Novel Missense and Splice Site Mutations in USH2A, CDH23, PCDH15, and ADGRV1 Are Associated With Usher Syndrome in Lebanon

Abstract

The purpose of this study was to expand the mutation spectrum by searching the causative mutations in nine Lebanese families with Usher syndrome (USH) using whole-exome sequencing. The pathogenicity of candidate mutations was first evaluated according to their frequency, conservation, and in silico prediction tools. Then, it was confirmed via Sanger sequencing, followed by segregation analysis. Finally, a meta-analysis was conducted to calculate the prevalence of USH genes in the Lebanese population. Three missense mutations, two splice site mutations, and one insertion/deletion were detected in eight of the families. Four of these variants were novel: c.5535C > A; p.(Asn1845Lys) in exon 41 of CDH23, c.7130G > A; p.(Arg2377Gln) in exon 32 of ADGRV1, c.11390-1G > A in USH2A, and c.3999–6A > G in PCDH15. All the identified mutations were shown to be likely disease-causing through our bioinformatics analysis and co-segregated with the USH phenotype. The mutations were classified according to the ACMG standards. Finally, our meta-analysis showed that the mutations in ADGRV1, USH2A, and CLRN1 are the most prevalent and responsible for approximately 75% of USH cases in Lebanon. Of note, the frequency USH type 3 showed a relatively high incidence (23%) compared to the worldwide prevalence, which is around 2–4%. In conclusion, our study has broadened the mutational spectrum of USH and showed a high heterogeneity of this disease in the Lebanese population.

The genetic landscape of inherited retinal dystrophies in Arabs

“…On the other hand, syndromic IRDs are subcategorized, conforming to the syndrome’s type [ 5 ]. The most substantial common syndromic condition is Usher syndrome, a combination of hearing loss and RCD [ 6 ]. Other syndromic forms include Bardet-Biedl (BBS [MIM: 209,900]) and Alström syndrome (ALMS [MIM: 203,800]) [ 7 ].…”

A novel compound heterozygous PCDH15 variants may be associated with arRP in a Chinese pedigree

“…Ahmed et al rst reported two pathogenic variants in PCDH15 in two DFNB23 families [8,9]. A genotype-phenotype correlation has been reported for pathogenic variants in PCDH15, with missense variants causing DFNB23 and null variants such as splicing, nonsense, frameshift, and large deletions lead to USH1F [11][12][13]. Diplenic inheritance, copy number variation and premature termination of PCDH15 translation to form truncated proteins are the most common pathogenic mutations.…”

Editorial: The genetics of inherited retinal diseases in understudied ethnic groups: Novel associations, challenges, and perspectives

“…This work described the clinical and genetic characteristics of IRD patients from understudied ethnic groups in Italy and expanded the epidemiological research on understudied ethnic groups. Jaffal et al, 2022a searched for the causative mutations in nine Lebanese families with USH using whole-exome sequencing. This study identified four novel disease-causing mutations in USH2A (OMIM 608400), ADGRV1 (OMIM 602851), PCDH15 (OMIM 601067) and CDH23 (OMIM 601067) genes, respectively.…”

“… Jaffal et al, 2022a searched for the causative mutations in nine Lebanese families with USH using whole-exome sequencing. This study identified four novel disease-causing mutations in USH2A (OMIM 608400) , ADGRV1 (OMIM 602851) , PCDH15 (OMIM 601067) and CDH23 (OMIM 601067) genes, respectively.…”

“…This study identified four novel disease-causing mutations in USH2A (OMIM 608400) , ADGRV1 (OMIM 602851) , PCDH15 (OMIM 601067) and CDH23 (OMIM 601067) genes, respectively. Moreover, a meta-analysis conducted by these authors showed that the frequency of USH type 3 had a relatively high incidence (23%) in Lebanon compared to the worldwide prevalence and that, till today, the major USH genes in the Lebanese populations are ADGRV1 , USH2A , and CLRN1 (OMIM 606397) since they are responsible for around 75% of the cases Jaffal et al, 2022a The study broadened the spectrum of USH-causing mutations also showing a high heterogeneity of this disease in Lebanon.…”