title: Refining the phenotype associated with CASC5 mutation.
abstract: Autosomal recessive primary microcephaly is a neurodevelopmental disorder characterized by congenitally reduced head circumference by at least two standard deviations (SD) below the mean for age and gender. It is associated with nonprogressive mental retardation of variable degree, minimal neurological deficit with no evidence of architectural anomalies of the brain. So far, 12 genetic loci (MCPH1-12) and corresponding genes have been identified. Most of these encode centrosomal proteins. CASC5 is one the most recently unravelled genes responsible for MCPH with mutations reported in three consanguineous families of Moroccan origin, all of whom harboured the same CASC5 homozygous mutation (c.6125G>A; p.Met2041Ile). Here, we report the identification, by whole exome sequencing, of the same missense mutation in a consanguineous Algerian family. All patients exhibited a similar clinical phenotype, including congenital microcephaly with head circumferences ranging from -3 to -4 standard deviations (SD) after age 5 years, moderate to severe cognitive impairment, short stature (adult height -3 SD), dysmorphic features included a sloping forehead, thick eyebrows, synophris and a low columella. Severe vermis hypoplasia and a large cyst of the posterior fossa were observed in one patient. Close microsatellite markers showed identical alleles in the Algerian the previously and Moroccan patients. This study confirms the involvement of CASC5 in autosomal recessive microcephaly and supports the hypothesis of a founder effect of the c.6125G>A mutation. In addition, this report refines the phenotype of this newly recognized form of primary microcephaly.
authors.affiliation: Service de Neurologie, Etablissement Hospitalier Spécialisé de Ben Aknoun, Université Benyoucef Benkhedda, Alger, Algeria. karimm.saadi@yahoo.fr.
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Saadi
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, Necker-Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cité University, 75015, Paris, France.
authors.forename: Florine
authors.initials: F
authors.lastname: Verny
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, Necker-Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cité University, 75015, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Siquier-Pernet
authors.affiliation: Genomic Platform, INSERM UMR 1163, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Bioinformatic Platform, INSERM UMR 1163, Imagine Institute, Paris Descartes- Sorbonne Paris Cité University, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, Necker-Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cité University, 75015, Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Service de Neurologie, Etablissement Hospitalier Spécialisé de Ben Aknoun, Université Benyoucef Benkhedda, Alger, Algeria.
authors.forename: Myriam
authors.initials: M
authors.lastname: Abada-Dendib
authors.affiliation: Service de Neurologie, Etablissement Hospitalier Spécialisé de Ben Aknoun, Université Benyoucef Benkhedda, Alger, Algeria.
authors.forename: Malika
authors.initials: M
authors.lastname: Chaouch
authors.affiliation: Service de Génétique médicale, Hôpital Erasme-ULB, Université Libre de Bruxelles, Bruxelles, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Abramowicz
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, Necker-Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cité University, 75015, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
mesh_terms: D000328:Adult; D000462:Algeria; D018389:Codon, Nonsense; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D018703:Founder Effect; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; C472643:Knl1 protein, human; D008869:Microtubule-Associated Proteins
keywords: Autosomal recessive primary microcephaly; CASC5; Founder effect; Short stature; Whole exome sequencing