Research ArticlePregnancy

Rare autosomal trisomies, revealed by maternal plasma DNA sequencing, suggest increased risk of feto-placental disease

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Science Translational Medicine  30 Aug 2017:
Vol. 9, Issue 405, eaan1240
DOI: 10.1126/scitranslmed.aan1240
  • Fig. 1. Overall study flow showing numbers and distribution of participants.

    n, number; BI, bioinformatics; TN, technical noise; WNL, within normal limits.

  • Fig. 2. Results of interpretation of visual sequence data for both cohorts, indicating absolute numbers of each abnormality.

    The “Uncertain” category reflected cases in which the technical noise precluded interpretation of the data. The “Other” category indicated two or three different abnormalities in the same sample (for example, trisomy plus sex chromosome aneuploidy).

  • Fig. 3. Bar graph indicating the absolute numbers of single RATs observed in both cohorts.

    The chromosome number is shown on the x axis. No trisomies were observed for chromosomes 1, 17, and 19, so they are not included in the figure.

  • Fig. 4. Dot plots of trisomic versus fetal fractions for cohorts 1 and 2.

    The x axis indicates the trisomic fraction, and the y axis shows the fetal fraction. Each dot represents a distinct pregnancy, and the colors represent different chromosomes. Results showed that, in many cases, the trisomic fraction was much less than the estimated fetal fraction (dots within yellow triangles). This disparity suggests that, in cases falling above the identity line, placental mosaicism is likely. (A) The circled data point in cohort 1 shows a trisomic fraction that was much greater than the fetal fraction (red circle). Maternal mosaicism for trisomy 8 was suspected. (B) The circled data point in cohort 2 is a confirmed case of trisomy 8 maternal mosaicism.

  • Table 1. Participant demographics.

    MA, maternal age; GA, gestational age; MAD, median absolute deviation; na, not available.

    Cohort 1 (n = 72,932)Cohort 2 (n = 16,885)Cohort 1 versus cohort 2
    VariableNo flagFlaggedPNo flagFlaggedPP (no flag)P (flagged)
    Samples, n (% total)72,414 (99.29%)518 (0.71%)na16,776 (99.35%)109 (0.65%)na0.383 (difference in
    proportions of flagged
    versus nonflagged,
    comparing cohort 1 to
    cohort 2)
    MA (years)
      Median ± MAD35.6 ± 4.436.1 ± 5.10.00334.4 ± 4.435.7 ± 5.50.01<0.00050.945
      Mean ± SD34.6 ± 5.435.1 ± 5.834.4 ± 4.335.6 ± 4.9
      Min–Max13.8–66.614.0–50.718.2–62.219.8–46.4
    GA (weeks)
      Median ± MAD12.0 ± 3.012.0 ± 3.00.8310.0 ± 010.0 ± 00.847<0.0005<0.0005
      Mean ± SD13.8 ± 4.213.9 ± 4.411.0 ± 1.911.2 ± 2.6
      Min–Max10–4010–3510–3610–31
    Trimester (% of samples)
      First (10–13.9 weeks)47,498 (65.60%)331 (63.80%)0.40215,560 (92.80%)97 (89.00%)0.025<0.0005<0.0005
      Second (14–27.9 weeks)23,956 (33.10%)177 (34.20%)1,207 (7.20%)11 (10.10%)
      Third (28–40+ weeks)960 (1.30%)10 (1.90%)9 (0.10%)1 (0.90%)
  • Table 2. Stratification of clinical samples by NCDQ values.
    NCDQ group labelNCDQ categoryNCDQ group rangeCohort 1 cases, n (%)Cohort 2 cases, n (%)Cohort 1 versus cohort 2 (P)
    No flagNormal+50 to +10272,414 (99.29)16,776 (99.35)0.383
    Flagged
      ABorderline0 to <50272 (0.37)64 (0.38)0.889
      BWarning−100 to 0125 (0.17)24 (0.14)0.463
      CAbnormal−1000 to <−10091 (0.12)18 (0.11)0.624
      DAbnormal<−100030 (0.04)3 (0.02)0.185
    Total518/72,932 (100)109/16,885 (100)0.535 (across all groups)
  • Table 3. Distribution of total samples across trimesters compared to the number and frequency of RATs.
    Trimester (weeks)Cohort 1Cohort 2P*
    Total cases, n (%)RATs, n (as % of trimester totals)Total cases, n (%)RATs, n (%)
    First (10–13)47,829 (65.6)163 (0.34)15,643 (92.6)53 (0.34)1.000
    Second (14–27.9)24,133 (33.1)78 (0.32)1,230 (7.3)6 (0.49)0.299
    Third (28–40)970 (1.3)5 (0.52)12 (0.1)1 (8.3)0.083
    Total72,932 (100)246 (0.34)16,885 (100)60 (0.36)0.122

    *Between frequencies of RATs in cohorts 1 and 2.

    • Table 4. Clinical outcome data for cohort 2 cases with RATs.

      Misc., miscarriage; MCA, multiple congenital abnormalities; NLB, normal live birth; NA, follow-up not available; Mat, maternal; Av., average; TF, trisomic fraction; FF, fetal fraction.

      Missed or early misc.TFMUPDIUFDIUGRMCANLBNAMatTotal
      Trisomy 23(2*)1(1*, 1)15
      Trisomy 3112
      Trisomy 4213
      Trisomy 511
      Trisomy 71(1*)539
      Trisomy 81113
      Trisomy 911114
      Trisomy 10123
      Trisomy 1411
      Trisomy 1513114
      Trisomy 16212(2)(1)27
      Trisomy 201113
      Trisomy 2231§115
      Total225 (+1§)5 (+2*)2 (+2)2 (+4*†‡)1148160
      Av. TF7.608.559.907.237.834.655.523.8414.05
      Av. FF7.158.328.826.987.524.458.978.8111.08
      Ratio Av. TF:FF1.061.031.121.041.041.040.620.441.27

      *Also recorded as TFM.

      †Also recorded as IUFD.

      ‡Also recorded as UPD.

      §Also recorded as miscarriage.

      Supplementary Materials

      • www.sciencetranslationalmedicine.org/cgi/content/full/9/405/eaan1240/DC1

        Fig. S1. Examples of amniocentesis SNP CMA results associated with UPD.

        Fig. S2. Comparison of the frequency of single RATs in current study versus CVS data from a published study.

        Fig. S3. Examples of DNA sequence displays used in cohort 1 to visually analyze results.

        Table S1. Summary of cytogenetic and clinical outcome data from the 60 cases of single RATs in cohort 2.

        Table S2. Frequencies of single RATs in the published literature using cfDNA and cytogenetic analysis.

        Table S3. Observed frequencies of single RATs in the combined current study cohorts compared with CVS data from a published study.

        Table S4. Definition of parameters used to grade technical noise in visual review of data.

        Reference (38)

      • Supplementary Material for:

        Rare autosomal trisomies, revealed by maternal plasma DNA sequencing, suggest increased risk of feto-placental disease

        Mark D. Pertile, Meredith Halks-Miller, Nicola Flowers, Catalin Barbacioru, Sarah L. Kinnings, Darcy Vavrek, William K. Seltzer, Diana W. Bianchi*

        *Corresponding author. Email: diana.bianchi{at}nih.gov

        Published 30 August 2017, Sci. Transl. Med. 9, eaan1240 (2017)
        DOI: 10.1126/scitranslmed.aan1240

        This PDF file includes:

        • Fig. S1. Examples of amniocentesis SNP CMA results associated with UPD.
        • Fig. S2. Comparison of the frequency of single RATs in current study versus CVS data from a published study.
        • Fig. S3. Examples of DNA sequence displays used in cohort 1 to visually analyze results.
        • Table S1. Summary of cytogenetic and clinical outcome data from the 60 cases of single RATs in cohort 2.
        • Table S2. Frequencies of single RATs in the published literature using cfDNA and cytogenetic analysis.
        • Table S3. Observed frequencies of single RATs in the combined current study cohorts compared with CVS data from a published study.
        • Table S4. Definition of parameters used to grade technical noise in visual review of data.
        • Reference (38)

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