The impact of HBB-related hemoglobinopathies carrier status on fetal fraction in noninvasive prenatal screening.

Objective: We evaluated whether there is an association between β-globin (HBB) pathogenic variants and fetal fraction (FF), and whether the association has a clinically relevant impact on non-invasive prenatal screening (NIPS).

Method: A whole-genome sequencing NIPS laboratory database was retrospectively queried for women who underwent NIPS and carrier screening of both HBB and the α-globin genes (HBA1/HBA2). Women affected with either condition were excluded from the study, yielding a cohort size of 15,853.

A guidelines-consistent carrier screening panel that supports equity across diverse populations.

Purpose: The American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) suggest carrier screening panel design criteria intended to ensure meaningful results. This study used a data-driven approach to interpret the criteria to identify guidelines-consistent panels.

Methods: Carrier frequencies in >460,000 individuals across 11 races/ethnicities were used to assess carrier frequency.

Evaluating the efficacy of three carrier screening workflows designed to identify at-risk carrier couples.

Objective: To evaluate the efficacy of three different carrier screening workflows designed to identify couples at risk for having offspring with autosomal recessive conditions.

Methods: Partner testing compliance, unnecessary testing, turnaround time, and ability to identify at-risk couples (ARCs) were measured across all three screening strategies (sequential, tandem, or tandem reflex).

Results: A total of 314,100 individuals who underwent carrier screening were analyzed.

Screening for Tay-Sachs disease carriers by full-exon sequencing with novel variant interpretation outperforms enzyme testing in a pan-ethnic cohort.

Background: Pathogenic variants in HEXA that impair β-hexosaminidase A (Hex A) enzyme activity cause Tay-Sachs Disease (TSD), a severe autosomal-recessive neurodegenerative disorder. Hex A enzyme analysis demonstrates near-zero activity in patients affected with TSD and can also identify carriers, whose single functional copy of HEXA results in reduced enzyme activity relative to noncarriers. Although enzyme testing has been optimized and widely used for carrier screening in Ashkenazi Jewish (AJ) individuals, it has unproven sensitivity and specificity in a pan-ethnic population.

Inter-lab concordance of variant classifications establishes clinical validity of expanded carrier screening.

Expanded carrier screening (ECS) panels that use next-generation sequencing aim to identify pathogenic variants in coding and clinically relevant non-coding regions of hundreds of genes, each associated with a serious recessive condition. ECS has established analytical validity and clinical utility, meaning that variants are accurately identified and pathogenic variants tend to alter patients' clinical management, respectively. However, the clinical validity of ECS, that is, correct discernment of whether an identified variant is indeed pathogenic, has only been shown for single conditions, not for panels.

Strategies to minimize false positives and interpret novel microdeletions based on maternal copy-number variants in 87,000 noninvasive prenatal screens.

Background: Noninvasive prenatal screening (NIPS) of common aneuploidies using cell-free DNA from maternal plasma is part of routine prenatal care and is widely used in both high-risk and low-risk patient populations. High specificity is needed for clinically acceptable positive predictive values. Maternal copy-number variants (mCNVs) have been reported as a source of false-positive aneuploidy results that compromises specificity.

Group Testing Approach for Trinucleotide Repeat Expansion Disorder Screening.

Background: Fragile X syndrome (FXS, OMIM #300624) is an X-linked condition caused by trinucleotide repeat expansions in the 5' UTR (untranslated region) of the fragile X mental retardation 1 (FMR1) gene. FXS testing is commonly performed in expanded carrier screening and has been proposed for inclusion in newborn screening. However, because pathogenic alleles are long and have low complexity (>200 CGG repeats), FXS is currently tested by a single-plex electrophoresis-resolved PCR assay rather than multiplexed approaches like next-generation sequencing or mass spectrometry.