Secondary Reporting of G6PD Deficiency on Newborn Screening.

In April 2019, the Alberta Newborn Screening Program expanded to include screening for classic galactosemia using a two-tier screening approach. This approach secondarily identifies infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The goals of this study were (i) to evaluate the performance of a two-tier galactosemia screening protocol, (ii) to explore the impact on and acceptability to families of reporting G6PD deficiency as a secondary finding, and (iii) assess the communication and follow-up process for positive G6PD deficiency screening results. The two-tiered galactosemia approach increased the positive predictive value (PPV) for galactosemia from 8% to 79%. An additional 119 positive newborn screen results were reported for G6PD deficiency with a PPV of 92%. The results show that there may be utility in reporting G6PD deficiency results. Most parents who participated in the study reported having some residual worry around the unexpected diagnosis; however, all thought it was helpful to know of their child's diagnosis of G6PD deficiency. Finally, the communication process for reporting G6PD deficiency newborn screen results was determined to result in appropriate follow up of infants.

Whole exome sequencing reveals putatively novel associations in retinopathies and drusen formation.

Inherited retinal dystrophies (IRDs) affect 1 in 3000 individuals worldwide and are genetically heterogeneous, with over 270 identified genes and loci; however, there are still many identified disorders with no current genetic etiology. Whole exome sequencing (WES) provides a hypothesis-free first examination of IRD patients in either a clinical or research setting to identify the genetic cause of disease. We present a study of IRD in ten families from Alberta, Canada, through the lens of novel gene discovery. We identify the genetic etiology of IRDs in three of the families to be variants in known disease-associated genes, previously missed by clinical investigations. In addition, we identify two potentially novel associations: LRP1 in early-onset drusen formation and UBE2U in a multi-system condition presenting with retinoschisis, cataracts, learning disabilities, and developmental delay. We also describe interesting results in our unsolved cases to provide further information to other investigators of these blinding conditions.

Two-Year Results After AAV2-Mediated Gene Therapy for Choroideremia: The Alberta Experience.

PURPOSE: To assess the safety of a recombinant adeno-associated viral vector expressing REP1 (rAAV2.REP1) in choroideremia subjects. METHODS: Design: Phase I clinical trial. PARTICIPANTS: Six adult male subjects, 30-42 years of age, with genetically confirmed choroideremia (CHM) were enrolled. The eye with the worse vision, for all subjects, received a single subfoveal injection of 0.1 mL rAAV2.REP1 containing 1011 genome particles. Subjects were followed up for 2 years thereafter. OUTCOME MEASURES: The primary outcome measure was safety, determined by the number of ocular and systemic adverse events assessed by ophthalmic examination, spectral-domain optical coherence tomography (SD-OCT), and short-wavelength autofluorescence (FAF). Secondary outcome measures were the change from baseline in best-corrected visual acuity (BCVA) in the treated eye compared to the untreated eye, changes in visual function using microperimetry, and the area of retinal pigment epithelium (RPE) preservation by FAF. RESULTS: One subject had an 8-ETDRS-letter BCVA loss from baseline measured at 24 months, while 1 subject had a ≥15-letter BCVA gain. A similar improvement was noted in the untreated eye of another subject throughout the follow-up period. Microperimetry sensitivity showed no improvement or significant change up to 2 years after vector administration. The area of preserved RPE as measured by FAF was noted to decline at a similar rate between the treated and untreated eyes. One subject experienced a serious adverse event: a localized intraretinal immune response, resulting in marked decline in visual function and loss of SD-OCT outer retinal structures. CONCLUSIONS: One serious adverse event was experienced in 6 subjects treated with a subfoveal injection of AAV2.REP1. The area of remaining functional RPE in the treated eye and untreated eye declined at the same rate over a 2-year period. Fundus autofluorescence area is a remarkably predictive biomarker and objective outcome measure for future studies of ocular gene therapy in CHM subjects.