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Q&A

Genetics

Poster Session 3

(910) Performance of SNP-based cell-free DNA prenatal screening for 22q11.2 deletion syndrome in a commercial population

Wednesday, February 14, 2024

8:30 AM – 10:00 AM

Location: Prince George's Exhibit Hall CDE, Lower Atrium Level

Primary Author(s)

WD

Wendy DiNonno, MS (she/her/hers)

Natera, Inc.
Austin, TX, United States

Coauthor(s)

Melissa Maisenbacher, MS (she/her/hers)

Director
Natera, Inc.
Austin, TX, United States
GG

Georgina Goldring, MS

Lead Genetic Counselor
Natera, Inc.
Austin, TX, United States
MB

Melda Balcioglu, BS

Natera, Inc.
Austin, TX, United States
KT

Kayla Turner, N/A

Natera, Inc.
Austin, TX, United States
MM

M. Caleb Meads, N/A

Natera, Inc.
Austin, TX, United States
KR

Kayla Ruiz, BA

Natera, Inc.
Austin, TX, United States
PA

Priyanka Arya, PhD

Natera, Inc.
Austin, TX, United States

Presenting Author(s)

Jeffrey Meltzer, MBA, MD

Senior Medical Director, Reproductive Health
Natera, Inc.
Austin, TX, United States

Coauthor(s)

KH

Katherine Howard, MS

Natera, Inc.
Austin, TX, United States

Objective: Evaluate positive predictive value (PPV) of 22q11.2 deletion syndrome (22q del) with SNP-based prenatal cfDNA screening in a commercial population.

Study Design: Included all domestic SNP-based prenatal cfDNA screening with a high-risk result for a fetal 22q del over a 21 month period. Suspected maternal 22q del results were excluded from analysis. Diagnostic testing and ultrasound (u/s) results were collected. PPVs were calculated for samples with genetic truth via microarray (CMA) performed prenatally, postnatally or on products of conception.

Results:
Out of 1,057,710 cases, 753(0.071% or 1/1400) were high-risk for fetal 22q del. Average (avg) maternal age was 30.2 yrs(range 18-46); avg maternal weight 165.6 lbs(91-321 lbs, n=723); avg gestational age 14.0 wks(7.0-35.4); avg fetal fraction 7.9%(2.8-28.6%). Outcomes obtained in 155 cases(20.6%, table 1).
PPV was 47.0%. Including cases with suggestive u/s findings raised the PPV to 56.7%. 46.3% of CMA-positive cases did not have u/s finding(s). For cases with u/s anomalies(n=73), PPV was 78.4%. When u/s findings were limited to a cardiac(CHD) or renal anomaly(n=51), PPV was 92.6%.

Conclusion:
The 22q del affects ~1/1,500-2000 pregnancies and is a common cause of developmental delay and CHDs. Early diagnosis allows for better pregnancy management and improves neonatal outcomes. This study shows a PPV ~50% in the general population and >90% in fetuses with cardiac and/or renal abnormalities. Importantly, less than 50% of true positive cases had u/s findings typically associated with 22q del. Without prenatal cfDNA screening, cases lacking u/s findings may be missed leading to delayed postnatal diagnosis (diagnostic odyssey) with previously reported median time to diagnosis of 4.7 yrs.
A previous prospective study (SNP-based Microdeletion and Aneuploidy RegisTry: SMART) showed a similar PPV of 52.6% in a cohort of 12 affected pregnancies. Results of this study confirm a PPV of ~50% in a larger, real-world study and illustrate the limitations of u/s findings as a screening tool for the 22q del.