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A homozygous AHI1 gene mutation (p.Thr304AsnfsX6) in a consanguineous Moroccan family with Joubert syndrome: a case report.
J Med Case Rep. 2015 Nov 05; 9:254.JM

Abstract

INTRODUCTION

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+Show Affiliations

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.Université d'Orléans & CNRS, INEM-UMR7355, Immunologie Expérimentale et Moléculaire & Neurogénétique, Orléans, France.Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.Service de Pédiatrie IIA, Hôpital d'Enfants, Rabat, Maroc.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.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.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.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.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26541515

Citation

Chafai-Elalaoui, Siham, et al. "A Homozygous AHI1 Gene Mutation (p.Thr304AsnfsX6) in a Consanguineous Moroccan Family With Joubert Syndrome: a Case Report." Journal of Medical Case Reports, vol. 9, 2015, p. 254.
Chafai-Elalaoui S, Chalon M, Elkhartoufi N, et al. A homozygous AHI1 gene mutation (p.Thr304AsnfsX6) in a consanguineous Moroccan family with Joubert syndrome: a case report. J Med Case Rep. 2015;9:254.
Chafai-Elalaoui, S., Chalon, M., Elkhartoufi, N., Kriouele, Y., Mansouri, M., Attié-Bitach, T., Sefiani, A., & Baala, L. (2015). A homozygous AHI1 gene mutation (p.Thr304AsnfsX6) in a consanguineous Moroccan family with Joubert syndrome: a case report. Journal of Medical Case Reports, 9, 254. https://doi.org/10.1186/s13256-015-0732-3
Chafai-Elalaoui S, et al. A Homozygous AHI1 Gene Mutation (p.Thr304AsnfsX6) in a Consanguineous Moroccan Family With Joubert Syndrome: a Case Report. J Med Case Rep. 2015 Nov 5;9:254. PubMed PMID: 26541515.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A homozygous AHI1 gene mutation (p.Thr304AsnfsX6) in a consanguineous Moroccan family with Joubert syndrome: a case report. AU - Chafai-Elalaoui,Siham, AU - Chalon,Matthias, AU - Elkhartoufi,Nadia, AU - Kriouele,Yamna, AU - Mansouri,Maria, AU - Attié-Bitach,Tania, AU - Sefiani,Abdelaziz, AU - Baala,Lekbir, Y1 - 2015/11/05/ PY - 2014/12/18/received PY - 2015/10/08/accepted PY - 2015/11/7/entrez PY - 2015/11/7/pubmed PY - 2016/6/28/medline SP - 254 EP - 254 JF - Journal of medical case reports JO - J Med Case Rep VL - 9 N2 - INTRODUCTION: 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. SN - 1752-1947 UR - https://www.unboundmedicine.com/medline/citation/26541515/A_homozygous_AHI1_gene_mutation__p_Thr304AsnfsX6__in_a_consanguineous_Moroccan_family_with_Joubert_syndrome:_a_case_report_ L2 - https://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-015-0732-3 DB - PRIME DP - Unbound Medicine ER -