Genetic Screening of the Usher Syndrome in Cuba

Abstract

Background Usher syndrome (USH) is a recessive inherited disease characterized by sensorineural hearing loss, retinitis pigmentosa, and sometimes, vestibular dysfunction. Although the molecular epidemiology of Usher syndrome has been well studied in Europe and United States, there is a lack of studies in other regions like Africa or Central and South America. Methods We designed a NGS panel that included the 10 USH causative genes ( MYO7A , USH1C , CDH23 , PCDH15 , USH1G , CIB2 , USH2A , ADGRV1 , WHRN , and CLRN1 ), four USH associated genes ( HARS , PDZD7 , CEP250 , and C2orf71 ), and the region comprising the deep-intronic c.7595-2144A>G mutation in USH2A . Results NGS sequencing was performed in 11 USH patients from Cuba. All the cases were solved. We found the responsible mutations in the USH2A , ADGRV1 , CDH23 , PCDH15 , and CLRN1 genes. Four mutations have not been previously reported. Two mutations are recurrent in this study: c.619C>T (p.Arg207 ∗ ) in CLRN1 , previously reported in two unrelated Spanish families of Basque origin, and c.4488G>C (p.Gln1496His) in CDH23 , first described in a large Cuban family. Additionally, c.4488G>C has been reported two more times in the literature in two unrelated families of Spanish origin. Conclusion Although the sample size is very small, it is tempting to speculate that the gene frequencies in Cuba are distinct from other populations mainly due to an “island effect” and genetic drift. The two recurrent mutations appear to be of Spanish origin. Further studies with a larger cohort are needed to elucidate the real genetic landscape of Usher syndrome in the Cuban population.

Review of Genotype-Phenotype Correlations in Usher Syndrome

“…Genotype-phenotype correlations have been studied for several specific mutations, revealing similar clinical phenotype across all USH2C patients (Hilgert et al 2009). Unlike USH2A patients who display a wide variation in clinical phenotype, USH2C patients show comparatively little variation (Schwartz et al 2005). One exception is reported in a recently studied Chinese family, with three affected siblings with novel mutations in ADGRV1 (p.Gly5003fs and p.His6130fs) displaying postlingual deafness and absence of night blindness, straying from the expected USH2 phenotype (Zhang et al 2018).…”

“…However, as our understanding of the genetic basis of USH continues to expand, this system has become increasingly insufficient to encompass the current state of knowledge. With the advent of NGS-based screening strategies, the number of causative mutations identified for each USH-associated gene has grown rapidly (Fuster-Garcia et al 2018;Wei et al 2018;Zhang et al 2018;Jouret et al 2019;Okano et al 2019;Pater et al 2019;Santana et al 2019;Qu et al 2020). This includes variants in common USH genes which result in atypical USH phenotypes, complicating the paradigm of assigning certain USH genes to either USH1, USH2, or USH3 (Pennings et al 2004;Bashir et al 2010;Pérez-Carro et al 2018;Zhang et al 2018;D'Esposito et al 2019;Valero et al 2019).…”

Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the CDH23 Gene Causing Usher Syndrome Type ID in a Chinese Patient

“…Genetic screening and the accurate diagnosis of Usher syndrome in different populations is necessary (Ben-Rebeh et al, 2016;Sun et al, 2018;Santana et al, 2019). Efficient molecular diagnosis of Usher syndrome in a patient's early childhood is of utmost importance, allowing better genetic counseling and therapeutic management (Ben-Rebeh et al, 2016;Ivanova et al, 2018;Maddalena et al, 2018;Jouret et al, 2019).…”

Novel compound heterozygous synonymous and missense variants in the MYO7A gene identified by next‐generation sequencing in a Chinese family with nonsyndromic hearing loss

“… 9 , 10 Thus, MYO7A pathogenic variants can cause both syndromic and NSHL, including autosomal dominant nonsyndromic hearing loss (ADNSHL, DFNA11), autosomal recessive nonsyndromic hearing loss (ARNSHL, DFNB2), and syndromic deaf‐blindness (Usher Type 1B, USH1B). 11 , 12 , 13 Studies have identified an interaction between the myosin VIIa protein, the SANS (encoded by USH1G gene) protein, and the harmonin (encoded by USH1C gene); this triplet in hair cell stereocilium transports the protein complex to the tip which, in turn, regulates mechanoelectrical transduction (MET). 14 , 15 The MYO7A protein contains a domain that provides its motor and cargo binding functions.…”