Molecular screening of deafness in Algeria: high genetic heterogeneity involving DFNB1 and the Usher loci, DFNB2/USH1B, DFNB12/USH1D and DFNB23/USH1F.
A systematic approach, involving haplotyping and genotyping, to the molecular diagnosis of non-syndromic deafness within 50 families and 9 sporadic cases from Algeria is described. Mutations at the DFNB1 locus (encompassing the GJB2 and GJB6 genes) are responsible for more than half of autosomal recessive prelingual non-syndromic deafness in various populations. A c.35delG mutation can account for up to 85% of GJB2 mutations and two large deletions del(GJB6-D13S1830) and del(GJB6-D13S1854) have also been reported in several population groups. In view of the genetic heterogeneity a strategy was developed which involved direct analysis of DFNB1. In negative familial cases, haplotype analysis was carried out, where possible, to exclude DFNB1 mutations. Following this, haplotype analysis of five Usher syndrome loci, sometimes involved in autosomal non-syndromic hearing loss, was carried out to identify cases in which Usher gene sequencing was indicated. When homozygosity was observed at a locus in a consanguineous family, the corresponding gene was exhaustively sequenced. Pathogenic DFNB1 genotypes were identified in 40% of the cases. Of the 21 cases identified with 2 pathogenic mutations, c.35delG represented 76% of the mutated alleles. The additional mutations were one nonsense, two missense and one splicing mutation. Four additional patients were identified with a single DFNB1 mutation. None carried the large deletions. Three families with non-syndromic deafness carried novel unclassified variants (UVs) in MYO7A (1 family) and CDH23 (2 families) of unknown pathogenic effect. Additionally, molecular diagnosis was carried out on two Usher type I families and pathogenic mutations in MYO7A and PCDH15 were found.
Ammar-Khodja
Fatima
F
Department of Molecular and Cell Biology, University of USTHB, El Alia, Bab-Ezzouar, Algiers, Algeria.
Faugère
Valérie
V
Baux
David
D
Giannesini
Claire
C
Léonard
Susana
S
Makrelouf
Mohamed
M
Malek
Rahia
R
Djennaoui
Djamel
D
Zenati
Akila
A
Claustres
Mireille
M
Roux
Anne-Françoise
AF
D000462:Algeria; D000483:Alleles; D000595:Amino Acid Sequence; D001299:Audiometry; D001665:Binding Sites; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics*; D016022:Case-Control Studies; D000072259:Connexin 26; D000075302:Connexin 30; D017630:Connexins / Q000235:genetics*; D003241:Consanguinity; D003638:Deafness / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D052245:Usher Syndromes / Q000235:genetics*
C442480:CDH23 protein, human; C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D000075302:Connexin 30; D017630:Connexins; C000607042:GJB2 protein, human; C491020:GJB6 protein, human; D000072259:Connexin 26