title: Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical blindness.
abstract: Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(∗)48] and c.3709C>T [p.Arg1237(∗)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328(∗)] and c.6232G>T [p.Glu2078(∗)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1163, Laboratory of Genetics in Ophthalmology, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Perrault
authors.affiliation: Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal H3T 1C5, Canada.
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France; Department of Genetics, Hôpital Necker - Enfants Malades, 75015 Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.affiliation: Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal H3T 1C5, Canada.
authors.forename: José-Mario
authors.initials: JM
authors.lastname: Capo-Chichi
authors.affiliation: Department of Pediatric Radiology, Hôpital Necker - Enfants Malades, Descartes University, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: Department of Medical Imaging, Sainte-Justine Hospital, Montreal, QC H3T 1C5, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Décarie
authors.affiliation: Division of Genetics, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Maranda
authors.affiliation: Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, Université Paris Descartes, 75015 Paris, France.
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.affiliation: Division of Neurology, Centre Hospitalier Universitaire de Québec, Quebec, QC G1V 4G2, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Sylvain
authors.affiliation: Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal H3T 1C5, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Lortie
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal QC H3C 3J7, Canada.
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Roux
authors.affiliation: Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal H3T 1C5, Canada.
authors.forename: Elsa
authors.initials: E
authors.lastname: Rossignol
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1163, Laboratory of Genetics in Ophthalmology, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Gérard
authors.affiliation: Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, Université Paris Descartes, 75015 Paris, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Barcia
authors.affiliation: Department of Pediatric Neurology, Centre Hospitalier Universitaire Amiens, 80054 Amiens Cedex, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Berquin
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France; Department of Genetics, Hôpital Necker - Enfants Malades, 75015 Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1163, Laboratory of Genetics in Ophthalmology, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Josseline
authors.initials: J
authors.lastname: Kaplan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1163, Laboratory of Genetics in Ophthalmology, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France. Electronic address: jean-michel.rozet@inserm.fr.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rozet
authors.affiliation: Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal H3T 1C5, Canada. Electronic address: jacques.michaud@recherche-ste-justine.qc.ca.
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
mesh_terms: D019575:Blindness, Cortical / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004831:Epilepsies, Myoclonic / Q000235:genetics; D004827:Epilepsy / Q000235:genetics*; D059472:Exome; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D005808:Genes, Recessive; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013036:Spasms, Infantile / Q000235:genetics
chemical_list: C514577:DOCK7 protein, human; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors