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

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 a few in <i>GJB2</i> and <i>LRTOMT</i>, differed considerably, suggesting an overrepresentation of private mutations. Biallelic missense mutations in <i>MYO7A</i>, <i>CDH23</i>, <i>PCDH15</i>, <i>USH1C</i> cause either DFNB forms or Usher syndrome type 1 (USH1) (<i>USH1/DFNB</i> 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 <i>USH1/DFNB</i> missense mutations reported to cause DFNB in the homozygous state, we identified some that, when associated with a loss-of-function mutation, resulted in USH1, a characteristic pattern of some recessive hypomorphic mutations. This reappraised classification of <i>USH1/DFNB</i> mutations has the potential to improve molecular diagnosis and patient management significantly.

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Proceedings of the National Academy of Sciences
Published
2025-12-08
DOI
https://doi.org/10.1073/pnas.2518445122
Primary Topic
Hearing, Cochlea, Tinnitus, Genetics
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article
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article

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

G. Besbes, Hassan Rouba, Médiha Trabelsi, Ahmed Houmeida et al.
Proceedings of the National Academy of Sciences
Hearing, Cochlea, Tinnitus, Genetics
article

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

G. Besbes, Hassan Rouba, Médiha Trabelsi, Ahmed Houmeida, Hicham Charoute, Ichraf Kraoua, Fabienne Wong Jun Tai, Hala El Hachmi, Éliane Chouery, Crystel Bonnet, Sophie Boucher, Ridha Mrad, J. Marrakchi, Chérine Charfeddine, Mouna Hadrami, Amina Bakhchane, Jean‐Pierre Hardelin, Sara Salime, Mustapha Detsouli, Houda Chahed, Malak Salame, Fatima Ammar Khodja, N. Beltaïef, Sonia Abdelhak, Asadollah Aghaie, Yosra Bouyacoub, Farid Boudjenah, Mohamed Makrelouf, Ghlana Meiloud, Khalid Snoussi, Fatimetou Veten, Ely Cheikh Boussaty, Sofiane Ouhab, Rahma Mkaouar, Sonia Talbi, Ghita Amalou, Zied Riahi, Mirna Mustapha, Asma Behlouli, Abdelhamid Barakat, Amrit Singh‐Estivalet, Amale Bousfiha, Magali Niasme-Grare, Soukaina Elrharchi, Djamel Djennaoui, Malika Dahmani, Rim Zaïnine, Akila Zenati, Samia Abdi
article en

Abstract

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 a few in <i>GJB2</i> and <i>LRTOMT</i>, differed considerably, suggesting an overrepresentation of private mutations. Biallelic missense mutations in <i>MYO7A</i>, <i>CDH23</i>, <i>PCDH15</i>, <i>USH1C</i> cause either DFNB forms or Usher syndrome type 1 (USH1) (<i>USH1/DFNB</i> 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 <i>USH1/DFNB</i> missense mutations reported to cause DFNB in the homozygous state, we identified some that, when associated with a loss-of-function mutation, resulted in USH1, a characteristic pattern of some recessive hypomorphic mutations. This reappraised classification of <i>USH1/DFNB</i> mutations has the potential to improve molecular diagnosis and patient management significantly.

Proceedings of the National Academy of SciencesVol. 122(50)
Tunis University (TN), University Frères Mentouri Constantine 1 (DZ), Centre National de la Recherche Scientifique (FR), Inserm (FR), University of Sciences and Technology Houari Boumediene (DZ), Institut Pasteur (FR), American Academy of Child and Adolescent Psychiatry (US), Collège de France (FR), Université Paris Cité (FR), University of California San Diego (US), Sorbonne Université (FR), Hôpital Armand-Trousseau (FR), Higher Institute of Management (RU), Centre Hospitalier Universitaire Mohammed VI (MA), Hôpital La Rabta (TN), Hôpital d'Enfants (FR), Institut de Biologie Paris-Seine (FR), Département Génétique Animale (FR), Hôpital Charles-Nicolle (TN), Université Mohammed VI des Sciences et de la Santé (MA), École Normale Supérieure de Nouakchott (MR), Child, Adolescent and Family Mental Health (CA), Institut Pasteur de Tunis (TN), Hôpital Universitaire International Cheikh Khalifa (MA), Institut Pasteur du Maroc (MA), Hôpital Mustapha Pacha (DZ), National Institute of Neurology Mongi-Ben Hamida (TN), Mouloud Mammeri University of Tizi-Ouzou (DZ), Hopital Universitaire Habib Bourguiba (TN), Université d'Angers (FR), Lebanese American University (LB), Tunis El Manar University (TN), Manouba University (TN), University of Blida (DZ), Université de Nouakchott (MR), University of Sheffield (GB), University of Hassan II Casablanca (MA)
Fondation Pour l'Audition, Agence Nationale de la Recherche
Openalex Percentile: Top 60%
Hearing, Cochlea, Tinnitus, Genetics
DOIOpen Access PDFOpenAlex
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