Editor's Choice

Frontline clinicians are unprepared to use genetic testing, raising demand for genetics providers

In the United States, medical genetics professionals are few and far between. Primary and non-genetics specialty care practices are increasingly confronted with patients who may benefit from genetic testing. In many cases, frontline clinicians are responsible for identifying patients that could benefit from genetic testing, ordering tests, interpreting results and communicating with patients about each aspect of the testing process. But a study published recently reveals that frontline clinicians rarely use genetic testing and are unprepared to do so.

Maren Scheuner and colleagues conducted a web-based survey to better understand the readiness of frontline clinicians within the Department of Veterans Affairs (VA) to use genetic services in clinical practice. The researchers emailed a survey link to clinicians with precision oncology expertise working at 20 VA facilities between August and September 2020 to participate in the survey. About 900 physicians, nurse practitioners, pharmacists and physician assistants completed the survey. Only one fifth of respondents reported feeling prepared to use genetic tests with just 13% currently ordering genetic tests. Common reasons for not ordering genetic tests included not believing that genetics is relevant to their practice, or uncertainty about the relevance, not knowing how to order or preferring to refer to genetics or other specialists. Indeed, most respondents indicated that they would prefer to refer all or some of their patients to genetics or have a genetics provider embedded in their clinic to facilitate genetic testing; yet fewer than a third had referred a patient to genetics in the past year. The most common reason for not referring patients to genetics was that they do not yet need advice from genetics. The findings suggest that many frontline clinicians lack awareness about genetic tests, are unprepared to use them and as such are not proactively recognizing patients who may benefit from genetic testing. Yet, encouragingly, about half to two-thirds of respondents were interested in learning about basic genetic concepts, common genetic disorders, types of genetic testing methods and other clinical aspects of genetic testing, including interpretation of results and genetic counseling topics.

Scheuner and colleagues conclude that genetics education is fundamental to frontline clinicians’ use of genetic tests and that the demand for genetics providers should increase as frontline clinicians integrate genetics into their practice. The findings should be considered not only in the education and training of frontline clinicians but also in workforce planning. – V. L. Dengler, News Editor

FOXI3 variants cause microtia and craniofacial microsomia

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet the genetic causes behind the spectrum of disorders are largely unknown. Many genes have been implicated in malformation of the ears or mandible, but most CFM cases are sporadic and the genetic cause remains unknown. Now, Daniel Quiat and colleagues have identified FOXI3 as a causative gene. The researchers performed genome sequencing and linkage analysis in patients with microtia and CFM and their families from two independent cohorts including a 5 generation kindred with microtia. The kindred included 5 affected individuals, 4 of whom underwent genome sequencing (GS). The researchers first used ultrarare biallelic single nucleotide variants (SNVs) to identify haplotypes shared by the 4 affected individuals and mapped 7 shared genomic intervals. They then assessed damaging SNVs, indels and genomic structural variants in or near those intervals to identify 2 missense variants in FOXI3 and PTCD3. FOXI3 is a transcriptional regulator of ectodermal development that plays a crucial role in ear development in mice. It is also associated with congenital ear malformations in dogs. When the researchers expressed the gene variant in cultured cells, they saw that wild-type FOXI3 protein localized to the nucleus, whereas FOXI3 p.Arg236Trp formed punctate signals in the cytoplasm. The team then analyzed exome sequencing and GS data from more than 400 additional kindreds to identify 3 additional families with novel FOXI3 damaging variants. Together the results implicate FOXI3 variants as a genetic cause of CFM, responsible for about 1% of cases in the cohort analyzed. The data thus support genetic testing for FOXI3 variants in patients with grade II/III microtia with atresia and add FOXI3 to the list of identified monogenic causes of microtia-CFM spectrum disorders. – V. L. Dengler, News Editor

A fully automated interpretation system for heritable thoracic aortic aneurysm

The vast majority of patients with a life-threatening condition called thoracic aortic aneurysm and dissection (TAAD) don’t have symptoms before catastrophic complications such as dissection and rupture may occur. When complications do occur, approximately a quarter of patients die before reaching the hospital. However, when recognized early enough to undergo surgery, patients have excellent survival rates with limited complications. To prevent such devastating events, early detection and diagnosis are critical. Although TAAD is challenging to detect based on symptoms alone, genetic testing can facilitate a definitive diagnosis and also help to identify at-risk relatives. Variant interpretation is a crucial but challenging step in this process. To improve reliability and efficiency of genetic testing in heritable TAAD (HTAAD), Wei-Zhen Zhou and colleagues developed an unbiased and fully automated system for TAAD variant interpretation and HTAAD molecular diagnosis called HTAADVar. To create HTAADVar, the researchers constructed a variant database that integrated expert panel recommendations and metadata from research publications, in-house sequencing data, and public datasets. They further developed an interpretation system using the American College of Medical Genetics and Genomics and Association for Molecular Pathology variant interpretation guidelines to assess variants automatically. When tested, HTAADVar showed multifold higher sensitivity and specificity than other public tools and produced a diagnostic yield in a real sequencing cohort that was comparable to manual interpretation and previous reports. For ease of use, the authors built a web server with an interactive and user-friendly interface, featuring powerful browse, search and variant interpretation functions. Stand-alone programs are also available for customized interpretations and generalization of the HTAADVar framework to other diseases. The authors conclude that HTAADVar is the first fully automated system for accurate variant interpretation for HTAAD, and that its framework and methodologies could substantially improve standardization for the molecular diagnosis of genetic diseases. – V. L. Dengler, News Editor

Tracking the progression of an ultra-rare and debilitating disease

Rare conditions often have high unmet medical needs. Comprehensive natural history studies are critical to understanding such diseases, especially ultra-rare conditions, and providing optimal care for patients. The autosomal dominant genetic disorder fibrodysplasia ossificans progressive (FOP) is an ultra-rare genetic condition caused by spontaneous missense variants in the activin A receptor type 1 gene (ACVR1). ACVR1 encodes a receptor that increases bone morphogenetic protein signaling, leading to the hardening of soft tissues such as muscles, tendons and ligaments into bony substances, a process called heterotopic ossification (HO). HO leads to painful flare-ups. Recurrent HO flare-ups start in childhood and progressively restrict movement. Individuals with FOP become increasingly immobile. Most patients need to use a wheelchair by the time they are in the 20s and require assistance in activities of daily living. Complications of the disease including stiffening of the jaw and the muscles and joints that assist in breathing, leading to markedly shortened life expectancy. In this article, Robert Pignolo and colleagues followed the progression of an initial cohort of more than 100 individuals with FOP from around the world. About a third of participants completed the 3-year study. The researchers tracked participants’ flare-ups over the course of the study. They imaged flare-ups at onset and about three months later to examine the extent of ossification using whole-body computed tomography scans. The researchers also examined pulmonary function and completed medical histories, tracked adverse events, and assessed participants for suicidal ideation. During the study period, the majority of participants (72%) experienced at least one flare-up. Participants between 2 and 8 years-old reported the highest proportion of flare-ups. Flare-ups commonly occurred in the upper back, hip, shoulder, and lower spine and abdomen. HO was already visible by imaging on the first day of the flare-up in most cases. Participants most commonly reported pain and soft tissue swelling with flare-ups. Most were treated with systemic corticosteroids. New HO appeared to progress from the upper to lower body with age. Adolescents and young adults experienced the greatest mean volume of new HO per year. Many participants experienced restricted chest expansion, hearing loss and depression as well as suicidal ideation. Altogether, the natural history study identified new HO as a clinically meaningful endpoint, enabling clinicians to measure FOP progression over time. The authors conclude that such data will be vital to designing and implementing potential therapeutics for individuals with FOP. – V. L. Dengler, News Editor

Monotherapy radically improves pediatric PIK3CA-associated head and neck overgrowth conditions

Head and neck overgrowth conditions can cause life-threatening complications. Overgrown tissues in this region of the body can compress or narrow the airway leading to respiratory distress, sleep apnea, and even death. Complications involving the tongue, mouth, ears, and bones of the face and skull also arise with these conditions. Surgical and other invasive interventions have been the central component of treatment. However, current therapeutic strategies are often insufficient to completely remove all affected tissue and can also lead to disfigurement. Yet, variants in a gene called PIK3CA underlie many head and neck conditions including head and neck lymphatic malformations (HNLM) and PIK3CA-related overgrowth spectrum (PROS), indicating that targeted therapies may benefit patients with these conditions. Here, Tara L. Wenger and colleagues report a prospective study treating 5 children with PIK3CA-associated HNLM and facial infiltrating lipomatosis with a PIK3CA inhibitor called alpelisib. Participants underwent baseline contrast head and neck magnetic resonance (MR) imaging and clinical three-dimensional photography before starting treatment. Then they took a daily dose of 50 mg by mouth while keeping a diary of symptoms and medication adherence. They also underwent monthly laboratory testing and additional 3D imaging every 3 months and MR imaging every 6 months. All participants stuck with the therapy for at least 9 months. They did not report any adverse events with the exception of one participant whose pre-existing eczema worsened while taking the therapy. The daily monotherapy treatment led to significant facial volume reduction in all participants. For a participant born with the left face larger than the right, facial asymmetry nearly normalized within 11 months on therapy. For another participant, facial malformation volume decreased by 23% over 10 months. This participant’s oral swelling subsided and their tongue size and mobility approached normal, leading to improved speech production and ease of understanding. The treatment helped stop drooling in another participant and led to normalized speech, as well as hearing and airway patency. Taken together, the study shows that alpelisib ameliorated many complications of head and neck PIK3CA-associated conditions in pediatric participants without significant adverse events suggesting that this monotherapy may have wide therapeutic benefits for this population though studies of additional children are warranted. – V. L. Dengler, News Editor

Treatment with flavanol supplement is safe in children with Down syndrome

Compounds derived from plants such as polyphenols are increasingly being recognized for their medicinal potential. A recent clinical study in young adults with Down syndrome (DS) showed that treatment with a flavanol from green tea called epigallocatechin gallate (EGCG) combined with cognitive training was not only safe but also improved cognition. Yet whether use of the supplement in children with DS is safe is still unknown, and there is concern about liver toxicity with EGCG supplementation. Now, Ce?cile Cieuta-Walti and colleagues evaluate the safety and tolerability of a dietary supplement enriched with EGCG in children aged 6 to 12 years with DS. The researchers recruited more than 70 participants for a Phase Ib randomized, double-blind, placebo-controlled, parallel-groups study. Caregivers administered to participants a chocolate flavored powder diluted in water that contained either the dietary supplement or a placebo twice a day for 6 months with dosage established by body weight up to a maximum dose of 400 mg. About a third of patients in both the treatment and placebo groups experienced treatment-emergent adverse events. Nearly all adverse events were mild with 3 severe adverse events seen only in the placebo group. Treatment did not affect liver or renal function, or produce cardiotoxicity or neurophysiological changes in participants. A similar number of participants in the treatment and placebo groups showed changes in thyroid stimulating hormone levels, suggesting no increased thyroid-related toxicity from EGCG supplementation. Altogether, the results indicate that EGCG treatment was well tolerated by participants. Yet, despite its safety, the researchers did not observe improvements in cognition in the EGCG group compared with placebo. They did, however, see a gender interaction. Girls that received EGCG showed global improvements in executive functioning, working memory and planning skills and quality of life. This result was not seen in boys. The authors conclude that dietary supplementation with EGCG up to a dose of 400 mg per day is safe and well tolerated in children with DS aged 6 to 12 years. However, as no improvements in cognitive or functional outcomes were seen over the treatment period, EGCG supplementation in children with DS is not yet clinically justified without further research. – V. L. Dengler, News Editor

New AI identifies monogenic disease patient cohorts from clinical notes

Identifying patients to build a cohort is laborious and time-consuming. Yet, patient cohorts help to put evidence-based medicine into practice and improve diagnosis and clinical care, especially in regard to monogenic diseases. To make finding molecularly confirmed monogenic disease patients for cohort-building more efficient, David Wei Wu and colleagues present MonoMiner, a natural language processing tool that automatically identifies confirmed monogenic disease patients directly from clinical notes. The authors first established a curated database of monogenic diseases and their causative genes using the Online Mendelian Inheritance in Man compendium. Then they introduced MonoMiner. The artificial intelligence (AI) works by searching through sentences in clinical notes for diagnosis information. It then classifies sentences based on the presence of positive trigger words such as “diagnosis” and the absence of negative trigger words such as “normal.” It performs a similar search for gene names and their synonyms within sentences. The process identifies patients with a potential monogenic disease diagnosis and associated causative gene. Using de-identified patient medical records from the Stanford Research Repository clinical data warehouse, MonoMiner achieved nearly 90% “clinically diagnosed” and 80% “molecularly confirmed” precision. The AI outperformed other methods of searching clinician notes, such as using International Classification of Disease codes to retrieve patients, and flagged more than 4,000 patients covering some 560 monogenic diseases and more than 500 causal genes. The authors call the results a “treasure trove.” Wei Wu and colleagues conclude that MonoMiner provides an efficient means of accurately discovering large cohorts of monogenic disease patients with an established genetic diagnosis. They also note that because the AI relies completely on clinical notes, the tool is highly portable and adaptable to other search queries. – V. L. Dengler, News Editor

Variants in fetal brain development gene lead to novel neurodevelopmental disorder

Amid the flurry of publications on the novel coronavirus in 2020, a dedicated team of researchers also reported on an individual with trigonocephaly, speech delay and autism spectrum disorder. The patient harbored a small de novo deletion in a gene known as ZMYND8 that was predicted to result in a frameshift. ZMYND8 encodes a large, multidomain zinc-finger protein involved in transcriptional regulation. Its expression occurs across the brain, and in particular, during a critical window in early fetal development. Variants in related gene family members, notably ZMYND5 and ZMYND11, are known to result in intellectual disability. The study implicated a role for ZMYND8 in brain development. Now, in this issue, Kerith-Rae Dias and an international team of colleagues report that variants in ZMYND8 cause a novel neurocognitive disorder. The researchers identified an additional 10 unrelated individuals with ZMYND8 variants. Variants in 10 of the 11 individuals were de novo with 9 missense and 2 truncating variants. Individuals harboring the variants presented with intellectual disability as well as variable cardiovascular, ophthalmologic and minor skeletal anomalies. The researchers probed the identified variants via molecular modeling, protein-protein interaction assays, and analysis of RNA sequencing data from more than 500 fetal and postnatal brain samples. The analysis revealed that all of the missense variants were heterozygous and in locations intolerant to variation and disrupted interactions with key molecular players involved in chromatin remodeling and nuclear localization. Neuronal knockdown of ZMYND8 in fruit flies disrupted the insects’ ability to adapt to and filter out meaningless stimuli, a form of learning known as habituation that is necessary for advanced cognitive function. Dias and colleagues conclude that de novo heterozygous variants in ZMYND8 lead to a novel monogenic neurodevelopmental disorder. – V. L. Dengler, News Editor

How to best counsel patients with genetic prion disease

An epidemic of mad cow disease in the 80s and 90s made prion disease something of a household name. The fatal neurodegenerative disorder advances rapidly. Within 6 months, most patients develop a progressive dementia, as abnormally shaped prion proteins accumulate in their brains and render the tissue with a characteristic sponge-like appearance. Few survive two years beyond the first symptoms.

Most arise sporadically without a known genetic or environmental cause. Yet, about 10% to 15% of cases are truly genetic, the result of variants in a gene called PRNP that encodes for the prion protein. The possibility of a genetic cause can shock patients and their families and finding providers ready and able to provide counseling around such news can present a challenge.

In this issue, genetic counselor Jill Goldman and research scientist Sonia Vallabh, who lost her mother to the disease and is a carrier of the deadly variant, provide updates and recommend best practices for counseling patients and families with genetic prion disease.

The authors outline the array of currently known genetic forms that prion disease can take as well as the diversity of potential presentations, especially early in the course of the disease. Patients from the same family and even identical twins have shown different signs and symptoms and vary in age of disease onset. Goldman and Vallabh note that counseling patients and families about this mismatch may help to avoid confusion.

They also point out that despite the disease’s rarity, it is well-characterized and abundant resources to aid counseling exist. They outline what topics to include and what questions to ask during informal and predictive genetic counseling sessions, and recommend working in a multidisciplinary team that includes a neurologist, genetic counselor, and social worker. Altogether, the authors aim to provide an update on the genetics of and genetic counseling for prion disease to equip providers with the information and resources to expand these necessary services. – V. L. Dengler, News Editor

Clinicians “cheat the system” to provide patients with comprehensive benefits

Genomic sequencing (GS) offers a host of benefits to patients and their families. Yet, policymakers and health plans typically prioritize diagnosis and clinical management in decisions about reimbursement for patient testing. As a result, research on GS’s usefulness often overlooks the full scope of benefits that such test results provide. Salma Shickh and colleagues wanted to address this gap and dive deeper into GS’s full range of benefits. To do so, the researchers interviewed more than two dozen Canadian clinicians working across a variety of specialties. The conversations revealed that similarly to decision makers, clinicians also value diagnosis and management the most. However, the surveyed clinicians highlighted GS results’ additional benefits such as the psychological relief of ending the diagnostic odyssey, informing reproductive decisions, and accessing community support as important. Yet, clinicians felt they had to “cheat the system” to obtain GS and provide their patients with these other benefits. They devised workarounds to gain access to GS for their patients such as relying on the patient to enroll in research studies or ordering a less comprehensive gene panel test first and then banking on commercial labs to offer GS for free after a negative result. Although the workarounds benefited patients, the clinicians acknowledged that they came at a cost. The workarounds were burdensome for clinicians and support staff, drove inequity in access to testing, and undermined patient care. Shickh and colleagues conclude that current policies and funding structures undervalue the real-world benefits of GS. This undervaluation ultimately jeopardizes patient care. The authors call for an expanded definition of clinical utility as well as further research to quantify the additional benefits of GS beyond diagnosis and clinical management. – V. L. Dengler, News Editor

For novel disease gene discovery is a gene-based approach better?

The number of disease genes that clinicians can test for is on the rise. Yet as much as 70% of patients with rare diseases are still without a definitive molecular diagnosis. One roadblock may be the approach, according to a new article in this issue. Molecular diagnosis typically uses a patient-to-gene approach that relies on clinical genetic testing via single gene or multigene panel testing or exome or genome analysis. But patients’ pathogenic variants may not be included in the test that is ordered or haven’t yet been associated with disease. The result is an unmet need for approaches to identify novel disease genes and their associated phenotypes. Here, Eleanor G. Seaby and colleagues challenge the patient-to-gene paradigm and instead propose a gene-to-patient approach by applying a filtering strategy across a large cohort to identify and assign rare, presumed pathogenic variation in predicted disease genes to patients. The researchers first filtered a large-scale database for high-confidence, rare, de novo predicted loss-of-function variants in genes with the highest probability of representing an autosomal dominant disease. Then, using data from the 100,000 Genomes Projects, they matched these variants to patients with associated phenotypes. Applying the strategy to nearly 14,000 trios revealed 168 novel disease genes that currently have no known disease-gene relationship. For close to 20 of these genes, multiple kindreds showed overlapping phenotypes. Subsequent analyses confirmed that more than half of these genes have indeed been validated and confirmed as causing disease. Now nearly 20% of genes identified in the study have provided diagnoses to patients who would have otherwise had a negative test result report. The authors conclude that when combined with large cohorts, gene-based approaches can rapidly accelerate the discovery of dominantly inherited novel disease genes by zeroing in on the most appropriate genes for functional validation. – V. L. Dengler, News Editor

Enzyme replacement therapy could transform lives of patients with sometimes fatal disorder, clinical trial results show

Without enough of the enzyme known as acid sphingomyelinase (ASM), patients lose the ability to properly metabolize complex lipids, leading to symptoms affecting the brain, spleen, liver, bone marrow and lungs. Historically known as Niemann-Pick disease, ASM deficiency (ASMD) is a rare, sometimes fatal disorder caused by recessive variants in SMPD1. Advanced lung disease, liver failure, and bleeding are serious complications in adults with the chronic form of ASMD. Currently, there is no disease-modifying treatment available for ASDM. The only management option is supportive care. However, an enzyme replacement therapy using a recombinant enzyme called olipudase alfa is in development to treat the disease. In open-label clinical trials, olipudase alfa alleviated major symptoms including reducing sphingomyelin storage and enlarged organs and improving lung and liver function in chronic ASMD. Now, Melissa Wasserstein and an international group of colleagues report the results of a randomized, placebo-controlled trial to see if the enzyme replacement therapy was helpful for adults with chronic ASMD. A total of 36 adults participated in the trial. Patients were given either the new enzyme or a placebo every two weeks in an escalating dosage up to 3 mg/kg. Over the course of one year of treatment, the therapy improved lung diffusing capacity and spleen and liver volumes better than the placebo treatment. In addition, treatment did not cause any serious adverse events and all patients were able to complete the trial. Wasserstein and colleagues conclude that olipudase alfa treatment can clear sphingomyelin from organs and at least partially reverse the clinical features of chronic ASMD. Furthermore, improvements in lung and liver function should lead to a decrease in disease burden, which could improve survival for these patients. Overall, the treatment has the potential to transform the lives of patients with ASMD, according to the authors. – V.L. Dengler, News Editor

Reporting practices vary substantially across laboratories

Across medical specialties, genomic sequencing is on the rise. However, few studies have evaluated whether different laboratories are consistent in their reporting practices. To address this gap, Danya Vears and colleagues invited more than 40 labs from across the globe to analyze sequencing data from a virtual patient and issue a standard report to the research team as if it were the referring clinician. The referring team created a virtual patient-parent trio by inserting 8 variants from patients into ‘normal’ exomes, 2 of which were relevant to the developmental delay and dysmorphic features present in the patient and her mother. Two other variants could have accounted for cardiac symptoms but could have been considered secondary findings, while the 4 remaining variants were unrelated to the patient’s phenotype, but would prove challenging for filtering and reflect different types of inheritance patterns. The researchers also provided the labs with a clinical history including details of the virtual patient’s phenotype and information about the parents and other family members that corresponded with the merged variants. Participating labs analyzed the data using their normal procedures and completed a reporting decisions questionnaire evaluating their rationale for reporting and classification of the variants. Overall, reporting varied substantially between participating labs. Although most labs used a standard variant classification system, only about three-quarters clearly stated the classification of all reported variants and few listed ample evidence supporting variant classification. Just over half of participating labs correctly listed the patient/parent identification information on the reports, while just less than half indicated which filtering strategies they used or provided quality control statistics and technical information on their reports. The reports also revealed differences in the comprehensiveness of exome analysis and whether the analysis was performed as a trio or as a singleton, the pathogenicity predictions of reported variants and whether the type of variant fits with known variant types associated with a particular genetic disease. The authors conclude that the extensive variability identified in the information that labs included in their reports suggests that existing reporting guidelines are not used consistently. In the hopes of improving patient care, Vears and colleagues plan to use the reports from this study together with current reporting guidelines to develop a template report for labs to use in the future. – V. L. Dengler, News Editor

Cardiologists feel unprepared to use genetics in practice

Although cardiovascular care providers recognize the benefits of genetics and genetic testing in patient care, recent studies suggest that many providers lack adequate preparation to use genetics in patient care. As part of a large study to develop an educational program about genetics advances in sudden cardiac death, Courtney Scherr and colleagues explored how, via qualitative interviews, cardiovascular care providers currently integrate genetic testing in their practice, as well as their interest in using genetics in cardiac care and their preferences for cardiovascular genetics education. Two investigators phone interviewed more than 40 cardiovascular care MDs and advanced practice nurses. The interviews revealed that although providers were generally optimistic about the clinical utility of genetic testing in cardiovascular care, participants’ perceived limitations of their current knowledge of genetics combined with the rapid changes in genetics science dampened their motivation to use genetics and genetic testing in their practice.

Access to a genetics expert, however, was especially helpful in motivating practitioners to use genetic testing, especially when a genetic counselor with cardiology expertise had a physical presence in the clinic. Participants with direct access to genetic counselors said they found it easy to reach out to them with questions. In contrast, those without direct access to a genetic counselor described thinking about genetic testing or referring for genetic testing less often. When asked about what could improve participants use of genetics in practice, additional education was often the answer, though practitioners did not want to become genetics experts as this was seen to be outside of their scope of practice. Participants instead desired easily accessible tools or care guides to reference when a patient presented with an indicative phenotype or received a positive test result, as well as more frequent educational briefs on genetics advancements to keep apace of the field. They were also amenable to short lectures presented by genetics experts within their own clinic or organization who could discuss relevant processes. Taken together, the interviews indicated that cardiovascular care providers value the benefits of genetics and genetic testing in patient care, and that additional training and access to a genetics expert would keep genetics top of mind and facilitate using genetics in their practices. – V.L. Dengler, News Editor

The true prevalence of Lynch syndrome in colorectal cancer patients may be higher than current estimates, according to a new systematic review

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, with an estimated worldwide prevalence of 2% to 3%. However, most prevalence studies have only included 500 or fewer patients and CRC screening for LS varied substantially, leading to a wide range of prevalence estimates. To get a better handle on the true prevalence of LS in CRC patients, Nadine Abu-Ghazaleh and colleagues conducted a systematic review and meta-analysis of the literature published in the last 22 years. Altogether, the review included more than 50 studies encompassing nearly 50,000 participants with CRC across 18 countries.

The team found an overall pooled prevalence of germline pathogenic variants of 2.2%, a proportion that was highly similar across multiple geographic, ethnic, and clinical populations and matched the generally reported worldwide estimate. However, Abu-Ghazaleh and colleagues believe that this overall prevalence finding is an underestimate, and that the true prevalence of LS in CRC patients is closer to 5%, an estimate that came out of studies reporting universal germline testing without tumor testing. Studies that performed universal germline testing had the highest overall prevalence of the studies analyzed, followed by studies that used recommended practices of diagnosis at 2.5%. The researchers found the lowest prevalence (1.1%) in studies that performed germline tests for patients with microsatellite unstable tumors. In accordance with the findings, the authors recommend universal germline testing for all newly diagnosed patients with CRC without the use of tumor-based triage as this approach will detect more cases of CRC with LS without excessive cost, and yield surveillance and prevention benefits. The authors conclude that while the results support universal germline CRC screening for LS, the findings, along with the cost-effectiveness of the strategy, should be confirmed with future studies, warranting future large-scale epidemiological studies of LS prevalence. – V. L. Dengler, News Editor

How to interpret germline variants for hematopoietic malignancies? New guide may help

Sequencing technology has exploded in the last two decades. With this explosion, genetic testing and the discovery of new candidate genes also skyrocketed, leading to challenges in variant interpretation. To overcome these challenges, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) presented in 2015 standards and guidelines for interpreting and classifying germline sequence variants identified in Mendelian disorders. Although they have served as an important framework for standardizing variant interpretation, the guidelines are inherently broad. In the last 7 years, working groups have made efforts to refine the criteria to be more user-friendly and specific for particular genes and diseases. While beneficial, these efforts are arduous and take time to publish. Meanwhile, germline predispositions to diseases are becoming more and more recognized. Germline variant interpretation for hematologic conditions is fraught with challenges. More than 200 genes are associated with germline predispositions to hematopoietic malignancies, bone marrow failure, and prolonged cytopenias, for example, but formal curation “rules” only exist for a few of them. This is due to challenges such as overlapping phenotypes, different inheritance patterns and mechanisms of disease, and a dearth of case-control studies on germline variants conferring risk for these conditions. Simone Feurstein and colleagues outline recommendations and tools to more specifically curate ACMG/AMP rules for classifying sequence variants involved in hematopoietic malignancies, bone marrow failure, and cytopenias. The researchers drew on a variety of methods including calculating minor allele frequency thresholds, quasi-case-control studies, counting probands, and comparing in silico predictors for missense and splicing variants. They found that all 28 ACMG/AMP rules can be modified in a gene- or disease-specific manner and/or by strength level, and they present practical recommendations based on criteria with high strength levels, are easy to specify, or provide a quick assessment. Given the ever-evolving nature of sequencing technology and discovery of new candidate genes, the authors acknowledge that these recommendations and guidelines will change over time as more data becomes available. They hope that the guide can help to ease the challenges of variant interpretation for inherited hematopoietic malignancies, bone marrow failure, and cytopenias by providing a framework for customizing some of the ACMG/AMP rules. – V. L. Dengler, News Editor

Sudden unexpected death in infants and children may be genetic

More children and infants in the US die from sudden, unexpected or unexplained death than from cancer and heart disease. Sudden unexpected infant death (SUID) or sudden unexplained death in children (SUDC) tends to affect little ones who are otherwise apparently healthy, often while they’re sleeping. Although the Safe to Sleep campaign, formerly known as the Back to Sleep campaign, lowered the risk of SIDS, rates have remained nearly the same since the introduction of the program. More recently, a consensus is emerging from the medical and research communities that SUID and SUDC, collectively known as sudden unexpected death in pediatrics (SUDP), is a diverse group of rare and undiagnosed diseases that sometimes have genetic underpinnings. The current model suggests that, especially for vulnerable infants and children, such as those born prematurely or exposed to alcohol or tobacco in the womb, modest extrinsic threats become fatal. In a recent study out of the Robert’s Program on SUDP at the Boston Children’s Hospital, Hyun Yong Koh, Alireza Haghighi, and colleagues add further proof that genetics contribute to SUDP. The research team performed exome sequencing on close to 300 cases and more than 70 parent-child trios, analyzing nearly 300 variants likely related to SUDP. For probands with trio data, they also performed an exome-wide analysis for rare, damaging variants. Along with detailed phenotypic interrogations involving parent interviews, autopsy reports, medical records and history, and physical findings, such as abnormalities in the hippocampus associated with seizures and epilepsy, the team identified genetic evidence for SUDP in 11% of the cases they assessed. When the researchers compared cases with control subjects, they additionally found an excess burden of rare, damaging SUDP variants. Despite the evidence they present, the authors acknowledge that genetics did not explain the majority of cases they examined and that more cases are needed to verify the associations they found. They therefore conclude that their findings provide strong genetic evidence for SUDP, while simultaneously highlighting the need for future investigations. They advise that when possible, a comprehensive genetic evaluation should be part of assessing SUDP cases. – V. L. Dengler, News Editor

RNA diagnostics reclassifies 75% of putative splice variants

Many genetic variants that cause disease occur in coding regions of the genome. But perhaps as much as half of disease-causing variants occur in regions involved in splicing of pre-messenger RNA. Splicing variants represent challenges to diagnostic classification. For example, splicing variants lacking the conserved essential splice site are classified as variants of uncertain significance. Predicting whether a genetic variant will disrupt splicing is difficult to know for certain without testing the spliced messenger RNA’s impact on the encoded protein. Although the use of RNA sequencing is improving diagnostic yield for some genetic disorders, many genes in the Online Mendelian Inheritance in Man (OMIM) database are not expressed at high enough levels in accessible patient tissues to confidently predict splicing outcomes. As part of the Australasian Consortium for RNA Diagnostics (SpliceACORD), Bournazos and colleagues present in this issue standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using RNA from patient samples easily accessible in the clinic, including blood, skin fibroblasts and urine. The researchers recruited more than 70 families with an array of monogenic conditions from across Australia and New Zealand to participate in the study. Then they performed reverse transcription PCR and Sanger sequencing on nearly 130 individuals, encompassing about 80 splicing variants. Using the newly devised practices, Bournazos and colleagues were able to obtain RNA assay data for nearly all cases, which enabled them to reclassify three-quarters of variants and provide a genetic diagnosis for nearly two-thirds of the cases they examined. The authors conclude that PCR-based RNA diagnostics can be used to analyze most clinically significant genes and they provide standardized protocols and recommendations for interpreting RNA assay data. – V. L. Dengler, News Editor

Summer Genetics Scholar Program: Success, Failure, or Too Early to Tell?

The MD clinical geneticist workforce is in short supply. One way to increase interest in medical genetics and genomics among medical trainees is early exposure. With this in mind, the ACMG Foundation for Genetic and Genomic Medicine began a program in 2011 to offer medical students exposure to the field through the Summer Genetics Scholars Program. The 6-week program is mainly about clinical experiences, but also includes a research component. Blatt and colleagues conducted a survey study to assess whether the program is meeting its goal of increasing interest in clinical genetics careers and to gather feedback on how to improve the program in the future. The researchers reached out by email to more than 100 former scholars who completed the program between 2011 and 2016 and have since begun residency for feedback. More than 50 former scholars completed a 13-question survey about the program via the online platform, SurveyMonkey. Most participants indicated that they completed the program because they were interested in learning more about medical genetics and genomics, rather than in fulfillment of a school requirement, and nearly all were either very satisfied or satisfied with their program experience. The vast majority of participants also indicated that they use knowledge from the summer experience in their current field. Nearly half of participants indicated that the program influenced their residency choice. However, the number of survey participants who were considering a career in medical genetics and genomics before and after the scholar program dropped by 10%. Participants revealed that they would like more structure and more research experience to be a part of the program. Because data are currently only available for 6 years, Blatt and colleagues conclude that it might be too early to assess the true influence of the Summer Genetics Scholars Program on entry into the field because many physicians choose a primary specialty before doing formal training in medical genetics and genomics. The authors instead suggest a re-evaluation of the program to incorporate more structure and encourage continued mentor/mentee interaction throughout the duration of medical school. – V. L. Dengler, News Editor

Pan-ethnic carrier screening panel consistent with ACOG and ACMG guidelines

Carrier screening aims to identify couples at risk for having offspring with autosomal recessive or X-linked genetic conditions. Until recently, the American College of Medical Genetics and Genomics (ACMG) and the American College of Obstetricians and Gynecologists (ACOG) recommended pan-ethnic carrier screening for only two conditions, with additional recommendations for those of certain races/ethnicities. Pan-ethnic screening, however, more effectively identifies heterozygotes and affected couples across all races/ethnicities than does screening that is restricted to certain races/ethnicities. To maximize identification of at-risk couples across all races/ethnicities, clearly defined criteria for carrier screening panel inclusion are needed. ACOG and ACMG recommend similar criteria, though ACMG’s thresholds for inclusion are more permissive than ACOG. For example, ACOG recommends a heterozygote frequency of 1 in 100 or greater, whereas ACMG recommends a heterozygote frequency of 1 in 200 or greater. Other criteria include conditions with a well-defined phenotype, that cause cognitive or physical impairment, with onset early in life, and that can be diagnosed prenatally. In this issue, Johansen Taber and colleagues apply a data-driven approach to assess nearly 200 conditions for their adherence to the criteria and identify a panel of conditions that conservatively meet the criteria. The researchers used heterozygote frequency data from more than 460,000 individuals across 11 ethnicities to assess heterozygote frequency and defined and evaluated the criteria using published studies. Of 176 conditions analyzed, 37 conditions met conservative thresholds and 74 conditions met permissive thresholds for inclusion.

To determine the composition of a panel consistent with both ACOG and ACMG panel design criteria, the authors combined the thresholds for each criterion that were applied to all 176 conditions. Taken together, this guidelines-consistent panel would consist of 37 conditions. That panel would capture 63% of heterozygotes and 85% of at-risk couples compared with a 176-condition panel. The authors conclude that the identified panels are consistent with evidence-based interpretations of ACOG and ACMG panel design criteria and that these panels more effectively identify heterozygotes and at-risk couples regardless of race/ethnicity than past screening paradigms that stratified care by race and/or ethnicity. – V. L. Dengler, News Editor