Deborah Levenson

Federal plan to advance targeted disease treatment unclear on benefits for children with rare diseases

Unveiled last January, President Barack Obama’s proposed plan to advance patient-targeted medical treatments by collecting genomic information from one million American volunteers has not yet specified how, or if, it could benefit children with rare diseases. Listed as a

New testing guidelines for hearing loss support next-generation sequencing: testing method may help determine genetic causes of hearing loss among patients whose phenotypes are not easily distinguished clinically.

215 million expenditure in the president’s 2016 budget, the Precision Medicine Initiative has earmarked

Higher prevalence of immune deficiency syndrome found in infants: study finds nearly twice as many newborns affected by severe combined immunodeficiency than previous research had estimated.

130 million for the National Institutes of Health (NIH) to create a voluntary, national research cohort of one million or more individuals. Health data from these volunteers— who would be active participants with a say in how their information is used and shared—are expected to advance clinicians’ understanding of how genetic, environmental, and lifestyle factors

Dual testing strategy in autism increases diagnostic yield: Chromosomal microarray and whole-exome sequencing combination may be best for children with multiple physical anomalies, study suggests.

Updated guidelines from the American College of Medical Genetics and Genomics (ACMG) recommend that clinicians consider next-generation sequencing (NGS) when testing for genetic causes of hearing loss. The latest recommendations, which build on guidelines issued in 2002, include panel tests targeted at genes related to hearing loss, whole-exome sequencing (WES), and whole-genome sequencing (WGS) after negative results are returned on initial single-gene testing indicated by a patient’s family medical history and presentation. NGS may also be appropriate in cases that clinicians suspect are nonsyndromic and result from autosomal recessive inheritance, especially after negative results are returned on tests for mutations in the autosomal recessive DFNB1 locus for GJB2 or GJB6, according to recently published guidelines [Alford et al., 2014]. GJB2 and GJB6, which encode the proteins connexin 26 and connexin 30, respectively, account for the largest proportion of autosomal recessive early childhood hearing loss in many populations, the authors note. The new guidelines come in response to published studies that look at causes of hearing loss across the genome and large panel-based genetic tests, says coauthor Heidi Rehm, PhD, Director of the Laboratory for Molecular Medicine Partners Healthcare Center for Personalized Genetic Medicine in Cambridge, Massachusetts.

GENETIC TESTING USING ARRAY COMPARATIVE GENOMIC HYBRIDIZATION MAY BENEFIT NEWBORNS WITH CONGENITAL HEART DISEASE Study shows aCGH more effective at detecting potential genetic causes of CHD than other methods

Severe combined immunodeficiency (SCID) is far more common than previously thought, according to data from 11 U.S. newborn screening programs. SCID occurs in one of every 58,000 births, a much higher incidence than previous estimates of one in 100,000, according to a recent paper published in JAMA [Kwan et al., 2014]. Earlier estimates were based on retrospective clinical diagnoses of SCID. SCID encompasses a group of inherited disorders that cause severe abnormalities of the immune system. These abnormalities lead to reduced or malfunctioning white blood cells produced by the thymus gland and bone marrow to fight infection, known as T and B cells. While infants with the disease appear healthy at birth, SCID is fatal in the first two years of life without treatments to reconstitute their immune systems. Exposure to nonirradiated blood transfusions, live vaccines such as that for rotavirus, or common infections can be life-threatening for these children. The Department of Health and Human Services recommends that all state newborn screening programs include SCID. Currently, 24 states test for SCID, and 18 more plan to add the disorder to screening panels by the end of 2015, according to the Immune Deficiency Foundation of Towson, Maryland. Eight states have no plans yet to add the test. The study by Kwan et al. is the first to examine the incidence of SCID in the general population, the authors say. It shows that “screening for SCID is clearly worthwhile,” says Karin Chen, MD, Assistant Professor in the Pediatric Allergy, Immunology, and Rheumatology division at the University of Utah in Salt Lake City and Lead Immunologist for SCID in Utah’s newborn screening program.

Facial analysis technology aids diagnoses of genetic disorders: applications narrow down potential genetic syndromes by matching facial phenotypes to distinct set of possible genetic conditions.

Chromosomal microarray and wholeexome sequencing (WES) are both important tools for diagnosing genetic causes of autism, particularly in children with several physical anomalies, recent research shows. Writing in JAMA, a research team led by Stephen W. Scherer, PhD, of The Hospital for Sick Children in Toronto, Ontario, reports that the diagnostic yields of both tests are comparable but best when used together, especially in children with several physical anomalies (Tammimies et al., 2015). The researchers studied 258 children with autism spectrum disorder (ASD), grouped according to the number of physical anomalies found during exams by developmental pediatricians. Overall, 9.3% of the children got a diagnosis from microarray and 8.4% from WES. Among the 95 children that had both microarray and WES, the diagnostic yield was signifi cantly higher at 15.8%. Among children who had dual testing and the most physical anomalies, the diagnostic yield was 37.5%. “Our data suggest that medical evaluation of ASD children may help identify populations more likely to achieve a molecular diagnosis with genetic testing,” the researchers write.

Next-generation sequencing may reduce cost and wait time for some genetic diagnoses: Experts argue that clinical evaluation remains crucial

rray comparative genomic hybrid-ization (aCGH) should be offered as a first-tier genetic test in seriously ill newborns with congenital heart disease (CHD), according to a recent study.CHD is a birth defect that affects nearly 1% of live births and is frequently identified in surveillance programs [Reller et al., 2008]. Genetic factors often cause CHD, but newborns and older children with the condition who could benefit from genetic testing do not always receive it [Connor et al., 2013]. For patients with CHD in cardiac intensive care units (CICUs) who do, aCGH is preferable to chromosome analysis because it can detect more potential genetic causes, write researchers at the University of Pittsburgh in Pennsylvania [Bachman et al., 2013].In their study, Bachman and colleagues found that aCGH detected disease-causing mutations in 26.2% of 45 newborns with CHD admitted to the hospital’s CICU, while chromosome analysis found such mutations in just 9.4%, a difference of 22%. Additionally, aCGH testing detected 10 copy number variants that chromosome analysis did not.“Comparative genomic hybrid-ization has become our standard of care for babies with heart defects admitted to CICU,” says senior author Suneeta Madan-Khetarpal, Associate Professor of Pediatrics at the University of Pittsburgh School of Medicine.

Personalized medicine presents challenges and opportunities.

Facial analysis technology that is becoming easier to use and more accessible may help geneticists narrow down possible genetic diagnoses behind disorders that often involve dysmorphic facial features. Researchers at the University of Oxford in the United Kingdom have developed a computer application based on an algorithm that employs facial analysis technology to extract various phenotypic information about facial dysmorphisms from nonclinical photographs. The application uses machine learning, a type of artificial intelligence that learns from data instead of following explicit programmed instructions. It then builds a description of the face structure, known as the facial mesh, and compares it against data from other facial meshes in the system before delivering a list of possible genetic diagnoses. The algorithm becomes better at spotting facial phenotypes associated with a disorder as it analyzes more photos of faces with those specific features [Ferry et al., 2014]. In contrast to older facial analysis systems that rely on costly equipment to analyze three-dimensional (3-D) images, the Oxford-based researchers used easily accessible two-dimensional (2-D) photographs of children’s faces to analyze specific facial features that are associated with up to 40% of genetic disorders.

Cell-free fetal DNA tests appropriately used by geneticists, often misunderstood by patients: survey finds many patients incorrectly think prenatal screening test is diagnostic.

Next-generation sequencing (NGS) may speed some genetic diagnoses and save money, but it is a tool best used by an experienced clinician guided by a patient’s clinical presentation and previous workup, according to a recent study. That’s because geneticists often diagnose inherited conditions without NGS—which includes advanced methods that can retrieve data from hundreds of genes at once—or results from older genetic tests. Researchers from Duke University in Durham, North Carolina did a retrospective review of 500 unselected, consecutive pediatric and adult cases seen at a Duke University Medical Center genetics clinic. Of the 500 patients, 46% were diagnosed by either clinical evaluation alone or an evaluation followed by targeted genetic testing at Duke. An overwhelming majority (72%) of these patients received a diagnosis at their first visit to the clinic, without any genetic testing, write researchers in a recent Genetics in Medicine article [Shashi et al., 2013]. Obtaining a genetic diagnosis for a patient who had to return for subsequent visits cost them an estimated

New test catches most Turner syndrome cases.

25,000, a figure that includes genetic tests [Shashi et al., 2013]. An earlier study of a wholeexome sequencing (WES) pilot program conducted at Duke produced a diagnostic yield of 50% [Need et al., 2012]. Shashi et al referred to that study to estimate that using NGS after the first clinical visit could save about