Genetics Insider: July 2020

Literature review
Did you catch what our colleagues are doing?

National Lipid Association statement on genetic testing in lipid disorders 

In the Journal of Clinical Lipidology, an expert panel from the National Lipid Association reviews the evidence and clinical considerations for genetic testing of dyslipidemias and makes several recommendations:

  • For familial hypercholesterolemia (FH), the most common inherited dyslipidemia, genetic testing can influence insurance eligibility for PCSK9 inhibitors and can guide treatment choice for homozygous individuals. The panel recommended cascade screening of all first-degree relatives of an individual genetically diagnosed with FH.
  • Genetic testing results can change the course of treatment in other dyslipidemias. For example, a genetic diagnosis of familial chylomicronemia syndrome allows access to an antisense oligonucleotide inhibitor of apolipoprotein C-III, and a genetic diagnosis of sitosterolemia changes treatment focus from statins to specific dietary changes that reduce plant sterol intake.
  • The panel advised that clinicians use CLIA-certified labs, ideally those with capabilities for detecting deletions/duplications and copy number variants since these cause about 10% of FH cases.
  • The panel cautioned that some direct-to-consumer tests may provide false positive and false negative results and that these results should be confirmed by a clinical genetic testing lab.
  • Finally, the panel recommended that genetic counseling be provided to all individuals with heritable lipid disorders before genetic testing. 



Intellectual disability and neuropsychiatric comorbidities in individuals with pathogenic PCDH19 variants

Girls clustering epilepsy is an X-linked disorder, caused by pathogenic variants in PCDH19, that affects heterozygous female and mosaic male individuals (but generally not hemizygous male individuals). Previous meta-analyses and retrospective studies have demonstrated negative correlations between age of seizure onset and severity of intellectual disability; however, the neuropsychiatric profile of this condition is less understood. In a new patient-centered survey including 112 female and male (both mosaic and hemizygous) individuals, researchers utilized standardized assessments of autism spectrum disorder, behavioral difficulties, executive dysfunction, and obsessive compulsive disorder to measure the prevalence of neuropsychiatric comorbidities. Results are described in the journal Translational Psychiatry:

  • Seventy unique PCDH19 variants were reported, 35 of which were novel. Penetrance was 92%, with 98 of 106 heterozygous female and mosaic male individuals not reporting symptoms.
  • Developmental delay was reported in 60% of cases (based on surveys completed by 83 caregivers). Delay before seizure onset was reported in 15 (31%) of 49 cases.  
  • Autism spectrum disorder, behavioral difficulties, and executive dysfunction were commonly reported in both heterozygous female and mosaic male individuals. This indicated that neuropsychiatric comorbidities are commonly associated with girls clustering epilepsy.
  • In examining seizure onset and activity in relation to phenotypes, seizure onset was more strongly associated with cognitive outcomes while seizure activity was associated with psychiatric outcomes.


Systematic review: Interest in expanded carrier screening among the general population 

The risk of passing on an autosomal recessive or X-linked disorder is often unknown because of a lack of family history of the disease. Expanded carrier screening (ECS) provides the ability to screen individuals and couples for up to hundreds of these disorders at one time, enabling informed reproductive decision making. Current guidelines recommend offering carrier screening to all women and couples prior to pregnancy. In Human Reproduction Update, a systematic review of 12 studies published between 2015 and 2019 reveals some key insights into women’s and couples’ attitudes toward and uptake of ECS:

  • Interest in pursuing ECS was considerable (32% to 76%) among individuals of reproductive age in the general population, but uptake of the test among prospective parents was much lower (8% to 50%). 
  • Sociodemographics, reproductive health care decisions, and other factors that were associated with ECS uptake varied greatly among studies, and contradictory results were reported. Differences were likely due to differences in geographic location and in the populations included in each study.
  • Additional research is needed to better assess the intention-behavior gap (interest in versus uptake of ECS) and to understand the decision-making process to pursue ECS for individuals and couples. 

New guidance on germline genetic testing for prostate cancer

Nearly 100 experts from a variety of clinical and scientific disciplines gathered at the 2019 Philadelphia Prostate Cancer Consensus Conference to discuss how clinicians can use genetic testing to help patients benefit from precision medicine approaches to prostate cancer. Detailed recommendations from the conference, published in the Journal of Clinical Oncology, encourage expanded use of germline testing to guide treatment:

  • Large germline panels and somatic next-generation sequencing are recommended for patients with metastatic prostate cancer. Large panels provide information that can better inform treatment options such as poly ADP ribose polymerase (PARP) inhibitors, immune checkpoint inhibitors, platinum chemotherapy, and clinical trials.
  • Germline test results are increasingly important for early detection. Men with certain genetic changes, such as specific variants in BRCA2, exhibit higher rates of prostate cancer than other men, often with a younger age at diagnosis and more clinically significant disease.
  • Additional research presented virtually at the 2020 American College of Medical Genetics and Genomics annual meeting further underscores the importance of expanded testing. The positivity rate among 2,252 men who participated in large germline panel testing through Invitae’s Detect Hereditary Prostate Cancer program was 13%. Only half of the patients with an actionable variant reported a family history that suggested increased risk, and almost three-quarters were eligible or potentially eligible for results-based clinical management or treatment. 



Genetic testing for patients with myocarditis

Some healthcare providers may hesitate to order genetic testing for patients with suspected or diagnosed myocarditis (i.e., inflammation of the heart muscle), as it has been unclear whether myocarditis can have an underlying genetic component. However, the results of three recently published studies show that genetic testing for these patients can help explain the occurrence of this heart condition and associated cardiomyopathy:

  • A case series published in Circulation: Genomic and Precision Medicine found pathogenic variants in plakophilin-2 (PKP2), desmoplakin (DSP), and several other genes in 9 (56%) of 16 patients with clinically suspected myocarditis. The results also suggest that myocarditis can be the first clinical sign of inherited cardiomyopathy.
  • Among six families with a history of acute myocarditis and either cardiomyopathy or sudden death, five had variants in DSP (four with pathogenic variants and one with variants of uncertain significance), and one had a pathogenic variant in desmoglein 2 (DSG2). Twenty-eight and four members of the families, respectively, were found to carry variants in DSP and DSG2. Detailed findings from all six families are described in ESC Heart Failure
  • Historically, the DSP gene has been associated with arrhythmogenic cardiomyopathy and right ventricular involvement, but a study published in Circulation provides evidence of substantial left ventricular involvement. The study found that 52 (51%) of 103 patients with pathogenic DSP variants had left ventricular predominant cardiomyopathy while 14 (14%) had right ventricular involvement. Some cases of acute left ventricular myocardial injury were associated with myocardial inflammation that was initially misdiagnosed as cardiac sarcoidosis or myocarditis. 



The May 2020 issue of the Genetics Insider contained errors in the literature review summary entitled “Large cohort analysis of the rare germline EGFR T190M variant.” In the title and throughout the summary, the variant was incorrectly referred to as EGFR T190M. The correct name of the variant is EGFR T790M. Also, the name of the journal was cited as Precision Oncology. The full name of the journal is JCO Precision Oncology. The original article that the summary was based on can be accessed here.


Invitae news
Here’s what we’ve been up to

Pilot program to identify primary immunodeficiencies through genetic sequencing 

The Jeffrey Modell Foundation, in partnership with Invitae, launched a free international pilot program in 2019 to identify genetic causes for patients clinically diagnosed with primary immunodeficiencies. The results, described in the journal Immunologic Research, highlight the importance of next-generation sequencing for reaching precise diagnoses and confirming or advancing appropriate management and treatment: 

  • One-hundred fifty-eight patients from sites within the Jeffrey Modell Centers Network were tested using the Invitae Primary Immunodeficiency Panel, which contains 207 genes associated with inherited disorders of the immune system. 
  • A molecular diagnosis was achieved for 21% of patients with a suspected monogenic disorder. Treatments are available for 80% of the conditions that were diagnosed.
  • Physicians reported that clinical diagnoses, disease management, treatment, and genetic counseling were altered in 45%, 40%, 36%, and 62% of all patients, respectively, as a result of genetic sequencing.
  • Program findings also suggest that the clinical expertise of immunologists, such as those within the Jeffrey Modell Centers Network, is important in determining which patients with primary immunodeficiencies may benefit the most from next-generation sequencing. 



Clinical evaluation and management of patients with secondary genomic findings

As exome and genome sequencing become more common, the incidence of secondary genomic findings (i.e., genetic variants that are not related to the primary reason for genetic testing but may nonetheless have medical implications) is also expected to rise. In a review article in the American Journal of Human Genetics, clinical and molecular geneticists from the National Institutes of Health, Invitae, and several other institutions offer guidance on how physicians can clinically evaluate and manage patients with these findings:

  • The authors outline five domains that should be included in evaluating patients with secondary findings: 1) medical history, 2) physical exam, 3) family history, 4) diagnostic phenotype testing, and 5) variant correlation. Although primary care providers may initiate the evaluation, referral to a clinician with genetics experience is ideal. 
  • Results of the evaluation should be used to develop a follow-up plan. Clinical management will depend on whether clinical and molecular diagnoses are reached and on factors such as the penetrance of the disorder.   
  • The article also contains example scenarios and a list of key resources for physicians, including the American College of Medical Genetics and Genomics ACT Sheets, GeneReviews, and the National Comprehensive Cancer Network.


Genetic testing telehealth solutions for genetic counselors

Juggling phone and video appointments, finding ways to connect with patients from afar, and adapting to today’s new normal can feel overwhelming—and that’s before adding personal and family responsibilities to the mix. As we think about a path forward in this new normal, Invitae Chief Medical Officer Dr. Bob Nussbaum shares a few of Invitae’s flexible telehealth solutions. Watch the short video here.


Helping patients understand what a genetic counselor does

Many patients, and even family and friends, often don’t fully understand what genetic counselors do—not to mention the essential role they play in healthcare. The blog post What is a genetic counselor and why do I need one?  addresses some of the most common questions around genetic counseling. We hope you will share this 3-minute read with those in your networks that might benefit from an explanation or a refresher.


Webinars: Keeping you informed

We’re dedicated to keeping you up to date on the most important issues in genetics today, especially at a time when many of us are unable to attend in-person conferences. Check out these recent webinars:


Sponsored testing

Invitae’s sponsored testing programs provide no-charge genetic testing to patients who meet certain eligibility criteria. Saliva kits can be shipped directly to patients for sample collection. Learn more here and see below for program updates:

  • Discover Dysplasias™ is now available in Canada. A sponsored genetic testing program brought to you by BioMarin and Invitae, Discover Dysplasias provides no-charge genetic testing for patients in the US, and now Canada, with signs or symptoms suggestive of or consistent with a diagnosis of skeletal dysplasia.
  • Invitae and Ultragenyx Pharmaceutical, Inc. are proud to announce the launch of our new Long-Chain Fatty Acid Oxidation Disorders program. This program offers sponsored, no-charge genetic testing for individuals suspected of having long-chain fatty acid oxidation disorders.


This is us.
At Invitae, we always ask, “What is your Why?”

Why are we inspired by Invitae’s mission? Why do we get up every day and put 110% into our work? Here’s a little insight into why we’re dedicated to increasing access to genetic information for everyone.

When I was 9 years old, I had a cousin born in Australia who died at 2 days old. It was my aunt and uncle’s first pregnancy and had been textbook perfect/normal. The delivery was normal, but my cousin had a tough time breastfeeding and, on his first day of life, my cousin slipped into a coma and passed away on day 2. 

To say that my aunt and uncle were devastated is an understatement. After an autopsy and some extensive genetic testing, my cousin was diagnosed with MCAD deficiency. At the time, he was the 90th person in the world to be diagnosed. My aunt and uncle met with genetic counselors and got pregnant again. They did genetic testing during that pregnancy and knew that their second baby was not affected. They still didn’t fully trust that information, though, and did not even tell the family that they were pregnant! Instead, we got a call saying that they had a healthy 3-day-old son. 

That had a profound impact on me. I remember my parents trying to explain genetics and why my first cousin passed away. And years later, when it was time to start my own family, the ability to have carrier screening for both me and my husband was huge. I was found to be a carrier and my husband was negative, so we were lucky and in a low-risk category. 

My brother wasn’t as lucky: both he and his wife are MCAD carriers. But knowing that information has given them the ability to make informed choices about their reproductive options. 

Access to genetic testing and genetic counseling has been incredibly important in my family, and I am proud to work for a company that is dedicated to providing high-quality genetic testing and increasing access to that testing for all families.

-Julia Wilkinson, Medical Affairs Liaison, Reproductive Health