Genetics of prelingual isolated deafness and Usher syndrome in the Maghreb and Jordan: Harnessing the potential of homozygosity
- Zied Riahi
- Sophie Boucher
- Samia Abdi
- Fabienne Wong Jun Tai
- Amrit Singh-Estivalet
- Asadollah Aghaie
- Magali Niasme-Grare
- Jean-Pierre Hardelin
- Asma Behlouli
- Malika Dahmani
- Sonia Talbi
- Yosra Bouyacoub
- Rahma Mkaouar
- Cherine Charfeddine
- Ghita Amalou
- Amina Bakhchane
- Amale Bousfiha
- Sara Salime
- Soukaina Elrharchi
- Malak Salame
- Mouna Hadrami
- Ely Boussaty
- Hicham Charoute
- Mustapha Detsouli
- Khalid Snoussi
- Hassan Rouba
- Hala El Hachmi
- Fatimetou Veten
- Ghlana Meiloud
- Jihene Marrakchi
- Rim Zainine
- Houda Chahed
- Ghazi Besbes
- Mediha Trabelsi
- Ridha Mrad
- Ichraf Kraoua
- Sofiane Ouhab
- Djamel Djennaoui
- Farid Boudjenah
- Eliane Chouery
- Mirna Mustapha
- Ahmed Houmeida
- Abdelhamid Barakat
- Fatima Ammar Khodja
- Mohamed Makrelouf
- Akila Zenati
- Najeh Beltaief
- Sonia Abdelhak
- Christine Petit
- Crystel Bonnet
2025-12-08
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.