Genetics of prelingual isolated deafness and Usher syndrome in the Maghreb and Jordan: Harnessing the potential of homozygosity #MMPMID41359850
Riahi Z; Boucher S; Abdi S; Wong Jun Tai F; Singh-Estivalet A; Aghaie A; Niasme-Grare M; Hardelin JP; Behlouli A; Dahmani M; Talbi S; Bouyacoub Y; Mkaouar R; Charfeddine C; Amalou G; Bakhchane A; Bousfiha A; Salime S; Elrharchi S; Salame M; Hadrami M; Boussaty E; Charoute H; Detsouli M; Snoussi K; Rouba H; Hachmi HE; Veten F; Meiloud G; Marrakchi J; Zainine R; Chahed H; Besbes G; Trabelsi M; Mrad R; Kraoua I; Ouhab S; Djennaoui D; Boudjenah F; Chouery E; Mustapha M; Houmeida A; Barakat A; Khodja FA; Makrelouf M; Zenati A; Beltaief N; Abdelhak S; Petit C; Bonnet C
Proc Natl Acad Sci U S A 2025[Dec]; 122 (50): e2518445122 PMID41359850show ga
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.
Proc+Natl+Acad+Sci+U+S+A 2025 ; 122 (50): e2518445122
