Genetics Insider: May 2020

Literature review
Did you catch what our colleagues are doing?

The genetics of arrhythmogenic cardiomyopathy: clinical implications for probands and family members

Arrhythmogenic cardiomyopathy (ACM), characterized by frequent ventricular arrhythmias and progressive ventricular dysfunction, is associated with a high risk of sudden cardiac death. In a recent review, authors discuss the clinical implications of genetic findings related to ACM:

  • The majority of ACM individuals with a family history of the disease have a detectable pathogenic or likely pathogenic variant, while those without a family history generally do not. 
  • ACM is considered an oligogenic or multifactorial disease, with both environmental modifiers (e.g., high-intensity endurance exercise) and genetic modifiers contributing to onset. A threshold model of ACM onset in individuals has been proposed, suggesting that pathogenic variants, genetic modifiers, and exercise in combination drive onset.
  • Genetic testing is recommended for individuals with an ACM diagnosis and in cases in which the diagnosis is made post-mortem. A panel of genes has been recommended for ACM molecular diagnosis via next-generation sequencing by the Heart Rhythm Society. The genetic testing results may help guide ACM management as well as cascade testing of relatives.


Gastric and breast cancer in patients with loss-of-function CTNNA1 variants

Hereditary diffuse gastric cancer syndrome is associated with an increased risk of diffuse gastric cancer and lobular breast cancer. The CTNNA1 gene has been suspected of being a risk gene for this syndrome, but little is known about the penetrance of gastric cancer in patients with pathogenic CTNNA1 variants, or about whether these variants increase breast cancer risk. In an article in Genetics and Medicine, researchers report insightful CTNNA1 findings from a large-scale germline cancer risk assessment:

  • More than 151,000 individuals underwent testing with a multi-gene panel that included the CTNNA1 gene.
  • Testing identified loss-of-function CTNNA1 variants in 52 individuals.
  • Among 33 individuals who carried the loss-of-function variants and had detailed histories available, four (12%) had diffuse gastric cancer and 22 (67%) had breast cancer. Of the 29 families represented, six (21%) had a history of gastric cancer and 24 (83%) had a history of breast cancer.
  • Three families with early-onset diffuse gastric cancer or breast cancer carried the CTNNA1 c.1351C>T nonsense variant.
  • The risk of gastric cancer may be lower than expected, and the risk of breast cancer higher than expected, for carriers of loss-of-function CTNNA1 variants. Certain variants such as CTNNA1 c.1351C>T may be significant risk factors for early-onset disease.


Large cohort analysis of the rare germline EGFR T190M variant

Most cases of the germline epidermal growth factor receptor (EGFR) T190M variant reported in the literature have been in white, female nonsmokers with lung cancer. An article in the journal Precision Oncology includes two new reports of this variant in women and their families who generally fit this profile. However, a cohort analysis of patients undergoing germline hereditary cancer risk assessment, also reported in the article, shows that the variant occurs in a much broader range of individuals:

  • Risk assessment was performed using a panel containing 83 cancer genes. Among the 65,218 patients who underwent testing, 29 were identified as heterozygous carriers of the germline EGFR T190M variant.
  • Cancer histories were available for 26 of the individuals with the variant. Review of these histories found that 16 (61.5%) of the 26 had a family history of lung cancer or lung nodules.
  • The incidence of the variant did not differ significantly by race or ethnicity, age, or sex. However, both the incidence of the variant and the incidence of lung cancer in carriers of the variant were highest among African Americans.
  • According to the authors of the study, a gene panel that includes the EGRF gene should be an option for all individuals undergoing hereditary cancer risk assessment.


Update on the genetics of developmental and epileptic encephalopathies

Developmental and epileptic encephalopathies (DEEs) are a family of rare disorders characterized by early-onset refractory seizures, sometimes in combination with developmental regression or plateauing. DEEs can be autosomal recessive, autosomal dominant, or X-linked. While exome sequencing has contributed to expanding the known genetic basis of DEEs, nearly half of individuals affected with DEEs do not have a molecular diagnosis. A recent review summarizes the current genetic landscape of DEEs and discusses recent discoveries and future research needed to discover additional genetic associations:

  • Autosomal recessive inheritance may account for up to 13% of DEEs, which is much more than previously thought. This type of inheritance has been associated with pathogenic de novo variants in a small subset of genes, and patients with these variants typically have severe clinical presentations.
  • Most recent gene discoveries have been facilitated by matchmaker exchanges (e.g., through the GeneMatcher tool), leading to the identification of novel genes such as CACNA1E, CUX2, KCNQ5, RHOBTB2, and RNF13.
  • One of the most unusual discoveries has been that pathogenic variants in some X-linked genes can affect both male and female individuals.
  • Somatic mosaicism is a possible explanation for individuals affected with DEE without a definitive molecular diagnosis.
  • The authors of this review expect DEE gene discoveries such as these to translate into opportunities for precision medicine in the coming years.


Importance of carrier screening for male partners

Although follow-up carrier screening is recommended for male partners of women who screen positive for an autosomal recessive disorder, little is known about the uptake behaviors of these men. To better understand their behaviors, researchers from the University of Texas Health Science Center in Houston analyzed data on all prenatal and preconception patients who had received genetic counseling in their maternal fetal medicine clinics between January 2017 and April 2018. The results are described in the journal Prenatal Diagnosis:

  • Among 6,087 patients, 661 were identified as carriers of an autosomal recessive disorder. Only 41.5% of the male partners of these women underwent carrier testing.
  • The researchers found two significant predictors of male partner uptake: gestational age and female parity. The rate of partner uptake was highest among preconception patients and decreased as gestational age increased. Similarly, it was highest among patients who had never given birth and decreased as parity increased.
  • This study highlights the discrepancy between guidelines and practice, which is preventing carrier screening from reaching its full clinical utility. More research is needed to understand the reasons for and potential barriers of male partner uptake.


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

In the clinic or at home, we’re here to help

The way that healthcare is delivered long term will undoubtedly be changed due to the COVID-19 pandemic. As states begin to reopen and we think about a path forward in this new normal, Invitae is here to help with flexible solutions. 

  • Gia is Invitae’s HIPAA-compliant clinical chatbot that facilitates virtual conversations with patients, including interactive family history intake and educational videos. Gia can help with patients with cancer, patients who may be at risk for cancer, and pregnant patients. Learn more and get started with Gia here.
  • We realize patient visits may be delayed, so we’ve temporarily extended the timeline to place an order for family variant testing or re-requisition to 150 days (from 90 days).
  • Test ordering and sample collection can be challenging. As a reminder, saliva kits can be shipped directly to a patient. We also have the option for patients to initiate their own genetic testing under the guidance of expert healthcare providers.
  • Learn about these options and more on Invitae’s telehealth webpage.


Diagnostic yield and clinical utility of multi-gene testing for neuromuscular disorders

Neuromuscular disorders display clinical and genetic heterogeneity, with some disparate disorders sharing overlapping clinical presentations that can make it difficult to diagnose without a molecular diagnosis. Reported in Neurology Genetics, Invitae and a colleague from Northwestern University describe a large unselected clinical cohort of individuals referred for genetic testing who were suspected of having a neuromuscular disorder. Among 25,356 individuals tested:

  • A definitive molecular diagnosis was obtained in 20% of the cohort, ranging from 4% to 33% depending on the panel used.
  • Among all positive variants observed in the cohort, 39% were copy number variants (CNVs) detected by high-resolution copy number analysis. The majority of these CNVs were observed in three genes—SMN1, PMP22, and DMD—but the remainder were observed in 77 other genes.
  • In 6% of cases in which a clinician suspected a certain disorder based on clinical features, multi-gene testing revealed a pathogenic variant in a gene associated with a different disorder but one within the same differential diagnosis.


Webinars: Keeping you informed

We’re dedicated to keeping you up to date on the most important issues in genetics today.

  • As conferences are cancelled across the country, Invitae is dedicated to ensuring you can still get the education you need. Invitae’s next CEU webinar is almost here! We’ll be presenting “Challenging variant types detected by next-generation sequencing and their contribution to monogenic disease” on Tuesday, June 9th at 9am Pacific. You can register here.
    • Don’t forget to check out our FAQ on how to claim educational credit from our webinar series.
  • Learn more about our sponsored testing programs on Tuesday, June 16, from 9:00-10:00 am Pacific. Register here.
  • All Invitae webinars are recorded and available on-demand after the live presentation. See them here.
  • Invitae is a proud supporter of the National Society of Genetic Counselors’ COVID-19 webinar series. You can access the recordings here (note: you must be logged in as a member to view). 
  • To view an MDA Industry Update webinar on Advancements in Genetic Testing for Muscular Dystrophy, click here.


Sponsored testing

Invitae’s sponsored testing programs provide no-charge genetic testing and, in some cases, genetic counseling, 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:

  • Detect Muscular Dystrophy – The Muscular Dystrophy Association recently partnered with Invitae to offer sponsored, no-charge genetic testing and counseling for patients suspected of having a muscular dystrophy.
  • PTC Pinpoint – A sponsored genetic testing program brought to you by PTC Therapeutics and Invitae, PTC Pinpoint provides no-charge genetic testing and counseling for individuals in the US suspected of having a neurotransmitter disorder.


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.

(Photo of Jenna)I’ve been interested in genetics for a long time, but recently I’ve gained a new “why.” I don’t have any significant personal or family history, so after taking Invitae’s Genetic Health Screen I was surprised to find I have a CHEK2 mutation (and am also an HFE carrier). 

We did family testing and found out the CHEK2 mutation came from my mom’s side of the family; we’re both now getting increased cancer screening and we’re in the process of getting additional family members tested. 

We also tested my dad because of the HFE carrier mutation; to our great surprise, he’s homozygous. Subsequent blood tests confirmed iron overload… he has hemochromatosis and is now getting treatment. This finding likely saved him many, many years of good health because without treatment, the iron overload would cause all types of problems including organ damage. I can’t tell you how thankful I am that we figured this out. We already found out that one of his brothers is also affected. You just don’t know until you test.

-Jenna Finley, Clinical Genomics