Genetics of prelingual isolated deafness and Usher syndrome in the Maghreb and Jordan: Harnessing the potential of homozygosity

• 成果类型: Article
• 署名作者: Riahi, Zied; Boucher, Sophie; Abdi, Samia; Tai, Fabienne Wongjun; Singh-Estivalet, Amrit; Aghaie, Asadollah; Niasme-Grare, Magali; Hardelin, Jean- Pierre; Behlouli, Asma; Dahmani, Malika; Talbi, Sonia; Bouyacoub, Yosra; Mkaouar, Rahma; Charfeddine, Cherine; Amalou, Ghita; Bakhchane, Amina; Bousfiha, Amale; Salime, Sara; Elrharchi, Soukaina; Salame, Malak; Hadrami, Mouna; Boussaty, Ely; Charoute, Hicham; Detsouli, Mustapha; Snoussi, Khalid; Rouba, Hassan; El Hachmi, Hala; Veten, Fatimetou; Meiloud, Ghlana; Marrakchi, Jihene; Zainine, Rim; Chahed, Houda; Besbes, Ghazi; Trabelsi, Mediha; Mrad, Ridha; Kraoua, Ichraf; Ouhab, Sofiane; Djennaoui, Djamel; Boudjenah, Farid; Chouery, Eliane; Mustapha, Mirna; Houmeida, Ahmed; Barakat, Abdelhamid; Khodja, Fatima Ammar; Makrelouf, Mohamed; Zenati, Akila; Beltaief, Najeh; Abdelhak, Sonia; Peti, Christine; Bonnet, Crystel
• 署名单位: Universite Paris Cite; Pasteur Network; Assistance Publique Hopitaux Paris (APHP); Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); Hopital Universitaire Saint-Louis - APHP; Institut Pasteur Paris; Universite de Tunis-El-Manar; Pasteur Network; Institut Pasteur Tunis; Universite d'Angers; Centre Hospitalier Universitaire d'Angers; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite d'Angers; CNRS - National Institute for Biology (INSB); Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Sorbonne Universite; Hopital Universitaire Saint-Louis - APHP; Hopital Universitaire Armand-Trousseau - APHP; Universite PSL; Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI); University Science & Technology Houari Boumediene; University Science & Technology Houari Boumediene; Universite de la Manouba; Pasteur Network; Institut Pasteur Du Maroc; Hassan II University of Casablanca; Hassan II University of Casablanca; University of Nouakchott; University of California System; University of California San Diego; Pasteur Network; Institut Pasteur Du Maroc; Pasteur Network; Institut Pasteur Du Maroc; Universite de Tunis-El-Manar; Hopital La Rabta; Universite de Tunis-El-Manar; Hopital Charles Nicolle; Universite de Tunis-El-Manar; Faculte de Medecine de Tunis (FMT); Universite de Tunis-El-Manar; Institut National de Neurologie; Universite de Tunis-El-Manar; Lebanese American University; University of Sheffield; Universite PSL; College de France
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2518445122
• 发表日期: 2025-12-16
• 页码: e2518445122
• 关键词: North Africa; homozygosity; hypomorphic mutations; USH1B/DFNB mutations; molecular diagnosis; hearing-loss; mutations; phenotype; families; PROTOCADHERIN-15; determinants; impairment; PREVALENCE; diagnosis; protein

摘要

The molecular genetic diagnosis of prelingual sensorineural hearing impairment (HI) is essential for genetic counseling and patient management. Effective diagnosis requires a knowledge of the genetic architecture of HI, which is often lacking. We established a cohort of 450 unrelated patients with familial (at least two affected relatives) severe-to-profound bilateral prelingual HI in five countries with high consanguinity rates: Tunisia, Jordan, Algeria, Morocco, and Mauritania (the TJAMM cohort). Recessive and dominant inheritance were observed in 92% and 8% of cases, respectively; 14% were syndromic. Genome analysis detected 211 different mutations (36% not reported before) in 49 deafness genes, and fully resolved 90% of cases of autosomal recessive isolated deafness (DFNB forms), 89% of the mutations being homozygous. The deafness genes involved were similar in different countries, but their mutations, except few in GJB2 and LRTOMT, differed considerably, suggesting an overrepresentation private mutations. Biallelic missense mutations in MYO7A, CDH23, PCDH15, USH1C cause either DFNB forms or Usher syndrome type 1 (USH1) (USH1/DFNB genes). Such mutations were overrepresented (13% of patients), highlighting the importance of distinguishing between these two mutation classes. We hypothesized that current difficulties might stem from the misclassification of certain mutations. By studying the 65 USH1/DFNB missense mutations reported to cause DFNB in the homozygous state, we identified some that, when associated with a loss-of-function mutation, resulted USH1, a characteristic pattern of some recessive hypomorphic mutations. This reappraised classification of USH1/DFNB mutations has the potential to improve molecular diagnosis and patient management significantly.