title: A homozygous AHI1 gene mutation (p.Thr304AsnfsX6) in a consanguineous Moroccan family with Joubert syndrome: a case report.
abstract: BACKGROUND
  Joubert syndrome is a rare congenital disorder characterized by brain malformation, developmental delay with hypotonia, ocular motor apraxia, and breathing abnormalities. Joubert syndrome is a genetically highly heterogeneous ciliopathy disorder with 23 identified causative genes. The diagnosis is based on brain imaging showing the "molar tooth sign" with cerebellar vermis agenesis. We describe a consanguineous Moroccan family with three affected siblings (18-year-old boy, 13-year-old girl, and 10-year-old boy) showing typical signs of Joubert syndrome, and attempt to identify the underlying genetic defect in this family.
  
  
  METHODS
  We performed genome-wide homozygosity mapping using a high-resolution array followed by targeted Sanger sequencing to identify the causative gene.
  
  
  RESULTS
  This approach found three homozygous regions, one including the AHI1 gene. Direct sequencing of the 26 coding exons of AHI1 revealed a homozygous mutation (p.Thr304AsnfsX6) located in exon 7 present in the three Joubert syndrome-affected Moroccan siblings. Of more interest, this truncating mutation was previously reported in patients with compound heterozygous Joubert syndrome originating from Spain (one patient) and from the Netherlands (two patients), suggesting a possible founder effect or mutational hotspot.
  
  
  CONCLUSIONS
  Combined homozygosity mapping and targeted sequencing allowed the rapid detection of the disease-causing mutation in the AHI1 gene in this family affected with a highly genetically heterogeneous disorder. Carriers of the same truncating mutation (p.Thr304AsnfsX6), originating from Spain and the Netherlands, presented variable clinical characteristics, thereby corroborating the extreme heterogeneity of Joubert syndrome.
authors.affiliation: Département de Génétique Médicale, Institut National d'Hygiène, Rabat, Maroc.|Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohammed V Souissi, Rabat, Maroc.
authors.forename: Siham
authors.initials: S
authors.lastname: Chafai-Elalaoui
authors.affiliation: Université d'Orléans & CNRS, INEM-UMR7355, Immunologie Expérimentale et Moléculaire & Neurogénétique, Orléans, France.
authors.forename: Matthias
authors.initials: M
authors.lastname: Chalon
authors.affiliation: Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Elkhartoufi
authors.affiliation: Service de Pédiatrie IIA, Hôpital d'Enfants, Rabat, Maroc.
authors.forename: Yamna
authors.initials: Y
authors.lastname: Kriouele
authors.affiliation: Département de Génétique Médicale, Institut National d'Hygiène, Rabat, Maroc.|Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohammed V Souissi, Rabat, Maroc.
authors.forename: Maria
authors.initials: M
authors.lastname: Mansouri
authors.affiliation: Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France, Institut IMAGINE, Paris, France.|INSERM UMR1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
authors.affiliation: Département de Génétique Médicale, Institut National d'Hygiène, Rabat, Maroc.|Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohammed V Souissi, Rabat, Maroc.
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Sefiani
authors.affiliation: Université d'Orléans & CNRS, INEM-UMR7355, Immunologie Expérimentale et Moléculaire & Neurogénétique, Orléans, France. lekbir.baala@cnrs-orleans.fr.|Centre Hospitalier Régional d'Orléans (CHRO), Pôle de Biopathologie, Orléans, France. lekbir.baala@cnrs-orleans.fr.
authors.forename: Lekbir
authors.initials: L
authors.lastname: Baala
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D033942:Adaptor Proteins, Vesicular Transport; D000293:Adolescent; D002526:Cerebellar Diseases / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D005124:Eye Abnormalities / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D009018:Morocco; D009154:Mutation; D010375:Pedigree; D012160:Retina / Q000002:abnormalities*
chemical_list: C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport