Maternal Malignancy After Atypical Findings on Single-Nucleotide Polymorphism-Based Prenatal Cell-Free DNA Screening.

OBJECTIVE: To evaluate the incidence and clinical outcomes of cell-free DNA results suspicious for maternal malignancy on prenatal cell-free DNA screening with single-nucleotide polymorphism (SNP)-based technology. METHODS: This retrospective cohort study included data from SNP-based, noninvasive prenatal screening samples from a commercial laboratory from January 2015 to October 2021. Maternal plasma was screened for trisomy 21, 18, and 13; monosomy X; and triploidy. Cases were considered suspicious for maternal malignancy if retrospective bioinformatics and visual inspection of the SNP plot were suggestive of multiple maternal copy number variants across at least two of the tested chromosomes. Clinical follow-up on patients was obtained by contacting individual referring clinician offices by telephone, facsimile, or email. RESULTS: A total of 2,004,428 noninvasive prenatal screening samples during the study period met criteria for inclusion in the analysis. Of these, 38 samples (0.002% or 1 in 52,748, 95% CI 1:74,539-1:38,430) had SNP-plot results that were suspicious for maternal malignancy. Maternal health outcomes were obtained in 30 of these patients (78.9%); eight were lost to follow-up. Maternal malignancy or suspected malignancy was identified in 66.7% (20/30) of the 30 patients with clinical follow-up provided by the clinic. The most common maternal malignancies were lymphoma (n=10), breast cancer (n=5), and colon cancer (n=3). CONCLUSION: Results suspicious for maternal malignancy are rare with SNP-based noninvasive prenatal screening (1:53,000), but two thirds of patients who had a noninvasive prenatal screening result concerning for malignancy in this study had a cancer diagnosis. Investigation for malignancy should be recommended for all pregnant patients with this type of result. FUNDING SOURCE: This study was funded by Natera, Inc.

Non-invasive prenatal screening for fetal triploidy using single nucleotide polymorphism-based testing: Differential diagnosis and clinical management in cases showing an extra haplotype.

OBJECTIVE: An extra haplotype is infrequently encountered in single nucleotide polymorphism(SNP)-based non-invasive prenatal testing (NIPT) and is usually attributed to an undetected twin or triploidy. We reviewed a large series to establish relative frequencies of these outcomes and identify alternative causes. METHODS: In 515,804 women receiving NIPT from September 2017 through March 2019, all results with an extra haplotype were reviewed. Known viable and vanished twin pregnancies were excluded. For positive cases, pregnancy outcome information was sought. RESULTS: Of 1005 results with an extra haplotype (1 in 513), pregnancy outcome was available for 773 cases: 11% were confirmed or suspected triploidy; 65% to vanished twin; 10% with pregnancy loss. Rare explanations included complete mole, chimera, undisclosed donor egg pregnancy, maternal organ transplant and one instance of maternal neoplasm. Among triploid cases that were detected and independently confirmed, 23/27 (85%) were diandric. CONCLUSION: SNP-based NIPT, with detection of an extra haplotype, is 11% predictive of triploidy. For results with an extra haplotype, ultrasound is recommended to establish viability, evaluate for twins (viable or vanished), and detect findings consistent with triploidy. Review of patient history, serum screening, and ultrasound will reduce the number of CVS or amniocenteses necessary to confirm a diagnosis of triploidy.

P4HA1 mutations cause a unique congenital disorder of connective tissue involving tendon, bone, muscle and the eye.

Collagen prolyl 4-hydroxylases (C-P4Hs) play a central role in the formation and stabilization of the triple helical domain of collagens. P4HA1 encodes the catalytic α(I) subunit of the main C-P4H isoenzyme (C-P4H-I). We now report human bi-allelic P4HA1 mutations in a family with a congenital-onset disorder of connective tissue, manifesting as early-onset joint hypermobility, joint contractures, muscle weakness and bone dysplasia as well as high myopia, with evidence of clinical improvement of motor function over time in the surviving patient. Similar to P4ha1 null mice, which die prenatally, the muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane. Patients were compound heterozygous for frameshift and splice site mutations leading to reduced, but not absent, P4HA1 protein level and C-P4H activity in dermal fibroblasts compared to age-matched control samples. Differential scanning calorimetry revealed reduced thermal stability of collagen in patient-derived dermal fibroblasts versus age-matched control samples. Mutations affecting the family of C-P4Hs, and in particular C-P4H-I, should be considered in patients presenting with congenital connective tissue/myopathy overlap disorders with joint hypermobility, contractures, mild skeletal dysplasia and high myopia.