Clinical and Molecular Delineation of AHI1-Associated Joubert Syndrome in a Consanguineous Pedigree: A Case Report
DOI:
https://doi.org/10.46531/sinapse/CC/169/2025Keywords:
Abnormalities, Multiple/genetics, Adaptor Proteins, Signal Transducing/genetics, Brain Diseases/diagnosis, Brain Diseases/genetic, Child, Ciliopathies/genetics, Exome Sequencing, Joubert Syndrome/diagnosisAbstract
Joubert syndrome (JS) is a rare autosomal recessive neurodevelopmental disorder characterized by the molar tooth sign (MTS) on brain magnetic resonance imaging (MRI), resulting from cerebellar vermis hypoplasia and elongated superior cerebellar peduncles. A 4-year-old female presenting with global developmental delay, hypotonia, oculomotor apraxia, and MTS on MRI underwent whole-exome sequencing (WES). Bioinformatic analysis, Sanger validation, and segregation studies were performed. Pathogenicity was assessed using ACMG/AMP guidelines and in silico tools. WES revealed a novel homozygous nonsense variant in AHI1 (c.2938A>T; p.Lys980Ter), absent in population databases. Segregation analysis confirmed autosomal recessive inheritance, with both parents as heterozygous carriers. Evolutionary conservation of Lys980 underscored its functional importance. This study expands the mutational spectrum of AHI1-related JS and highlights the utility of WES in consanguineous populations. The findings facilitate precise diagnosis, genetic counseling, and informed reproductive planning for at-risk families.Downloads
References
Neissi M, Mabudi H, Mohammadi-Asl J. AHI1 gene mutation in a consanguineous Iranian family affected by Joubert syndrome: A case report. Clin Case Rep. 2021 Oct 23;9(10):e05002. doi: 10.1002/ccr3.5002. PMID: 34721863; PMCID: PMC8538011.
Joubert M, Eisenring JJ, Andermann F. Familial dysgenesis of the vermis: a syndrome of hyperventilation, abnormal eye movements and retardation. Neurology. 1968 Mar;18(3):302-3. PMID: 5690407.
Fang X, Ma M, Rong W, Lian YY, Wu X, Gao Y, Li HP, Sheng X. Exome sequencing confirms the clinical diagnosis of both joubert syndrome and klinefelter syndrome with keratoconus in a han Chinese family. Front Genet. 2024 Jul 15;15:1417584. doi: 10.3389/fgene.2024.1417584. PMID: 39076169; PMCID: PMC11284097.
Forsyth R, Parisi MA, Altintas B, Malicdan MC, Vilboux T, Knoll J, Brooks BP, Zein WM, Gahl WA, Toro C, Gunay-Aygun M. Systematic analysis of physical examination characteristics of 94 individuals with Joubert syndrome: Keys to suspecting the diagnosis. Am J Med Genet C Semin Med Genet. 2022 Mar;190(1):121-130. doi: 10.1002/ajmg.c.31966. Epub 2022 Mar 21. PMID: 35312150; PMCID: PMC9117497.
Neissi M, Al-Badran AI, Mohammadi-Asl J. Homozygous AHI1 gene mutation (c. 1213A> C; Thr405Pro) leads to Joubert syndrome in a consanguineous Iranian family: A case report. Neurology Asia. 2022 Jun 1;27(2). doi: 10.54029/2022anp
Al-Mozani SK, Al-Tulaibawi KJ, Al-Zaalan AR, Neissi M, Al-Badran AI, Nekouei E, Mohammadi-Asl J. Clinical and genetic findings in an Iraqi family with TMEM67-associated Joubert syndrome. Neurology Asia. 2025 Mar 1;30(1). doi: 10.54029/2025xkd
Doherty D. Joubert syndrome: insights into brain development, cilium biology, and complex disease. Semin Pediatr Neurol. 2009 Sep;16(3):143-54. doi: 10.1016/j.spen.2009.06.002. PMID: 19778711; PMCID: PMC2804071.
Jasim RA, Abed AY, AL-Fahdawi MH, Al-Zaalan AR, Hamid RT, Shibab RN, Neissi M, Mohammadi-Asl J, Al-Badran AI. Joubert Syndrome and the AHI1 p. Gln981Glu Variant: A Molecular and Clinical Study. Sinapse. 2025 May 12. doi: 10.46531/sinapse/CC/141/2025
Rusterholz TDS, Hofmann C, Bachmann-Gagescu R. Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome. Front Genet. 2022 Jun 30;13:939527. doi: 10.3389/fgene.2022.939527. PMID: 35846153; PMCID: PMC9280682.
Parisi MA. Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet C Semin Med Genet. 2009 Nov 15;151C(4):326-40. doi: 10.1002/ajmg.c.30229. PMID: 19876931; PMCID: PMC2797758.
Alizadeh P, Babadi AJ, Ghadiri N, Neissi M, Zeinali M. Gene variant analysis in pediatrics with early-onset epilepsy: Identification of novel variants. Pract Lab Med. 2025 Mar 19;45:e00462. doi: 10.1016/j.plabm.2025.e00462. PMID: 40230662; PMCID: PMC11995797.
Neissi M, Al-Zaalan AR, Mohammadi-Asl M, Roghani M, Mohammadi-Asl J, Jorfi K. ARV1 p. Gln62Ter, a novel mutation linked to developmental and epileptic encephalopathy-38. Journal of Rare Diseases. 2025 Dec;4(1):1-8.
Neissi M, Sheikh-Hosseini M, Mohammadi-Asl J. Retinitis pigmentosa-1 due to an RP1 mutation in a consanguineous Iranian family: Report of a novel mutation. Clin Case Rep. 2024 Mar 14;12(3):e8666. doi: 10.1002/ccr3.8666. PMID: 38487646; PMCID: PMC10940001.
Neissi M, Al-Badran AI, Mohammadi-Asl M, Al-Badran RA, Sheikh-Hosseini M, Roghani M, Mohammadi-Asl J. Clinical and genetic analysis of Niemann-Pick disease type C with a novel NPC1 variant. Journal of Rare Diseases. 2024 Jul 8;3(1):19. doi: 10.1007/s44162-024-00043-0
Valente EM, Brancati F, Silhavy JL, Castori M, Marsh SE, Barrano G, Bertini E, Boltshauser E, Zaki MS, Abdel-Aleem A, Abdel-Salam GM, Bellacchio E, Battini R, Cruse RP, Dobyns WB, Krishnamoorthy KS, Lagier-Tourenne C, Magee A, Pascual-Castroviejo I, Salpietro CD, Sarco D, Dallapiccola B, Gleeson JG; International JSRD Study Group. AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders. Ann Neurol. 2006 Mar;59(3):527-34. doi: 10.1002/ana.20749. PMID: 16453322.
Valente EM, Rosti RO, Gibbs E, Gleeson JG. Primary cilia in neurodevelopmental disorders. Nat Rev Neurol. 2014 Jan;10(1):27-36. doi: 10.1038/nrneurol.2013.247. Epub 2013 Dec 3. PMID: 24296655; PMCID: PMC3989897.
Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, Zhou Z, Shu G, Yin G. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022 Jan 3;7(1):3. doi: 10.1038/s41392-021-00762-6. PMID: 34980884; PMCID: PMC8724284.
Kroes HY, van Zon PH, Fransen van de Putte D, Nelen MR, Nievelstein RJ, Wittebol-Post D, van Nieuwenhuizen O, Mancini GM, van der Knaap MS, Kwee ML, Maas SM, Cobben JM, De Nef JE, Lindhout D, Sinke RJ. DNA analysis of AHI1, NPHP1 and CYCLIN D1 in Joubert syndrome patients from the Netherlands. Eur J Med Genet. 2008 Jan-Feb;51(1):24-34. doi: 10.1016/j.ejmg.2007.10.001. Epub 2007 Oct 6. PMID: 18054307.
Valente EM, Dallapiccola B, Bertini E. Joubert syndrome and related disorders. Handb Clin Neurol. 2013;113:1879-88. doi: 10.1016/B978-0-444-59565-2.00058-7. PMID: 23622411.
Karamzade A, Babaei M, Saberi M, Golchin N, Khalil Nejad Sani Banaei A, Eshaghkhani Y, Golchehre Z, Keramatipour M. Identification of a novel truncating variant in AHI1 gene and a brief review on mutations spectrum. Mol Biol Rep. 2021 Jun;48(6):5339-5345. doi: 10.1007/s11033-021-06508-5. Epub 2021 Jun 30. PMID: 34191236.
Ben-Salem S, Al-Shamsi AM, Gleeson JG, Ali BR, Al-Gazali L. Mutation spectrum of Joubert syndrome and related disorders among Arabs. Hum Genome Var. 2014 Nov 6;1:14020. doi: 10.1038/hgv.2014.20. Erratum in: Hum Genome Var. 2015 Mar 26;2:15001. doi: 10.1038/hgv.2015.1. PMID: 27081510; PMCID: PMC4785524.
Parisi MA, Doherty D, Eckert ML, Shaw DW, Ozyurek H, Aysun S, Giray O, Al Swaid A, Al Shahwan S, Dohayan N, Bakhsh E, Indridason OS, Dobyns WB, Bennett CL, Chance PF, Glass IA. AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. J Med Genet. 2006 Apr;43(4):334-9. doi: 10.1136/jmg.2005.036608. Epub 2005 Sep 9. PMID: 16155189; PMCID: PMC2563230.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Doaa Haqi Ismael, Almuthana K. Hameed, Shaymaa Muneam Saeed, Sahar Kareem Al-Mozani, Kamele Jorfi, Motahareh Sheikh-Hosseini, Ehab Neissi
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
