Reproductive Risk Estimation Calculator for Balanced Translocation Carriers.

Balanced translocation carriers experience elevated reproductive risks, including pregnancy loss and children with anomalies due to generating chromosomally unbalanced gametes. While understanding the likelihood of producing unbalanced conceptuses is critical for individuals to make reproductive decisions, risk estimates are difficult to obtain as most balanced translocations are unique. To improve reproductive risk estimates, Drs. Trunca and Mendell created models based on a logistic regression analysis of a dataset of over 6000 individuals from over 1000 translocation families. While risk assessments using these models have been offered as a free service for years, this protocol aims to create a sustainable model for genetics professionals to obtain risk estimates for their patients directly. This protocol guides the user through collecting clinical information, using a risk-generating Java program based on the models, and interpreting the program outputs. A practice tutorial is provided to ensure competency in interpretation prior to use. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Estimation of reproductive risks for balanced translocation carriers Basic Protocol 2: Practical examples of typical patient encounters with instructive interpretations.

Noninvasive prenatal screening for aneuploidy: positive predictive values based on cytogenetic findings.

OBJECTIVE: We sought to determine the positive predictive value (PPV) of noninvasive prenatal screening (NIPS) for various aneuploidies based on cases referred for follow-up cytogenetic testing. Secondarily, we wanted to determine the false-negative (FN) rate for those cases with a negative NIPS result. STUDY DESIGN: We compared the cytogenetic findings (primarily from chromosome analysis) from 216 cases referred to our laboratories with either a positive or negative NIPS result, and classified NIPS results as true positive, false positive, true negative, or FN. Diagnostic cytogenetic testing was performed on the following tissue types: amniotic fluid (n = 137), chorionic villi (n = 69), neonatal blood (n = 6), and products of conception (n = 4). RESULTS: The PPV for NIPS were as follows: 93% for trisomy (T)21 (n = 99; 95% confidence interval [CI], 86-97.1%), 58% for T18 (n = 24; 95% CI, 36.6-77.9%), 45% for T13 (n = 11; 95% CI, 16.7-76.6%), 23% for monosomy X (n = 26; 95% CI, 9-43.6%), and 67% for XXY (n = 6; 95% CI, 22.3-95.7%). Of the 26 cases referred for follow-up cytogenetics after a negative NIPS result, 1 (4%) was FN (T13). Two cases of triploidy, a very serious condition but one not claimed to be detectable by the test providers, were among those classified as true negatives. CONCLUSION: T21, which has the highest prevalence of all aneuploidies, demonstrated a high true-positive rate, resulting in a high PPV. However, the other aneuploidies, with their lower prevalence, displayed relatively high false-positive rates and, therefore, lower PPV. Patients and physicians must fully understand the limitations of this screening test and the need in many cases to follow up with appropriate diagnostic testing to obtain an accurate diagnosis.

X inactivation in triploidy and trisomy: the search for autosomal transfactors that choose the active X.

Only one X chromosome functions in diploid human cells irrespective of the sex of the individual and the number of X chromosomes. Yet, as we show, more than one X is active in the majority of human triploid cells. Therefore, we suggest that (i) the active X is chosen by repression of its XIST locus, (ii) the repressor is encoded by an autosome and is dosage sensitive, and (iii) the extra dose of this key repressor enables the expression of more than one X in triploid cells. Because autosomal trisomies might help locate the putative dosage sensitive trans-acting factor, we looked for two active X chromosomes in such cells. Previously, we reported that females trisomic for 18 different human autosomes had only one active X and a normal inactive X chromosome. Now we report the effect of triplication of the four autosomes not studied previously; data about these rare trisomies - full or partial - were used to identify autosomal regions relevant to the choice of active X. We find that triplication of the entire chromosomes 5 and 11 and parts of chromosomes 1 and 19 is associated with normal patterns of X inactivation, excluding these as candidate regions. However, females with inherited triplications of 1p21.3-q25.3, 1p31 and 19p13.2-q13.33 were not ascertained. Thus, if a single key dose-sensitive gene induces XIST repression, it could reside in one of these locations. Alternatively, more than one dosage-sensitive autosomal locus is required to form the repressor complex.