March Newsletter
Articles, webinars, and Modern Reproduction is in an accelerator program!
“The whole difference between construction and creation is exactly this: that a thing constructed can only be loved after it is constructed; but a thing created is loved before it exists.”
―Charles Dickens
With the numerous patients, tasks to complete, and the challenge of maintaining work-life balance, it can sometimes be easy to forget the personal experience of patients and the enormity of their fertility journey. Full disclosure: I don’t know the context of the above quote, but it makes me reflect on a fertility journey and the love people have for their embryos, whether created through IVF or conceived spontaneously. The idea and creation of an embryo are wrapped in love. In that moment, it matters more than anything else in that person’s life.
Lil Lit Review:
This article is extraordinarily important. Working in prenatal and preconception care creates a heightened sense of legal risk compared to when a child is already born. There is genuine fear in the field about not disclosing all risks regarding a child’s health and later being sued for something that was supposed to be predictable with prenatal testing. However, that sense of legal risk may extend to pediatrics as well. If a parent expected their child to achieve a certain milestone but didn’t, is that the clinician’s fault and considered a nondisclosure event?
It’s challenging to balance the reality of our litigation-prone society with the very real human experiences involved. Regardless, there are important points from this article that can be integrated into our conversations without increasing legal risk: consider strengths-based framing. Specifically, “those producing online information about genetic neurodevelopmental conditions should consider providing balanced information highlighting both strengths and challenges for individuals living with these conditions and their families.” With this in mind, our team had a discussion about our outgoing posts on genetic conditions - we are trying to be succinct, balanced, accurate, and informative all at once.
PGT-HLA programmes for the cure of a sick sibling: clinical strategies for this challenging search
The commentary explores clinical programs and their impact on families who have chosen to undergo HLA typing of their embryos to identify an embryo (and hopeful child) that is both free of the genetic condition in the family and a match for the child diagnosed with the genetic condition. These conditions have included Fanconi anemia, beta-thalassemia, Wiskott-Aldrich syndrome, hyperimmunoglobulin M syndrome, X-linked adrenoleukodystrophy, acute lymphoid leukemia, acute myeloid leukemia, and Diamond-Blackfan anemia (DBA), among others. Most often, PGT-HLA is performed for beta-thalassemia, acute lymphoid leukemia, and alpha-thalassemia.
Interestingly, the commentary did not discuss the risk of recombination within the HLA region. Fortunately, ASRM has published more information related to this important counseling point for these patients. Recombination means there is DNA exchanges during meiosis, a normal part of biology. In this context, the risk of recombination pertains to DNA exchange occurring within the region of interest and disrupting the linkage analysis created for the PGT-M assessment.
Additionally, recombination may have occurred for the child with the genetic condition that the test is being designed for. If so, then the chance to have another embryo with the same recombinant event is needed in order to find a match - which is possible but the chances are lowered.
Long Read Sequencing
To discuss long-read sequencing, it’s helpful to first understand that mainstream genetic testing primarily utilizes short-read sequencing. Short-read sequencing involves reading short DNA sequences, usually about 50–300 base pairs (or 50-300 nucleotides - remember adenine (A), cytosine (C), thymine (T), and guanine (G)). There are three primary methods for short-read sequencing, all of which aim to identify the next nucleotide in the sequence. As the name suggests, long-read sequencing can read thousands of base pairs at a time.
One step unique to short-read sequencing is that the DNA strand obtained from the patient is actually fragmented into shorter sequences, whereas long-read sequencing does not necessarily require this step (this may not be true for all long-read sequencing).
Why does that matter? Those short sequences will be mapped to the reference genome to determine where they belong in the genome. If they are incorrectly aligned to the reference genome, then there could be errors in the interpretation. Misalignment may result from an incomplete picture—meaning, a longer sequence length might be needed to accurately determine its position in the genome. Long read can be particularly helpful cases where there is “a lack a high quality reference genome, possess numerous repeat sequences, or contain rare variants”. This article goes into examples of when to consider long read sequencing.
This commentary discusses an application of long-read sequencing in prenatal testing. It review the article, Evaluating the Clinical Utility of a Long-Read Sequencing-Based Approach in Prenatal Diagnosis of Thalassemia, highlighting a critical finding: PCR-based methods for detecting alpha and beta thalassemia via amniocentesis produced a false positive in this study. The PCR based method reported homozygosity for the variant c.52A>T in the HBB gene, while long read sequencing reported heterozygosity. In the study, the long read approach was called: comprehensive analysis of thalassemia alleles (CATSA"). “Independent PCR and Sanger sequencing confirmed the CATSA results” according to the article.
The commentary also highlights the ever-existing issue with prenatal diagnosis: the lack of phenotypic information to use for interpretation of genetic data - particularly relevant for alpha and beta thalassemia, aside from the potential hydrops presentation in alpha thalassemia major.
This new method would also allow for the expansion of variant evaluation as most tests assess for the most common deletion in the HBA1 and HBA2 genes (e.g. lab one, lab two, lab three). Some tests do include sequence variant assessment as well, so it’s important to check with your preferred lab regarding what is being analyzed.
A key challenge in testing the HBA1 and HBA2 genes is determining whether deletions are in cis or trans. While ethnicity can provide a clue (e.g., individuals of Asian descent generally have two deletions on the same chromosome (cis), whereas those of African descent more often have one deletion on each chromosome (trans)), long read sequencing may be able to provide more concrete evidence.
Long read sequencing does not come without its challenges. One of which, turnaround time, is important to weigh in the context of prenatal diagnosis. Check out the above articles for those challenges.
Prenatal Therapy:
I’d like to create a panel of genes for carrier screening that have immediate treatment and management needs, similar to the premise for newborn screening. This article, Promising results from first prenatal therapy for spinal muscular atrophy, highlights the utility of amniocentesis and early diagnosis for treatment, as opposed to waiting until after birth for diagnosis and subsequent treatment.
One of the most common questions I received when meeting with a patient with a positive screen was whether we would be doing anything differently for their pregnancy, if they received the diagnosis during pregnancy or shortly after. For some, delivering in a different hospital was the change, but that was usually due to birth defects seen on ultrasound, not the genetic diagnosis. Similarly, in cases where palliative care was important, it was often not because of the genetic diagnosis but rather the ultrasound findings. In many cases, there wasn’t a treatment administered to the patient specifically for the genetic diagnosis during pregnancy. Advances such as in utero treatment will eventually change this paradigm. Johns Hopkins, UCSF, and CHOP offer many prenatal treatments.
The notion of focusing on offering information on conditions with treatment is supported by this group’s work in this preprint paper: Advancing precision care in pregnancy through an actionable fetal findings list
Webinars:
ISUOG Twin Guideline Update - free - April 6th
Are Independent Labs Facing Extinction in 2025? Examining Regulatory Shifts and New Opportunities - free - April 2nd, 11:30am
GeneDx On Demand Webinars
What’s Happening at MR?
We were selected to participate in a local accelerator: Regional Accelerator and Mentoring Program (RAMP)!!!
What does this mean? A lot of work and a lot of connecting. We are currently seeking anyone in the fertility/reproductive space who is open to chatting about their experience with genetic testing and genetic counseling, including patients.
We are particularly interested in hearing from those who feel their genetic counseling/testing referrals and experiences are positive, as well as those frustrated by the many genetic counseling pipelines for their patients - when one patient is sent to one lab for counseling, another to a different genetic counselor with another lab, or to a hospital genetic counselor, leaving you to keep track of who goes where.
Please reach out to genetics@modernreproduction.org, if you care about genetic counseling and testing in reproductive medicine. Please share with anyone you think would be interested as well. We really appreciate your help in this endeavor.