Patient Care Situations Benefiting from Pharmacogenomic Testing

Purpose of Review Pharmacogenomics is an evolving area in precision medicine that aims to identify patients who have variable drug response, detect those at risk for developing adverse events, and guide drug dosing. Guidelines for optimization of PGx testing are available for a number of drug-gene pairs, and evidence supporting the clinical utility of this service is growing in specific patient contexts. This report reviews a variety of patient care situations in which evidence is emerging to show patient benefit from pharmacogenomic (PGx) testing. Recent Findings Preemptive PGx testing minimizes delays in treatment, reducing costs and time to therapeutic effect; however, preemptive testing is currently not feasible in all healthcare settings. Therefore, specific patient care situations that could benefit from PGx testing to be prioritized include medications requiring PGx testing, adverse drug reactions, therapeutic failures, polypharmacy, special populations, and specialty care settings such as cardiology, oncology, and psychiatry. Summary Although preemptive PGx testing is likely the best option for patient care, implementation challenges are impeding its uptake. PGx testing is beneficial and more feasible in certain patient situations and may be a starting point for implementation of PGx testing in a care setting. Continued efforts to evaluate patient and provider use and outcomes of PGx testing services will be helpful in informing the current evidence base and standard of care

Cone Responses in Usher Syndrome Types 1 and 2 by Microvolt ElectroretinographyCone ERGs in Usher Syndrome

PurposeProgressive decline of psychophysical cone-mediated measures has been reported in type 1 (USH1) and type 2 (USH2) Usher syndrome. Conventional cone electroretinogram (ERG) responses in USH demonstrate poor signal-to-noise ratio. We evaluated cone signals in USH1 and USH2 by recording microvolt level cycle-by-cycle (CxC) ERG.MethodsResponses of molecularly genotyped USH1 (n = 18) and USH2 (n = 24) subjects (age range, 15-69 years) were compared with those of controls (n = 12). A subset of USH1 (n = 9) and USH2 (n = 9) subjects was examined two to four times over 2 to 8 years. Photopic CxC ERG and conventional 30-Hz flicker ERG were recorded on the same visits.ResultsUsher syndrome subjects showed considerable cone flicker ERG amplitude losses and timing phase delays (P < 0.01) compared with controls. USH1 and USH2 had similar rates of progressive logarithmic ERG amplitude decline with disease duration (-0.012 log μV/y). Of interest, ERG phase delays did not progress over time. Two USH1C subjects retained normal response timing despite reduced amplitudes. The CxC ERG method provided reliable responses in all subjects, whereas conventional ERG was undetectable in 7 of 42 subjects.ConclusionsCycle-by-cycle ERG showed progressive loss of amplitude in both USH1 and USH2 subjects, comparable to that reported with psychophysical measures. Usher subjects showed abnormal ERG response latency, but this changed less than amplitude with time. In USH syndrome, CxC ERG is more sensitive than conventional ERG and warrants consideration as an outcome measure in USH treatment trials

Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes

BackgroundRecessive mutant alleles of MYO7A, USH1C, CDH23, and PCDH15 cause non-syndromic deafness or type 1 Usher syndrome (USH1) characterised by deafness, vestibular areflexia, and vision loss due to retinitis pigmentosa. For CDH23, encoding cadherin 23, non-syndromic DFNB12 deafness is associated primarily with missense mutations hypothesised to have residual function. In contrast, homozygous nonsense, frame shift, splice site, and some missense mutations of CDH23, all of which are presumably functional null alleles, cause USH1D. The phenotype of a CDH23 compound heterozygote for a DFNB12 allele in trans configuration to an USH1D allele is not known and cannot be predicted from current understanding of cadherin 23 function in the retina and vestibular labyrinth.Methods and resultsTo address this issue, this study sought CDH23 compound heterozygotes by sequencing this gene in USH1 probands, and families segregating USH1D or DFNB12. Five non-syndromic deaf individuals were identified with normal retinal and vestibular phenotypes that segregate compound heterozygous mutations of CDH23, where one mutation is a known or predicted USH1 allele.ConclusionsOne DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome.Accession numbersThe cDNA and protein Genbank accession numbers for CDH23 and cadherin 23 used in this paper are AY010111.2 and AAG27034.2, respectively