Non-invasive prenatal screening: Testing motivations and decision making in the low-risk population.

Non-invasive prenatal screening provides a risk assessment for aneuploidies by utilizing cell-free DNA (cfDNA). It is recommended that cell-free DNA screening (cfDNA screening) be offered to all pregnant people regardless of a priori risk for aneuploidy. In the absence of an increased risk, alternative motives for electing cfDNA screening and different levels of informed decision making may arise. Therefore, our study aimed to characterize low-risk patients' motivations for cfDNA screening election, determine how often informed decisions are being made, and compare motivations between informed and uninformed decision makers. A survey that included a modified, validated measure of informed choice (MMIC) and questions to assess patients' motivations for cfDNA screening was offered at four MFM clinics following genetic counseling. It was found that 44% of participants (n = 100) made an uninformed decision about testing. Participants with private insurers were 4.25 times more likely to make an informed decision (95% CI = 1.10-16.37). Informed decision makers scored avoiding invasive procedures higher (p = 0.007) and ranked doing what family/friends desire lower (p = 0.005) than uninformed decision makers. While most participants scored receiving information about genetic conditions highest, 12% of participants reported fetal sex disclosure as a priority. However, this was not found to be associated with uninformed decision making. This study ultimately established that following genetic counseling, a low-risk population shared motivations with high-risk populations which highlights the importance of complete pre-test counseling for all. Future research should investigate the effect of modifying variables, such as socioeconomic status, on the performance of informed choice measures and critically evaluate the parameters that determine informed choice.

First trimester ultrasound in the age of cell-free DNA screening: What are we missing?

OBJECTIVES: To evaluate the utility of first trimester (FT) ultrasound (US) between 10 and 14 weeks gestation in identifying fetal findings that would impact clinical management. METHODS: We performed a retrospective review of FT US associated with an abnormal ICD-10 code from August 2016 to December 2018. Results of FT US, genetic testing, and management decisions were abstracted from the electronic health record. RESULTS: A total of 20,594 FT US were performed within our study period, representing 6064 unique patients. Of these, 278 ultrasounds were noted to have fetal findings (278/6064, 4.6%). The most frequent fetal findings were fetal demises (98/278, 35.3%), followed by increased NT/cystic hygroma (67/278, 24.1%), and multiple anomalies (35/278, 12.6%). There was a significant difference between the frequency of fetal findings between patients considered advanced maternal age (AMA) and those who were not (p = 0.017). However, there was no significant difference in the frequency of specific anomalies between these two groups (p = 0.103). CONCLUSION: FT US provides clinical information outside the scope of cfDNA screening in both AMA and non-AMA populations regarding viability and fetal anatomy. Earlier detection of these findings is crucial to allow for the opportunity of informed discussion of testing strategy and decision making.

Two different genetic etiologies for tuberous sclerosis complex (TSC) in a single family.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic condition that involves abnormalities of the skin, hamartomas in the heart, brain, and kidneys, seizures, as well as TSC-associated neuropsychiatric disorders (TAND). About 90%-95% of individuals with TSC will have an identifiable pathogenic variant in either TSC1 or TSC2. We present here two family members with clinical diagnoses of TSC that were later determined to be due to two different genetic etiologies. METHODS: A 2-year-old Caucasian female (Patient 1) was born to non-consanguineous healthy parents and was determined to have a clinical diagnosis of TSC at 2 months old. Her paternal great-uncle (Patient 2) was also known to have a clinical diagnosis of TSC. Sequencing and deletion/duplication analysis for TSC1 and TSC2 were performed on both individuals. RESULTS: Mutation analysis revealed that both Patient 1 and Patient 2 had identifiable pathogenic variants in TSC2. Patient 1 had c.4800_4801delTG (p.Cys1600Trpfs*2), while Patient 2 had c.4470_4471delinsTT (p.Glu1490_Lys1491delinsAsp*). CONCLUSION: To our knowledge, our clinical report is of significance as it is the third kindred to be identified with affected members with two distinct genetic etiologies for TSC. Our case report highlights the importance of incorporating genetic testing into the clinical evaluation for individuals with features suggestive of TSC.

Variations in MALT1 Gene Disruptions Detected by FISH in 109 MALT Lymphomas Occurring in Different Primary Sites.

Mucosa-associated lymphoid tissue (MALT) lymphoma is a type of B-cell non-Hodgkin lymphoma that can originate in the gastrointestinal (GI) tract, thyroid, breasts, lungs, and skin. The most common genetic abnormality occurring in MALT lymphomas involves t(11;18)(q21;q21) in the gene MALT1. This translocation results in a chimeric fusion product between the genes ATI2 and MALT1, which generates a survival advantage in the lymphoma cells. The MALT1 disruption is more common in some MALT lymphomas, distinguished by site, than others. If identified, this variation in frequency could affect treatment courses and outcomes for each type of MALT lymphoma. The study included 109 MALT lymphoma sample specimens. The sample paraffin-embedded slides were pretreated, hybridized for FISH using a MALT1 break-apart probe, post-washed, and viewed using a fluorescent microscope. On each slide, 100 individual cells were counted by two independent readers, totaling 200 cells per case, and the percentage of cells containing a translocation within each sample was recorded. A conservative threshold of 8% was used to make a positive call. There were a total of 18 positive results in the 109 samples tested. The tissue specimens tested that yielded positive results include the colon (62.5%), lung (57.14%), skin (25%), eyelid/lacrimal gland (16.67%), stomach (6.45%), kidney (50%), and thyroid (100%). The sites that yielded only negative results (0%) include the breast, salivary gland, salivary gland/parotid, soft tissue/skin, conjunctiva/orbital, small intestine, nasal, and epidural mass. As hypothesized, a variation in the MALT1 disruption was found. This is the first study to examine MALT1 disruption in the soft tissue, nasal, and epidural mass. The positive results of this study, specifically the results for the colon and lung, and the negative breast and salivary gland results are consistent with previous studies examining the genetic aberrations in MALT lymphomas. These results indicate that MALT lymphoma at different locations differentially display MALT1 disruption, and these disruptions may be responsible for the variance in patient response to therapy. Surgery, radiation therapy, and/or administration of cladribine (2CdA) result in the best outcomes in treating MALT lymphomas with MALT1 disruption.