname: Golla
authors.affiliation: Neuropediatrics Service, Saint Vincent de Paul Catholic Hospitals Association of Lille, Free Faculty of Medicine, Lille, France. Boidein.Francoise@ghicl.net.
authors.forename: Francoise
authors.initials: F
authors.lastname: Boidein
authors.affiliation: Cytogenetics Service, Saint Vincent de Paul Catholic Hospitals Association of Lille, Free Faculty of Medicine, Lille, France. Duban-Bedu.Benedicte@ghicl.net.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Duban-Bedu
authors.affiliation: Cytogenetics Service, Saint Vincent de Paul Catholic Hospitals Association of Lille, Free Faculty of Medicine, Lille, France. Delobel.Bruno@ghicl.net.
authors.forename: Bruno
authors.initials: B
authors.lastname: Delobel
authors.affiliation: Laboratory of Medical Genetics, University Hospital, Lille, France. joris.andrieux@chru-lille.fr.
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.affiliation: Medical Genetics Center, Munich, Germany. kerstin.becker@mgz-muenchen.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Becker
authors.affiliation: Medical Genetics Center, Munich, Germany. Elke.Holinski-Feder@mgz-muenchen.de.
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. scheung@bcm.edu.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: Interdepartmental Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. pawels@bcm.edu.|Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. pawels@bcm.edu.
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000818:Animals; D002675:Child, Preschool; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018628:Gene Dosage; D020440:Gene Duplication; D006801:Humans; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D010375:Pedigree
chemical_list: C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors