title: Microdeletions in 9q33.3-q34.11 in five patients with intellectual disability, microcephaly, and seizures of incomplete penetrance: is STXBP1 not the only causative gene?
abstract: BACKGROUND
  Most microdeletions involving chromosome sub-bands 9q33.3-9q34.11 to this point have been detected by analyses focused on STXBP1, a gene known to cause early infantile epileptic encephalopathy 4 and other seizure phenotypes. Loss-of-function mutations of STXBP1 have also been identified in some patients with intellectual disability without epilepsy. Consequently, STXBP1 is widely assumed to be the gene causing both seizures and intellectual disability in patients with 9q33.3-q34.11 microdeletions.
  
  
  RESULTS
  We report five patients with overlapping microdeletions of chromosome 9q33.3-q34.11, four of them previously unreported. Their common clinical features include intellectual disability, psychomotor developmental delay with delayed or absent speech, muscular hypotonia, and strabismus. Microcephaly and short stature are each present in four of the patients. Two of the patients had seizures. De novo deletions range from 1.23 to 4.13 Mb, whereas the smallest deletion of 432 kb in patient 3 was inherited from her mother who is reported to have mild intellectual disability. The smallest region of overlap (SRO) of these deletions in 9q33.3 does not encompass STXBP1, but includes two genes that have not been previously associated with disease, RALGPS1 and GARNL3. Sequencing of the two SRO genes RALGPS1 and GARNL3 in at least 156 unrelated patients with mild to severe idiopathic intellectual disability detected no causative mutations. Gene expression analyses in our patients demonstrated significantly reduced expression levels of GARNL3, RALGPS1 and STXBP1 only in patients with deletions of the corresponding genes. Thus, reduced expression of STXBP1 was ruled out as a cause for seizures in our patient whose deletion did not encompass STXBP1.
  
  
  CONCLUSIONS
  We suggest that microdeletions of this region on chromosome 9q cause a clinical spectrum including intellectual disability, developmental delay especially concerning speech, microcephaly, short stature, mild dysmorphisms, strabismus, and seizures of incomplete penetrance, and may constitute a new contiguous gene deletion syndrome which cannot completely be explained by deletion of STXBP1.
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Ehret
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Cremer
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Becker
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Johannes P
authors.initials: JP
authors.lastname: Zimmermann
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.|Present Address: Center for Human Genetics, Freiburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wohlleber
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Grasshoff
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.|Present Address: Genetikum, Neu-Ulm, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Rossier
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.|Present Address: IMGM Laboratories GmbH, Martinsried, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.affiliation: Children's Hospital, University of Tübingen, Tübingen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bevot
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.|MVZ Dr. Eberhard & Partner, Dortmund, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schön
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann-Heimbach
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dennert
authors.affiliation: Centre de Génétique, CHU d'Amiens, Amiens, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Mathieu-Dramard
authors.affiliation: Service de génétique, CHU de Caen, Caen, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Lacaze
authors.affiliation: Service de génétique, CHU de Caen, Caen, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Plessis
authors.affiliation: Service de Neurologie Pédiatrique, CHU d'Amiens, Amiens, France.
authors.forename: Alain
authors.initials: A
authors.lastname: de Broca
authors.affiliation: Centre de Génétique, CHU d'Amiens, Amiens, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jedraszak
authors.affiliation: Medical Genetics, Centre of Laboratory Medicine, Cantonal Hospital Aarau, Aarau, Switzerland.
authors.forename: Benno
authors.initials: B
authors.lastname: Röthlisberger
authors.affiliation: Medical Genetics, University Hospital Basel, Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Miny
authors.affiliation: Medical Genetics, University Hospital Basel, Basel, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Filges
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dufke
authors.affiliation: Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France.
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Present Address: Greenwood Genetic Center, Greenwood, SC USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lee
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Zink
keywords: Contiguous gene syndrome; Haploinsufficiency; Intellectual disability; Microdeletion 9q33.3-q34.11; STXBP1