expanded carrier screening | The DNA Exchange

This post was modified on 3/30/2022 with input presented by some DNA Exchange readers. First – the original post did not account for the fact that ELP1 is reported out as IKBKAP by Natera, SEMA4 and Quest. Table and graph were updated to reflect this.

While the list of labs surveyed for this post was not intended to include all labs that offer carrier screening, it has been noted since this was initially posted that Fulgent does offer a carrier screening panel based on the ACMG Tier 3 recommendation. A paragraph has been added to reflect Fulgent’s test offering.

In July 2021, the American College of Medical Genetics and Genomics published a new carrier screening guideline, Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). The gist of this recommendation is that all individuals who are considering pregnancy or who are pregnant should be offered a carrier screening panel inclusive of 113 specific genes. In a prior post, Bob Resta and I shared our concerns regarding ethical issues and the ways in which this panel was designed.

With this post I have a practical question regarding implementation: How does one order a carrier screening panel of these ACMG-recommended genes when such a panel does not exist?

A quick recap of the ACMG carrier recommendation. The guideline defines 4 tiers of carrier screening:

Carrier Screening Tiers defined in the ACMG Practice resource, *Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG)*.

The carrier frequencies utilized are based on the public database gnomAD and represent carrier frequencies for any subpopulation that makes up at least 1% of the United States total population.

The goal of this ACMG recommendation was to define a standard panel that could be offered to all patients. The guideline recommends that all patients who are pregnant or are considering pregnancy be offered the “Tier 3” panel, and that reproductive partners may also be offered the Tier 3 panel simultaneously. This panel is inclusive of 113 genes, 86 of which were derived from the gnomAD data as having a carrier frequency of 1 in 200 or higher; 11 additional genes were “highly represented in one or more patient populations and have potential to be underrepresented in gnomAD”; and 16 genes associated with X-linked conditions with a prevalence of 1 in 40,000 or higher.

ACMG recommends against using the Tier 1 or Tier 2 panel for any patient. Further, it states that the Tier 4 panel be reserved “for consanguineous pregnancies (second cousins or closer) and in couples where family or medical history suggests Tier 4 screening might be beneficial.”

A huge problem with this recommendation is that the Tier 3 panel, as it is described by ACMG, does not exist as an orderable test through most labs. I have surveyed several labs, and those with the biggest commercially available panels do not provide coverage for somewhere between 25 and 49 genes of the 113 that are outlined by ACMG for the Tier 3 panel.

Analysis of carrier screening labs performed on March 24, 2022. For a full list of genes by lab, see Table below.

Some of the labs I have highlighted in this analysis have published press releases and sent emails to their client base in enthusiastic support of these guidelines that call for expanded carrier screening, even though NONE of them actually offer what ACMG currently recommends. The Industry lobbying group for Myriad, Natera, SEMA4 and ThermoFisher, the Access to Equitable Carrier Screening Coalition “applauds American College Of Genetics And Genomics” on this new recommendation that none of these labs can currently fulfill.

One lab, Fulgent Genetics, offers a panel that is based on the Tier 3 recommendation, along with several caveats and limitations for some of the recommended genes that have common variants that may be missed or are expected to escape detection by their platform. While the Fulgent panel includes all 113 ACMG-recommended genes, these caveats and limitations demonstrate that sensitivity across the genes included can vary dramatically and may be low in cases where the common mutation is a trinucleotide repeat, inversion or other alteration not reliably identified through next generation sequencing. For example, Fulgent reports including FXN analysis on their panel with the caveat that their analysis will only detect sequence variants which account for <5% of pathogenic variants in this gene (the vast majority of FXN pathogenic variants are due to GAA repeat expansion.)

Perhaps Fulgent along with other labs that are working to develop a panel that meets the ACMG requirements and will be able to identify most pathogenic variants in the 113 gene set. It may be difficult to do this and keep the cost of testing down as there are technical challenges to assessing some of the genes that ACMG recommends. For example, the most common mutation in the F8 gene is a gene inversion. With PLP1 the most common mutation is a gene duplication. Rearrangements are common with the OCA2 gene. These technical variations present a challenge to labs as they expand their carrier screening panels. From the marketing perspective, adding 50 genes to their currently existing platform may seem more impressive than adding a small handful of more technically difficult ACMG-recommended genes.

Do obstetrical care providers recognize that when they are ordering an expanded panel that it may include hundreds of genes that are not recommended while missing several genes that are part of this ACMG-produced panel? What does this mean for our liability as providers when we cannot order a test that is recommended by our professional society?

In a future post I plan to focus on carrier screening for cystic fibrosis and some of the harm seen from reporting practices on expanded carrier screening. But for now I would like to reflect back to the time when we first considered screening for cystic fibrosis, the rollout of which was not without challenges. Before guidelines were issued by the American College of Obstetricians and Gynecologists and the American College of Medical Genetics, there was significant preparation for implementation. Care was taken to determine whether we knew that the variants included on the CFTR panel cause disease. We thought we were clear about this but even with great scrutiny, the original 25 mutation panel included a variant that we eventually learned did not cause disease. There were standards written for laboratories regarding how to do the testing and what should be included in the report. There were educational resources developed for patients and providers. There appears to be much less care and preparation with these current guidelines in spite of the recommendations for testing for many more as well as increasingly complex conditions.

In today’s world of carrier screening, we see both the 113 gene Tier 3 panel recommended by the ACMG as well as commercial laboratories in constant competition to expand the size of their carrier panels. Yes, labs are expanding their genetic carrier screening offerings, but it does not appear (regardless of their marketing materials) that the recommendations from ACMG are the reason why. Even some of the biggest panels available don’t include 22-43% of the genes recommended by the ACMG while providing coverage for numerous genes that are not included in the recommendation. Data regarding performance characteristics of screening for many of these genes both within and beyond the panel are lacking. As a result, pre and post test counseling our patients regarding carrier screening and the downstream challenges are just going to become increasingly more complex.

ACMG Tier 3 Panel	Labcorp / Integrated Inheritest® 500 PLUS Panel	SEMA4 Expanded Carrier Screen (502 Genes)	Natera Horizon™ 421	Myriad Foresight®	Invitae Comprehensive Carrier Screen	Quest QHerit(R) Extended
ABCA3	✘	✔	✘	✘	✘	✘
ABCC8	✔	✔	✔	✔	✔	✔
ABCD1	✔	✔	✔	✔	✔	✔
ACADM	✔	✔	✔	✔	✔	✔
ACADVL	✔	✔	✔	✔	✔	✔
ACAT1	✔	✔	✔	✘	✔	✔
AFF2	✘	✘	✘	✘	✘	✘
AGA	✔	✔	✔	✔	✔	✔
AGXT	✔	✔	✔	✔	✔	✔
AHI1	✔	✘	✔	✘	✘	✘
AIRE	✔	✔	✔	✔	✔	✔
ALDOB	✔	✔	✔	✔	✔	✔
ALPL	✔	✔	✔	✔	✔	✔
ANO10	✘	✘	✘	✘	✘	✘
ARSA	✔	✔	✔	✔	✔	✔
ARX	✘	✘	✔	✘	✘	✘
ASL	✔	✔	✔	✔	✔	✔
ASPA	✔	✔	✔	✔	✔	✔
ATP7b	✔	✔	✔	✔	✔	✔
BBS1	✔	✔	✔	✔	✔	✔
BBS2	✔	✔	✔	✔	✔	✔
BCKDHB	✔	✔	✔	✔	✔	✔
BLM	✔	✔	✔	✔	✔	✔
BTD	✔	✔	✔	✔	✔	✔
CBS	✔	✔	✔	✔	✔	✔
CC2D2A	✘	✘	✔	✘	✘	✘
CCDC88C	✘	✘	✘	✘	✘	✘
CEP290	✔	✔	✔	✘	✔	✔
CFTR	✔	✔	✔	✔	✔	✔
CHRNE	✘	✔	✔	✘	✔	✘
CLCN1	✘	✘	✘	✘	✘	✘
CLRN1	✔	✔	✔	✔	✔	✔
CNGB3	✘	✔	✔	✘	✔	✘
COL7A1	✘	✔	✔	✘	✔	✘
CPT2	✔	✔	✔	✔	✔	✔
CYP11A1	✘	✔	✘	✘	✘	✘
CYP21A2	✔	✔	✔	✔	✔	✘
CYP27A1	✔	✔	✔	✔	✔	✔
CYP27B1	✘	✔	✔	✘	✘	✘
DHCR7	✔	✔	✔	✔	✔	✔
DHDDS	✔	✔	✔	✘	✔	✔
DLD	✔	✔	✔	✔	✔	✔
DMD	✔	✔	✔	✔	✔	✘
DYNC2H1	✘	✘	✘	✘	✘	✘
ELP1	✔	✔	✔	✔	✔	✔
ERCC2	✔	✘	✔	✘	✘	✘
EVC2	✘	✔	✔	✔	✔	✘
F8	✘	✘	✘	✘	✘	✘
F9	✘	✔	✔	✘	✔	✘
FAH	✔	✔	✔	✔	✔	✔
FANCC	✔	✔	✔	✔	✔	✔
FKRP	✔	✔	✔	✔	✔	✘
FKTN	✔	✔	✔	✔	✔	✔
FMO3	✘	✘	✘	✘	✘	✘
FMR1	✔	✔	✔	✔	✔	✔
FXN	✘	✘	✘	✘	✘	✘
G6PC	✔	✔	✔	✔	✔	✔
GAA	✔	✔	✔	✔	✔	✔
GALT	✔	✔	✔	✔	✔	✔
GBA	✔	✔	✔	✔	✔	✔
GBE1	✔	✔	✔	✘	✔	✔
GJB2	✔	✔	✔	✔	✔	✔
GLA	✔	✔	✔	✔	✔	✘
GNPTAB	✔	✔	✔	✔	✔	✔
GRIP1	✔	✘	✘	✘	✘	✘
HBA1	✔	✔	✔	✔	✔	✔
HBA2	✔	✔	✔	✔	✔	✔
HBB	✔	✔	✔	✔	✔	✔
HEXA	✔	✔	✔	✔	✔	✔
HPS1	✔	✔	✔	✘	✔	✔
HPS3	✔	✔	✔	✘	✔	✔
IDUA	✔	✔	✔	✔	✔	✔
L1CAM	✔	✔	✔	✘	✘	✘
LRP2	✔	✘	✘	✘	✘	✘
MCCC2	✔	✔	✔	✘	✔	✔
MCOLN1	✔	✔	✔	✔	✔	✔
MCPH1	✘	✘	✘	✘	✘	✘
MID1	✘	✘	✘	✘	✘	✘
MLC1	✔	✔	✔	✔	✔	✘
MMACHC	✔	✔	✔	✔	✔	✔
MMUT	✔	✘	✘	✔	✘	✘
MVK	✘	✘	✘	✘	✘	✘
NAGA	✘	✘	✘	✘	✘	✘
NEB	✔	✔	✔	✔	✔	✔
NPHS1	✔	✔	✔	✔	✔	✔
NR0B1	✔	✔	✔	✔	✔	✘
OCA2	✘	✘	✘	✘	✘	✘
OTC	✔	✔	✔	✔	✔	✔
PAH	✔	✔	✔	✔	✔	✔
PCDH15	✔	✔	✔	✔	✔	✔
PKHD1	✔	✔	✔	✔	✔	✔
PLP1	✘	✘	✘	✘	✘	✘
PMM2	✔	✔	✔	✔	✔	✔
POLG	✘	✔	✔	✘	✘	✘
PRF1	✔	✘	✔	✘	✘	✘
RARS2	✔	✔	✔	✘	✔	✘
RNASEH2B	✔	✘	✔	✘	✘	✘
RPGR	✔	✘	✘	✘	✘	✘
RS1	✘	✔	✔	✔	✔	✘
SCO2	✘	✘	✘	✘	✘	✘
SLC19A3	✘	✘	✘	✘	✘	✘
SLC26A2	✔	✔	✔	✔	✔	✔
SLC26A4	✔	✔	✔	✔	✔	✔
SLC37A4	✔	✔	✔	✔	✔	✔
SLC6A8	✔	✔	✔	✘	✔	✘
SMN1	✔	✔	✔	✔	✔	✔
SMPD1	✔	✔	✔	✔	✔	✔
TF	✘	✘	✘	✘	✘	✘
TMEM216	✔	✔	✔	✔	✔	✔
TNXB	✘	✘	✘	✘	✘	✘
TYR	✘	✔	✘	✘	✘	✘
USH2A	✔	✔	✔	✔	✔	✔
XPC	✔	✔	✔	✔	✔	✘

As of March 23, 2022

Quest Diagnostics QHerit™ Extended

Myriad Foresight® Carrier ScreenUniversal Panel

Invitae Comprehensive Carrier Screen

Labcorp / IntegratedInheritest® 500 PLUS Panel

SEMA4 Expanded Carrier Screen (502 Genes)

Natera Horizon 421 (from printed materials provided by Natera)

“All human beings are commingled out of good and evil.” Robert Louis Stevenson, author of The Strange Case of Dr. Jekyll and Mr.Hyde

Genetic counselors are good people who want to do good. And that also goes for the vast majority of clinicians in all specialties and support staff who I have ever worked with. We may have brief dalliances with cynicism but overall we strive to be highly competent professionals who deliver compassionate care to patients in hopes of improving their physical and emotional health in small and large ways. We subscribe to the ethos of Do-Goodism – we strive to do good because it is the right thing to do. It’s why we drag ourselves out of bed and show up for work every day. It sure isn’t out of love for the daily commute, an overloaded work schedule, or the out-of-touch-with-reality dictates of upper level management.

Do-Goodism is a, well, good thing. There should be lots more of it in the world (especially among governments). But Do-Goodism has its downsides. Okay, let me stop right there. I am not criticizing Do-Goodism nor am I advocating for D0-Badism. So don’t accuse me of criticizing people for being good. But a problem inherent to Do-Goodism is that can make it very difficult for us to see and acknowledge that when we try to do good things there can be bad outcomes. Our Good Filters block out the Bad Rays generated by our well-meaning actions. Recall what the road to you-know-where is paved with.

A good historical example of the blinders of Do-Goodism is eugenics, that bogeyman of every historical narrative of genetics. While nowadays we look down on eugenics with moral scorn, in fact, with a few obvious exceptions, many eugenics advocates in the US, the UK, and elsewhere genuinely thought they were improving not only the greater good of society but also the “dysgenic” families themselves. Philosophically, eugenics may have been closer to “a kind of genetic social work” than Sheldon Reed would have been comfortable acknowledging. Another historical example are the 19th century alienists who ran the so-called madhouses – whose records were critical to the development of modern genetics and eugenics – where “lunatics” were housed and supposedly cured with fantastical rates of supposed psychiatric problems such as masturbation and menstrual disorders.

https://www.theparisreview.org/blog/2015/04/22/madness-and-meaning/

Br. Benjamin Rush’s Tranquilizer for treating patients with mental illness. It “binds and confines every part of the body … Its effects have been truly delightful to me. It acts as a sedative to the tongue and temper as well as to the blood vessels.”

Do-Goodism still pervades genetic practice today, albeit in different forms. We sometimes advances policies, practices, and tests in the name of “helping people” when the benefit/downside ratio has not been well established. In my own practice of cancer genetic counseling, I think of how seamlessly BRCA testing has expanded to gene panels that include dozens of genes, many of which are of uncertain clinical utility. Even after ~25 years of research on BRCA we still debate the lifetime cancer risks, the mortality reduction of risk-reducing mastectomy, and the benefits of endocrine prophylaxis. In the US, Lynch syndrome patients are encouraged to join The Annual Colonoscopy for Life Club but the data is still not settled as to whether an annual colonoscopy is more beneficial than less frequent exams . And these are the genes that we know fairly well. The clinical implications and best risk-reducing strategies for carriers of other typically tested genes like NBN, RAD51D, or BARD1 are pretty much anyone’s educated guess.

There are complex reasons why gene panel testing has become so widely incorporated into medical care. but I am pretty sure one of the motivating reasons we offer panel testing is that we think that by “finding an answer” to explain the family history, we are benefiting our patients. But are we really helping these patients by offering breast MRI screening with its high cost and false positive findings, risk-reducing surgeries, etc.? Are we explaining their family histories with these tests? Maybe we are, maybe we aren’t. We should have had that answer in hand before the testing was incorporated into clinical practice instead of turning a bunch of clinical patients into an unplanned and haphazard research project.

This was brought into sharp focus for me with a BRCA positive kindred I have been working with. A family member was identified as an asymptomatic BRCA mutation carrier, subsequently underwent risk-reducing surgery, and an occult Fallopian tube cancer was identified at an early enough stage that cure was highly likely. This made me feel like I should notch a victory mark on my belt. After all, preventing ovarian cancer is understandably offered as one of the urgent justifications of BRCA testing. I felt that I pulled the rug out from under ovarian cancer’s evil legs – until the patient died of complications of MRSA acquired during her hospital stay. And this in a situation where everyone would agree that the data strongly supports surgical risk-reduction. Should we be risking such outcomes by offering testing for genes in which there is no large body of research to support clinical recommendations?

Do-Goodism also pervades other areas of genetic testing and counseling. Expanded carrier screening. Noninvasive Prenatal Testing. Advocating for whole exome sequencing of newborns or of healthy adults. Direct-to-Consumer genetic testing. Clinicians and labs offer these tests in the name of helping people and democratizing genetic testing, but this can lead us to psychologically manipulate ourselves into ignoring or downplaying studies that suggest that maybe we should step back before we aggressively offer these tests. The blinders of Do-Goodism can be further exacerbated when our jobs seem to compel us to offer bigger and supposedly better tests to keep up patient volumes or corporate profits. Do-Goodism is not confined to genetics, of course. It also underlies long-standing debates about routine mammography, PSA screening for prostate cancer, and cardiac defibrillators in medically fragile elderly patients, to name a few.

We are not bad clinicians or evil profiteers, just human beings struggling with our psychological limitations. It’s why we need to thoughtfully listen to thoughtful critics who question our clinical practices. They make some very good points but only if we can allow ourselves to see them.

Tag Archives: expanded carrier screening

ACMG Carrier Screening Guideline: The Hypothetical “Tier 3” Panel

The Benefits and Blinders of Do-Goodism

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