Identification of Novel and Recurrent Variants in MYO15A in Ashkenazi Jewish Patients With Autosomal Recessive Nonsyndromic Hearing Loss

Hearing loss is a genetically and phenotypically heterogeneous disorder. The purpose of this study was to determine the genetic cause underlying hearing loss in four Ashkenazi Jewish families. We screened probands from each family using a combination of targeted mutation screening and exome sequencing to identifiy the genetic cause of hearing loss in each family. We identified four variants in MYO15A, two novel variants never previously linked to deafness (c.7212+5G>A and p.Leu2532ArgfsTer37) and two recurrent variants (p.Tyr2684His and p.Gly3287Gly). One family showed locus heterogeneity, segregrating two genetic forms of hearing loss. Mini-gene assays revealed the c.7212+5G>A variant results in abnormal splicing and is most likely a null allele. We show that families segregrating the p.Gly3287Gly variant show both inter and intra-familial phenotypic differences. These results add to the list of MYO15A deafness-causing variants, further confirm the pathogenicity of the p.Gly3287Gly variant and shed further light on the genetic etiology of hearing loss in the Ashkenazi Jewish population.

Can population BRCA screening be applied in non-Ashkenazi Jewish populations? Experience in Macau population

BackgroundPathogenic mutation in BRCA genes causes high cancer risk. Identifying the mutation carriers plays key roles in preventing BRCA mutation-related cancer. Population screening has demonstrated its power for comprehensive identification of the mutation carriers. However, it is only recommended for the Ashkenazi Jewish population with high prevalence of three founder mutations, but not for non-Ashkenazi Jewish populations as the cost-effectiveness could be too low due to their lower mutation prevalence and lack of founder mutation. Population screening would not benefit the majority of the human population for BRCA mutation-related cancer prevention.MethodsWe used population BRCA screening in 6000 residents, 1% of the Macau population, an ethnic Chinese population with unique genetic, linguistic and cultural features, and its BRCA mutation has not been analysed before.ResultsWe called BRCA variants, identified 18 carriers with 14 pathogenic mutations and determined the prevalence of 0.29% in the population (95% CI 0.15% to 0.42%). We compared the testing cost between the Ashkenazi Jewish population, the Sephardi Jewish population and the Macau population, and observed only a few fold differences.ConclusionOur study shows that testing cost is not the most important factor in considering population BRCA screening, at least for the populations in the developed countries/regions, regardless of the status of mutation prevalence and founder mutation.

ACE2 coding variants in different populations and their potential impact on SARS-CoV-2 binding affinity

The susceptibility of different populations to the SARS-CoV-2 infection is not yet understood. A deeper analysis of the genomes of individuals from different populations might explain their risk for infection. In this study, a combined analysis of ACE2 coding variants in different populations and computational chemistry calculations are conducted in order to probe the potential effects of ACE2 coding variants on SARS-CoV-2/ACE2 binding affinity. Our study reveals novel interaction data on the variants and SARS-CoV-2. We could show that ACE2-K26R; which is more frequent in the Ashkenazi Jewish population decrease the electrostatic attraction between SARS-CoV-2 and ACE2. On the contrary, ACE2-I468V, R219C, K341R, D206G, G211R were found to increase the electrostatic attraction and increase the binding to SARS-CoV-2; ordered by the strength of binding from weakest to strongest. I468V, R219C, K341R, D206G and G211R were more frequent in East Asian, South Asian, African and African American, European and European and South Asian populations, respectively. SARS-CoV-2/ACE2 interface in the WT protein and corresponding variants is showed to be a dominated by van der Waals (vdW) interactions. All the mutations except K341R induce an increase in the vdW attractions between the ACE2 and the SARS-CoV-2. The largest increase of is observed for the R219C mutant.