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

Lama Jaffal; Hanane Akhdar; Hawraa Joumaa; Mariam Ibrahim; Zahraa Chhouri; Alexandre Assi; Charles Helou; Hane Lee; Go Hun Seo; Wissam H Joumaa; Said El Shamieh

doi:10.3389/fgene.2022.864228

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

Front Genet. 2022 May 16:13:864228. doi: 10.3389/fgene.2022.864228. eCollection 2022.

Authors

Lama Jaffal^{1

2}, Hanane Akhdar^{1

2}, Hawraa Joumaa¹, Mariam Ibrahim¹, Zahraa Chhouri¹, Alexandre Assi³, Charles Helou³, Hane Lee⁴, Go Hun Seo⁴, Wissam H Joumaa¹, Said El Shamieh^{1

5}

Affiliations

¹ Rammal Hassan Rammal Research Laboratory, PhyToxE Research Group, Faculty of Sciences, Lebanese University, Nabatieh, Lebanon.
² Department of Biological and Chemical Sciences, School of Arts and Sciences, Lebanese International University, Beirut, Lebanon.
³ Retinal Service, Beirut Eye & ENT Specialist Hospital, Beirut, Lebanon.
⁴ Rare Genetic Disease Research Center, 3billion Inc, Seoul, South Korea.
⁵ Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, 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.

Keywords: Usher syndrome; developing countries; genetics; mutation; next-generation sequencing; rare disease.