By Aaron Krol

October 28, 2013 | Each year, the American Society of Human Genetics convenes a meeting drawing together thousands of professionals from the field. As genetic testing begins to enter the realm of diagnosis, and gene therapy advances toward practical treatments for rare genetic diseases, many of the presenters at ASHG described research that pushes genetic science into real use in the clinic. Here are some highlights you may have missed:

Fang Chen (BGI-Shenzhen) reported on the results of large-scale clinical use of non-invasive prenatal testing (NIPT) in 49 Chinese clinics. Over 78,000 prospective mothers in these clinics received NIPT for three chromosomal disorders – trisomies 21, 18, and 13 – including 44,000 mothers considered to be at high risk for these disorders, and 12,000 at normal risk. (The remainder did not have medical records complete enough to make a determination.) While smaller-scale studies have shown these tests to be effective in high-risk populations, this much larger integration of NIPT into routine clinical practice was able to demonstrate specificity and sensitivity of over 99% for both populations in detecting trisomies 21 and 13. Sensitivity for trisomy 18 in the non-high-risk population was only 87.5%, but the very low prevalence of this disorder in the normal-risk population makes it more difficult to identify all true positives. Chen is confident that this large study demonstrates the reliability of NIPT even for non-high-risk mothers when screening for trisomies 21 and 13, alleviating the need for invasive and painful tests for these disorders.

Luk Vandenberghe (Harvard Medical School) demonstrated an effective gene therapy treatment for patients with Leber congenital amaurosis (LCA), a rare recessive disease causing retinal degeneration and blindness. Vandenberghe considered LCA a promising target for gene therapy using a viral vector, because the eye is accessible and amenable to non-invasive follow-up, and has a less robust immune response and low dosage requirements. Vandenberghe chose the AAV8 viral vector to deliver healthy copies of the RPE65 gene, implicated in LCA, into the retinal cells of affected individuals. While the effects were variable, certain patients experienced marked vision improvement within three months of treatment. In a remarkable demonstration of the therapy’s efficacy, an LCA patient with treatment in one eye was able to easily navigate a maze using the eye that received therapy, while failing to move through the maze with his treated eye covered.

Kelly Metcalfe (University of Toronto) presented a timely poster on the efficacy of preventive mastectomies in women with BRCA mutations. As BRCA1 and BRCA2 mutations are widely considered among the most actionable findings in any genetic test, understanding best courses of intervention can have immediate clinical relevance. Metcalfe’s team tracked the long-term survival rates of 390 women with BRCA mutations, comparing those who received double mastectomies against those who received only a single mastectomy, and found that over a twenty-year period, the cohort with double mastectomies experienced a 48% reduction in mortality.

Vandana Shashi (Duke University) attempted to define best practices for ordering next-generation sequencing (NGS) tests as diagnostic tools for unknown genetic disorders. Her study consisted of a retrospective chart review of 500 randomly-selected patients with no previous genetic diagnosis who underwent targeted genetic panels, quantifying the costs of each genetic test and comparing to the cost of NGS whole-genome or whole-exome sequencing. Shashi found that, of those patients who could be diagnosed, 72% were diagnosed as a result of the first clinical visit. Additionally, among the 28% diagnosed after the first visit, the mean cost of a diagnosis was $25,000, higher than the cost of NGS. Shashi therefore suggests that NGS tests are clinically indicated for patients who have already received one targeted genetic panel that did not result in a diagnosis.

Misha Angrist (Duke University) advocated the complete sharing of incidental findings with patients who undergo whole exome sequencing (WES) in any context, noting that in a poll at Duke of families who participated in WES projects, 24 of 25 families wanted to be notified of all clinically relevant findings, as well as favoring open communication with the researchers to understand those results. Acknowledging that the time burden on researchers to chase down and validate incidental findings can be considerable, Angrist suggested that top-down incentives need to be implemented to encourage researchers to help their study participants access any information they want on their genetic results.

Representatives from Baylor College of Medicine described the results to date of a two-year-old program offering whole exome sequencing on a diagnostic basis. A comprehensive analysis is now available of the 1200 cases handled between June 2012 and July 2013. Baylor has so far been able to diagnose approximately 25% of patients who pursue whole exome sequencing for unknown disorders, while discovering incidental findings in about 5% of cases. Baylor currently administers about 180 whole exome sequences each month.