Utility of expanded carrier screening in pregnancies with ultrasound abnormalities.

OBJECTIVE: Explore the utility of expanded carrier screening in evaluating heritable causes of congenital anomalies detected by prenatal ultrasound. METHOD: A retrospective chart review was conducted to collect structural abnormality and genetic testing data on infants who were evaluated postnatally by a medical geneticist. These were used to determine if expanded carrier screening could have determined the etiology prior to delivery. Additionally, recessive and X-linked conditions on clinically available carrier screening panels were evaluated to determine the number of conditions associated with abnormal ultrasound findings. RESULTS: Our retrospective chart review found 222 patients with genetic etiologies, including eight unique autosomal recessive conditions and six X-linked conditions in the 23% who underwent exome sequencing. Of these 14 unique conditions detected, three were included on a list of 271 conditions for which screening was available in 2019 and five were included on a 500 condition panel available in 2020. A literature review was performed on the list of 271 conditions and 88 were reported to be associated with one or more ultrasound abnormalities. CONCLUSION: This study demonstrates limited but potential utility for expanded carrier screening to determine the underlying etiology of congenital anomalies.

Capillary electrophoresis as alternative method to detect tumor genetic mutations: the model built on the founder BRCA1 c.4964_4982del19 variant.

Despite some populations show a wide spectrum of different BRCA pathogenic variants (PVs), particular ethnic groups carry at high frequency a single or a few recurrent PVs, usually due to a founder effect. The identification of these founder PVs, with simple molecular methods, improves BRCA1/2 testing and cancer risk assessment. In this study, we developed a rapid and reliable PCR method, coupled with capillary electrophoresis (CE) for genotyping the Italian founder BRCA1 c.4964_4982del19 (rs80359876) variant. In addition, we compared the performance of two CE platforms: (Agilent 2100 Bioanalyzer and the Experion Automated Electrophoresis system) to identify this variant. Our findings suggest that CE represents a simple and standardized diagnostic strategy for the unambiguously identification of the BRCA1 c.4964_4982del19 variant, on both germline and somatic DNA samples. The results and performance obtained by two platforms are absolutely superimposable in terms of specificity and sensitivity, as well as for their feasibility, time of analysis and costs.

Medical Devices; Exemption From Premarket Notification; Class II Devices; Autosomal Recessive Carrier Screening Gene Mutation Detection System. Final order.

The Food and Drug Administration (FDA or Agency) is publishing an order to exempt autosomal recessive carrier screening gene mutation detection systems from the premarket notification requirements, subject to certain limitations. This exemption from 510(k), subject to certain limitations, is immediately in effect for autosomal recessive carrier screening gene mutation detection systems. This exemption will decrease regulatory burdens on the medical device industry and will eliminate private costs and expenditures required to comply with certain Federal regulations. FDA is also amending the codified language for the autosomal recessive carrier screening gene mutation detection system devices classification regulation to reflect this final determination.

Finding Middle Ground in Constructing a Clinically Useful Expanded Carrier Screening Panel.

Expanded carrier screening for autosomal-recessive conditions effectively identifies more carrier couples than traditional guideline-based carrier screening. However, clinically available expanded carrier screening panels include numerous conditions, some of which have questionable clinical utility as a result of very low carrier frequency, low or unknown testing sensitivity, and mild or incompletely penetrant phenotypes. Using the 2013 American College of Medical Genetics and Genomics Position Statement on Prenatal and Preconception Expanded Carrier Screening and the 2017 American College of Obstetricians and Gynecologists' Committee Opinion on Carrier Screening in the Age of Genomic Medicine as guidance, we propose specific criteria for the development of expanded carrier screening panels that will maximize clinical utility and minimize patient stress, unnecessary cost of follow-up testing, and clinician time spent facilitating and performing follow-up counseling and testing. We identified 96 conditions that meet our proposed criteria, far more than current guidelines recommend. On the other hand, a considerable percentage (73%) of conditions on current expanded carrier screen panels does not meet our proposed criteria. The purpose of this commentary is to acknowledge the benefits of expanded panels, but to also recognize that in their current state, we are putting patients at risk for undue stress and spending excessive time and money on follow-up testing for remarkably rare or mild conditions and conditions with low screening performance. We encourage laboratories and clinicians to work together to create the most clinically useful screening panels for patients desiring reproductive risk information.

Preconceptional genetic carrier testing and the commercial offer directly-to-consumers.

Recently, a number of commercial companies are offering preconceptional carrier tests directly-to-consumers. This offer raises a number of concerns and issues above and beyond those encountered with preconceptional tests offered within the traditional health care setting. In order to bring some of these issues to light and to initiate dialogue on this topic, this article discusses the following issues: the current offer of preconceptional carrier tests (until the end of 2010) through online commercial companies; the implications for the informed consent procedure and the need for good information; the need for medical supervision and follow-up; and the appropriate use of existing resources. The article concludes with some reflections about the potential sustainability of the offer of preconceptional carrier tests directly-to-consumers.

Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband.

It is important to have accurate knowledge of the range of cancers associated with various CHEK2 mutations, and of the lifetime risks of cancer associated with each. We wished to establish the relationship between family history, mutation type and cancer risk in families with a CHEK2 mutation. We obtained a blood sample and pedigree information from 2012 unselected women with breast cancer, from 2007 men with prostate cancer and from 1934 patients with colon cancer, from hospitals throughout Poland. Genetic testing was carried out for four founder CHEK2 mutations on all 5953 specimens and 533 carriers were identified. We estimated the risk to age 75 for any cancer in the 2544 first-degree relatives to be 22.3%. After adjusting for mutation type, the risk of breast cancer was much higher among relatives of probands with breast cancer than among relatives of patients with prostate or colon cancer (HR=3.6; 95% CI=2.1-6.2; P=0.0001). Similarly, the risk of prostate cancer was higher among relatives of probands with prostate cancer than among relatives of patients with breast or colon cancer (HR=4.4; 95% CI=2.2-8.7; P=0.0001) and the risk of colon cancer was higher among relatives of probands with colon cancer than among relatives of patients with prostate or breast cancer (HR=4.2; 95% CI=2.4-7.8; P=0.0001). These analyses suggest that the risk of cancer in a carrier of a CHEK2 mutation is dependent on the family history of cancer.

Bias-corrected diagnostic performance of the naked-eye single-tube red-cell osmotic fragility test (NESTROFT): an effective screening tool for beta-thalassemia.

It is being increasingly recognized that a majority of the countries in the thalassemia-belt need a cost-effective screening program as the first step towards control of thalassemia. Although the naked eye single tube red cell osmotic fragility test (NESTROFT) has been considered to be a very effective screening tool for beta-thalassemia trait, assessment of its diagnostic performance has been affected with the reference test- and verification-bias. Here, we set out to provide estimates of sensitivity and specificity of NESTROFT corrected for these potential biases. We conducted a cross-sectional diagnostic test evaluation study using data from 1563 subjects from Central India with a high prevalence of beta-thalassemia. We used latent class modelling after ensuring its validity to account for the reference test bias and global sensitivity analysis to control the verification bias. We also compared the results of latent class modelling with those of five discriminant indexes. We observed that across a range of cut-offs for the mean corpuscular volume (MCV) and the hemoglobin A2 (HbA2) concentration the average sensitivity and specificity of NESTROFT obtained from latent class modelling was 99.8 and 83.7%, respectively. These estimates were comparable to those characterizing the diagnostic performance of HbA2, which is considered by many as the reference test to detect beta-thalassemia. After correction for the verification bias these estimates were 93.4 and 97.2%, respectively. Combined with the inexpensive and quick disposition of NESTROFT, these results strongly support its candidature as a screening tool-especially in the resource-poor and high-prevalence settings.

N19S, a new SOD1 mutation in sporadic amyotrophic lateral sclerosis: no evidence for disease causation.

In a group of 331 sporadic amyotrophic lateral sclerosis (ALS) cases, we identified a new Cu/Zn superoxide dismutase single base substitution, N19S, in two patients. In the first case, seven healthy family members of 15 carried the substitution. Controls (n = 268) and familial ALS index cases (n = 180) were screened and one control subject with N19S was identified. Our data show that, despite a possible role of susceptibility factor for ALS, N19S alone cannot be considered as a direct cause for the disease.