Genetics of prelingual isolated deafness and Usher syndrome in the Maghreb and Jordan: Harnessing the potential of homozygosity
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 GJB2 and LRTOMT , differed considerably, suggesting an overrepresentation of 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 in 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (50)
Zied Riahi
Université Paris Cité, Institut Pasteur, Assistance Publique-Hôpitaux de Paris, INSERM, CNRS, Fondation Pour l’Audition, Institut de l’Audition, Institut Hospitalo-Universitaire reConnect, Auditory Therapies Innovation Laboratory
Sophie Boucher
Department of ear, nose, throat, University Hospital Center in Angers
Samia Abdi
Laboratoire de Recherche Biochimie Génétique, Université des sciences de la santé
Fabienne Wong Jun Tai
Université Paris Cité, Institut Pasteur, Assistance Publique-Hôpitaux de Paris, INSERM, CNRS, Fondation Pour l’Audition, Institut de l’Audition, Institut Hospitalo-Universitaire reConnect, Auditory Therapies Innovation Laboratory
Amrit Singh-Estivalet
Université Paris Cité, Institut Pasteur, Assistance Publique-Hôpitaux de Paris, INSERM, CNRS, Fondation Pour l’Audition, Institut de l’Audition, Institut Hospitalo-Universitaire reConnect, Auditory Therapies Innovation Laboratory
Asadollah Aghaie
Université Paris Cité, Institut Pasteur, Assistance Publique-Hôpitaux de Paris, INSERM, CNRS, Fondation Pour l’Audition, Institut de l’Audition, Institut Hospitalo-Universitaire reConnect, Auditory Therapies Innovation Laboratory
Magali Niasme-Grare
Université Paris Cité, Institut Pasteur, Assistance Publique-Hôpitaux de Paris, INSERM, CNRS, Fondation Pour l’Audition, Institut de l’Audition, Institut Hospitalo-Universitaire reConnect, Auditory Therapies Innovation Laboratory
Jean-Pierre Hardelin
Brain Plasticity Unit, CNRS, École Supérieure de Physique et de Chimie Industrielles Paris, Paris Sciences et Lettres Research University, Sorbonne Université, Inserm, CNRS, Neuroscience Paris Seine-Institut de Biologie Paris Seine
Asma Behlouli
Laboratoire de Recherche Biochimie Génétique, Université des sciences de la santé
Malika Dahmani
Equipe de Génétique, Laboratoire de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, Université des Sciences et de la Technologie Houari Boumédiène
Sonia Talbi
Equipe de Génétique, Laboratoire de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, Université des Sciences et de la Technologie Houari Boumédiène
Yosra Bouyacoub
Université Paris Cité, Institut Pasteur, Assistance Publique-Hôpitaux de Paris, INSERM, CNRS, Fondation Pour l’Audition, Institut de l’Audition, Institut Hospitalo-Universitaire reConnect, Auditory Therapies Innovation Laboratory
Rahma Mkaouar
Laboratory of Biomedical Genomics and Oncogenetics LR16IPT05, Pasteur Institute in Tunis, University of Tunis El Manar
Cherine Charfeddine
Laboratory of Biomedical Genomics and Oncogenetics LR16IPT05, Pasteur Institute in Tunis, University of Tunis El Manar
Ghita Amalou
Genomics and Human Genetics Laboratory, Institut Pasteur du Maroc
Amina Bakhchane
Genomics and Human Genetics Laboratory, Institut Pasteur du Maroc
Amale Bousfiha
Laboratory of Integrative Biology, Faculty of Sciences Ain Chock, Hassan II University, BP 2693, Maarif
Sara Salime
Genomics and Human Genetics Laboratory, Institut Pasteur du Maroc
Soukaina Elrharchi
Genomics and Human Genetics Laboratory, Institut Pasteur du Maroc
Malak Salame
Biomarker Research Unit for Mauritanian Populations, Nouakchott University
Mouna Hadrami
Biomarker Research Unit for Mauritanian Populations, Nouakchott University
Ely Boussaty
Division of Otolaryngology, Department of Surgery, University of California, 9500 Gilman Drive, Mail Code 0666, La Jolla
Hicham Charoute
Genomic Sequencing Laboratory, Institut Pasteur du Maroc
Mustapha Detsouli
Genomics and Human Genetics Laboratory, Institut Pasteur du Maroc
Khalid Snoussi
Mohammed VI University of Sciences and Health (UM6SS)
Hassan Rouba
Genomics and Human Genetics Laboratory, Institut Pasteur du Maroc
Hala El Hachmi
Biomarker Research Unit for Mauritanian Populations, Nouakchott University
Fatimetou Veten
Biomarker Research Unit for Mauritanian Populations, Nouakchott University
Ghlana Meiloud
Biomarker Research Unit for Mauritanian Populations, Nouakchott University
Jihene Marrakchi
Laboratory of Biomedical Genomics and Oncogenetics LR16IPT05, Pasteur Institute in Tunis, University of Tunis El Manar
Rim Zainine
Laboratory of Biomedical Genomics and Oncogenetics LR16IPT05, Pasteur Institute in Tunis, University of Tunis El Manar
Houda Chahed
Department of Otorhinolaryngology and Maxilofacial Surgery, La Rabta Hospital in Tunis
Ghazi Besbes
Department of Otorhinolaryngology and Maxilofacial Surgery, La Rabta Hospital in Tunis
Mediha Trabelsi
Department of Congenital and Hereditary Diseases, Charles Nicolle Hospital in Tunis
Ridha Mrad
Department of Congenital and Hereditary Diseases, Charles Nicolle Hospital in Tunis
Ichraf Kraoua
Child and Adolescent Neurology Department of Neurology, National Institute of Neurology
Sofiane Ouhab
Otorhinolaryngology Department, Etablissement Public Hospitalier Bachir Mentouri
Djamel Djennaoui
Otorhinolaryngology Department, Mustapha Pacha Hospital
Farid Boudjenah
Otorhinolaryngology Department, Tizi Ouzou University Hospital Center
Eliane Chouery
Department of Human Genetics, Gilbert and Rose-Mary Chagoury School of Medicine, Lebanese American University
Mirna Mustapha
Department of Biomedical Science, University of Sheffield
Ahmed Houmeida
Biomarker Research Unit for Mauritanian Populations, Nouakchott University
Abdelhamid Barakat
Genomics and Human Genetics Laboratory, Institut Pasteur du Maroc
Fatima Ammar Khodja
Equipe de Génétique, Laboratoire de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, Université des Sciences et de la Technologie Houari Boumédiène
Mohamed Makrelouf
Laboratoire de Recherche Biochimie Génétique, Université des sciences de la santé
Akila Zenati
Laboratoire de Recherche Biochimie Génétique, Université des sciences de la santé
Najeh Beltaief
Department of Otorhinolaryngology and Maxilofacial Surgery, La Rabta Hospital in Tunis
Sonia Abdelhak
Laboratory of Biomedical Genomics and Oncogenetics LR16IPT05, Pasteur Institute in Tunis, University of Tunis El Manar
Christine Petit
Université Paris Cité, Institut Pasteur, Assistance Publique-Hôpitaux de Paris, INSERM, CNRS, Fondation Pour l’Audition, Institut de l’Audition, Institut Hospitalo-Universitaire reConnect, Auditory Therapies Innovation Laboratory
Crystel Bonnet
Université Paris Cité, Institut Pasteur, Assistance Publique-Hôpitaux de Paris, INSERM, CNRS, Fondation Pour l’Audition, Institut de l’Audition, Institut Hospitalo-Universitaire reConnect, Auditory Therapies Innovation Laboratory