Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Sample Preparation
2.2. Whole Genome Sequencing at Different Coverage Depths
2.3. Bioinformatics Analysis of AOH Detection
2.4. Validation of AOH Detection by CMA/SNP Array
3. Results
3.1. Assessment of Minimum Sequencing Coverage for AOH Detection
3.2. Performance of Detection of AOH for Prenatal Samples with CMA-seq
3.3. Evaluation and Analysis of Normal Sample and Detection of Chromosomal Level AOH
3.4. Evaluation and Analysis of Whole Genome Level AOH
3.5. Evaluation and Analysis of Segmental AOH
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Samle ID | Sample Types | Clinical Indication(s) | CMA | GS | Result of Comparison | Classification | Diseases | ||
---|---|---|---|---|---|---|---|---|---|
‘001 | amniotic fluid | Advanced Maternal Age, The couple had a child with chromosomal disease (46, X, iY(p10)) | 7q21.11q21.3(80,832,371–94,133,800)×2 hmz | 13.3 | 7q21.11q21.3(81,000,000–94,100,000), ×2 hmz | 13.1 | Consistently | VUS | Silver–Russell syndrome |
‘002 | amniotic fluid | advanced maternal age, abnormal NIPT result (Z2 = 9.9) | 2p25.3p24.3(50,814–13,311,915)×2 hmz | 13 | 2p25.3p24.3(200,000–13,100,000), ×2 hmz | 12.9 | Consistently | VUS | |
2q32.3q36.3(192,341,274–230,205,775)×2 hmz | 37.9 | 2q33.2q36.3(204,100,000–230,100,000), ×2 hmz | 26 | Consistently | VUS | ||||
2p21p11.2(45,974,855–87,053,152)×2 hmz | 41.1 | 2p21p13.2(45,700,000–72,400,000), ×2 hmz; 2p13.1p11.2(75,000,000–89,000,000), ×2 hmz | 26.7 14 | Consistently | VUS | ||||
2q11.1q12.3(95,550,958–109,626,929)×2 hmz | 14 | 2q11.2q12.3(98,700,000–108,200,000), ×2hmz | 9.5 | Consistently | VUS | ||||
‘027 | peripheral blood | parental validation for abnormal fetal CMA result. The fetus had an ultrasound abnormality of omphalocele, and the CMA indicated a 539 kb duplication on chromosome 16p11.2, which was associated with 16p11.2 duplication syndrome, as well as a 1.7 Mb duplication on chromosome Xp22.31 of unknow significance. | Xp22.31(6,455,152–8,135,568)×4 | Xp22.31(6,455,152–8,135,568)x3.88 | Consistently | VUS | |||
4q25q28.3(111,718,067–137,498,491)×2 hmz | 25 | 4q25q28.3(111,800,000–137,400,000), ×2hmz | 25.6 | Consistently | VUS | ||||
6q14.1q21(83,539,461–113,232,989)×2 hmz | 29 | 6q14.1q21(83,500,000–113,200,000), ×2hmz | 29.7 | Consistently | VUS | transient neonatal diabetes mellitus | |||
7q31.1q33(112,161,869–136,999,883)×2 hmz | 24 | 7q31.1q33(112,300,000–136,400,000), ×2hmz | 24.1 | Consistently | VUS | Silver–Russell syndrome | |||
Xp22.31p21.2(8,485,023–31,282,369)×2 hmz, | 23 | Xp22.31p22.2(7,900,000–10,200,000), ×2 hmz; Xp22.2(11,500,000–14,300,000), ×2 hmz; Xp22.2p22.13(15,300,000–17,800,000), ×2 hmz; Xp22.12p21.3(20,400,000–27,700,000), ×2 hmz; Xp21.3p21.2(28,500,000–31,200,000), ×2 hmz; Xp11.21(49,00,000–57,600,000), ×2 hmz; Xq21.1(80,100,000–82,400,000), ×2 hmz | 2.3 2.8 2.5 7.3 2.7 2.7 2.3 | Consistently | VUS | ||||
Xq23q25(114,567,797–128,598,791)×2 hmz | 14 | Xq24q25(117,900,000–128,600,000), ×2 hmz | 10.7 | Consistently | VUS | ||||
7q36.2q36.3(154,400,000–158,800,000), ×2 hmz | 4.4 | Additional findings | VUS | ||||||
20p13p12.3(100,000–5,800,000), ×2 hmz | 5.7 | Additional findings | P | Pseudohypoparathyroidism type 1B | |||||
‘030 | chorionic villus sampling | The ultrasound indicated fetal abnormality (NT = 3.3 mm) | 2p12p11.2(75,632,552–87,053,152)×2 hmz, | 11.4 | 2p12p11.2(75,600,000–87,100,000), ×2 hmz | 11.5 | Consistently | VUS | |
15q25.1q26.1(79,625,730–94,285,672)×2 hmz | 14.7 | 15q25.1q26.1(78,900,000–94,200,000), ×2 hmz | 15.3 | Consistently | VUS | Prader Willi syndrome, Angelman syndrome | |||
‘031 | peripheral blood | systemic scleroderma | 1p13.3p11.2(107,624,475_121,339,317)×2 hmz, | 13.7 | 1p13.3p12(107,500,000–120,500,000), ×2 hmz | 13 | Consistently | ||
1q21.1q32.2(144,077,594_207,345,376)×2 hmz, | 63.3 | 1q21.3q22(151,200,000–155,300,000), ×2 hmz; 1q22q32.1(155,900,000–206,000,000), ×2 hmz | 4.1 50.1 | Consistently | VUS | ||||
7q11.22q21.11(71,236,774_83,356,842)×2 hmz, | 12 | 7q11.23q21.11(75,200,000–83,400,000), ×2 hmz | 8.2 | Consistently | VUS | Silver–Russell syndrome | |||
10p14p12.1(7,588,527_29,290,352)×2 hmz | 21.7 | 10p14p12.31(7,700,000–21,600,000), ×2 hmz; 10p12.31p12.1(22,200,000–29,600,000), ×2 hmz | 13.9 7.4 | Consistently | VUS | ||||
Xp22.33p22.31(2,100,000–8,500,000), ×2 hmz | 6.4 | Additional findings | VUS | ||||||
Xp11.21(54,900,000–57,600,000), ×2 hmz | 2.7 | Additional findings | VUS | ||||||
Xq13.3q21.1(74,400,000–77,000,000), ×2 hmz | 2.6 | Additional findings | VUS | ||||||
Xq24q26.3(119,500,000–136,400,000), ×2 hmz | 16.9 | Additional findings | VUS | ||||||
7p14.1(40,390,001–40,530,000), ×1 | ~140 kb, deletion | Additional findings | LP | Glutaric aciduria type III | |||||
‘032 | amniotic fluid | abnormal NIPT result (Z3 = 18.49) | arr(3)×2 hmz | 3UPD | chr3 | 3UPD | Consistently | VUS | |
‘033 | amniotic fluid | advanced maternal age | 18q21.2q22.3(49,750,952_71,592,671)×2 hmz | 21.8 | 18q21.2q22.3(49,900,000–71,700,000), ×2 hmz | 21.8 | Consistently | VUS | |
‘034 | peripheral blood | parental validation for fetal CMA result. The fetus had abnormal NIPT result (Z18 = −7.11) and the CMA indicated a pathogenic variant of 15Mb deletion on chromosome 18q22.1q23, as well as a 6.4 Mb duplication on chromosome 1q43q44 of unknow significance. | 1q43(241,124,639_242,772,875)x1, | 1.65 | 1q43(241,110,001–242,770,000), ×2 hmz | 1.66, deletion | Consistently | P | |
2q32.3q34(192,406,884_209,298,633)×2 hmz | 16.9 | 2q32.3q34(192,700,000–209,300,000), ×2 hmz | 16.6 | Consistently | VUS | ||||
2q31.1q31.2(176,400,000–178,600,000), ×2 hmz | 2.2 | Additional findings | VUS | ||||||
18q22.1(63,100,001–63,680,000), ×2 hmz | ~580 kb, deletion | Additional findings | VUS | ||||||
‘036 | amniotic fluid | NT thickening | 13q11q34(19,450,957–115,095,705)×2 hmz | 95.6 | 13q11q34(19,300,000–115,100,000), ×2 hmz | 95.8 | Consistently | VUS | |
‘048 | amniotic fluid | fetal growth restriction | 8q12.1q13.3(58,247,980–71,953,755)×2 hmz | 13.7 | 8q12.1q13.3(58,400,000–73,000,000), ×2 hmz | 14.6 | Consistently | VUS | |
‘049 | amniotic fluid | nasal bone absence | 3p23p21.31(31,569,962–44,915,992)×2 hmz, | 13.3 | 3p23p22.2(31,700,000–44,400,000), ×2 hmz | 13.6 | Consistently | VUS | |
(21)×3 | trisomy 21 | chr21×3 | trisomy 21 | Consistently | P | Down syndrome | |||
‘053 | peripheral blood | parental validation for abnormal fetal CMA result. The pregnancy women underwent chorionic villus sampling because the first child of the couple had phenylketonuria. The CMA indicated a 208 kb deletion on chromosome 4q25 of unknown significance. | 4q21.23q26(85,439,001–116,726,668)×2 hmz | 31.2 | 4q21.23q26(85,400,000–116,500,000), ×2 hmz | 31.1 | Consistently | VUS | |
8q22.2q24.21(101,423,593–128,671,420)×2 hmz | 27.2 | 8q22.3q24.21(101,700,000–129,100,000), ×2 hmz | 27.4 | Consistently | VUS | ||||
12p13.31p12.1(8,146,161–25,668,635)×2 hmz | 17.5 | 12p13.31p12.1(8,200,000–25,700,000), ×2 hmz | 17.5 | Consistently | VUS | ||||
4q28.3q31.1(138,700,000–141,000,000), ×2 hmz | 2.3 | Additional findings | VUS | ||||||
8q12.3q13.1(64,500,000–66,600,000), ×2 hmz | 2.1 | Additional findings | VUS | ||||||
‘054 | chorionic villus sampling | twin molar pregnancy | 19p13.3p11(260,911–24,462,369)×2 hmz, | 19 UPD | 19p13.3p12(400,000–20,900,000), ×2 hmz | 20.5 | Consistently | VUS | |
19q11q13.43(28,274,010–58,955,556)×2 hmz | 19p12(21,900,000–24,400,000), ×2 hmz | 2.5 | Consistently | VUS | |||||
19q11q13.2(28,500,000–42,500,000), ×2 hmz | 14 | Consistently | VUS | ||||||
19q13.31q13.43(43,500,000–58,900,000), ×2 hmz | 15.4 | Consistently | VUS | ||||||
‘055 | chorionic villus sampling | omphalocele | 13q12.11q13.3(22,951,566–38,289,937)×2 hmz, | 15.3 | 13q12.11q13.3(23,100,000–38,300,000), ×2 hmz | 15.2 | Consistently | VUS | |
18p11.32q23(136,227–78,013,728)×3 | trisomy 18 | chr18×3 | trisomy 18 | Consistently | VUS | ||||
‘056 | peripheral blood | intrauterine demise | Xq22.1q26.3(99,176,543–135,657,966)×2 hmz, | 36.4 | Xq22.1q22.3(99,600,000–104,300,000), ×2 hmz; Xq23q24(111,600,000–117,100,000), ×2 hmz; Xq24q25chrX:117,400,000–123,900,000, ×2 hmz; Xq25q26.3(126,700,000–134,800,000), ×2 hmz | 4.1 5.3 6.4 6.4 | Consistently | VUS | |
2q21.3q24.3(135,219,538–164,635,629)×2 hmz, | 29.4 | 2q21.2q24.1(134,700,000–158,200,000), ×2 hmz; 2q24.1q24.3(158,600,000–164,600,000), ×2 hmz | 23.5 6 | Consistently | VUS | ||||
7p22.3p21.2(50,943–14,472,953)×2 hmz, | 14.4 | 7p22.3p21.2(500,000–14,600,000), ×2 hmz | 14.1 | Consistently | VUS | Silver–Russell syndrome | |||
12p13.33p11.21(257,935–31,063,131)×2 hmz, | 30.8 | 12p13.33p11.21(400,000–31,300,000), ×2 hmz | 30.9 | Consistently | VUS | ||||
12q12q14.2(42,805,029–63,265,817)×2 hmz | 20.4 | 12q12q14.2(42,600,000–64,800,000), ×2 hmz | 22.2 | Consistently | VUS | ||||
7q31.32q31.33(122,600,000–125,200,000), ×2 hmz | 2.6 | Additional findings | VUS | ||||||
2p15p14(62,900,000–65,000,000), ×2 hmz | 2.1 | Additional findings | VUS | ||||||
2p12p11.2(81,700,000–84,000,000), ×2 hmz | 2.3 | Additional findings | VUS | ||||||
‘057 | Placenta | twin molar pregnancy | 19p13.3p11(260,911–24,462,369)×2 hmz, | 19 UPD | 19p13.3p13.11(400,000–19,500,000), ×2 hmz, | 19.1 | Consistently | VUS | |
19q11q13.43(28,274,010–58,955,556)×2 hmz | 19q11q13.43(28,500,000–59,100,000), ×2 hmz | 30.6 | Consistently | VUS | |||||
‘058 | amniotic fluid | congenital diaphragmatic hernia | 6p25.3q27(203,877–170,896,644)×2 hmz | 6 UPD | 6p25.3p11.1(200,000–58,900,000), ×2 hmz | 58.7 | Consistently | VUS | transient neonatal diabetes mellitus |
6q11.1q27(62,100,000–171,200,000), ×2 hmz | 109.1 | Consistently | VUS | transient neonatal diabetes mellitus | |||||
‘059 | chorionic villus sampling | twin molar pregnancy | arr(1–22,X)×2 hmz | Genome-wide | chr(1–22,X)×2 hmz | Consistently | P? | ||
‘061 | amniotic fluid | advanced maternal age | 15q22.2q25.3(61,837,131–86,568,353)×2 hmz | 24.7 | 15q22.2q25.2(61,900,000–82,600,000), ×2 hmz | 20.7 | Consistently | VUS | Prader Willi syndrome, Angelman syndrome |
15q25.2q25.3(83,300,000–87,300,000), ×2 hmz | 4 | Consistently | VUS | Prader Willi syndrome, Angelman syndrome | |||||
Xp22.13(18,800,001–19,180,000), x3 | ~380 kb, duplication | Additional findings | VUS | ||||||
‘062 | peripheral blood | parental validation for fetal CMA result. The fetus had ultrasound abnormality of hyperechogenic kidneys and the CMA indicated a 1.4 Mb deletion on chromosome 17q12, which was associated with 17q12 recurrent deletion syndrome. | 6q15q21(91,258,687–106,596,685)×2 hmz | 15.3 | 6q15q21(91,400,000–106,500,000), ×2 hmz | 15.1 | Consistently | VUS | transient neonatal diabetes mellitus |
‘064 | chorionic villus sampling | megacystis, single umbilical artery | 20p12.3p11.23(9,051,988–20,268,154)×2 hmz | 20p12.3p11.23(9,000,000–20,300,000), ×2 hmz | 11.3 | Consistently | VUS | Pseudohypoparathyroidism type 1B | |
‘065 | cord blood | amniotic fluid sample revealing karotype of 47,XXY/46,XY | arr(X)×2 hmz,(Y)×1 | XXY, XUPD | arr(X)×2 hmz,(Y)×1 | X UPD | Consistently | VUS | |
‘066 | amniotic fluid | abnormal NIPT result | 3p24.1p14.2(30,639,805–63,601,962)×2 hmz, | 32.9 | 3p24.1p21.31(30,800,000–48,200,000), ×2 hmz; 3p21.31p14.2(50,100,000–63,500,000), ×2 hmz | 17.4 13.4 | Consistently | VUS | |
5q11.2q13.2(54,259,794–68,826,246)×2 hmz, | 14.5 | 5q11.2q13.2(54,100,000–71,200,000), ×2 hmz | 17.1 | Consistently | VUS | ||||
9p23p21.2(11,072,446–25,606,655)×2 hmz, | 14.5 | 9p23p21.3(11,200,000–25,500,000), ×2 hmz | 14.3 | Consistently | VUS | ||||
18q21.1q21.32(44,375,110–57,719,351)×2 hmz | 13.3 | 18q21.1q21.32(44,400,000–57,700,000), ×2 hmz | 13.3 | Consistently | VUS | ||||
3p26.1p25.2(6,800,000–12,300,000), ×2 hmz | 5.5 | Additional findings | VUS | ||||||
VUS | |||||||||
‘067 | peripheral blood | parental validation for fetal CMA result. The fetus had ultrasound abnormality of congenital diaphragmatic hernia and the CMA indicated a 335 kb duplication on chromosome 7q36.1 of unknow significance. | 7q36.1(151,842,964–152,178,027)×3 | 335 kb, duplication | 7q36.1(151,840,001–152,070,000)×3 | ~230 kb, duplication | Consistently | VUS | |
12q23.1q24.13(98,658,599–114,095,220)×2 hmz | 15.4 | 12q23.1q24.11(99,500,000–110,300,000), ×2 hmz | 10.8 | Consistently | VUS | ||||
16p13.3(5,910,001–6,260,000), ×1 | ~350 kb, deletion | Additional findings | VUS | ||||||
‘068 | peripheral blood | parental validation for fetal CMA result. The fetus had ultrasound abnormality of cleft lip and palate and the CMA indicated a 14.9 Mb deletion on chromosome 18p11.32p11.21, which was associated with Chromosome 18p deletion syndrome. | arr[hg19] 9q31.1q33.3(105,122,292–129,460,914)×2 hmz, | 24.3 | 9q31.1q33.3(104,800,000–129,400,000), ×2 hmz | 24.6 | Consistently | VUS | Temple syndrome, Kagami-Ogata syndrome |
12p13.2p12.1(10,121,410–24,518,044)×2 hmz | 14.3 | 12p13.2p12.1(10,200,000–24,700,000), ×2 hmz | 14.5 | Consistently | VUS | ||||
14q24.3q31.3(77,100,000–85,800,000), ×2 hmz | 8.7 | Additional findings | VUS | ||||||
‘069 | amniotic fluid | consanguineous marriage | 9p22.3p13.1(16,315,832–38,771,831)×2 hmz | 22.4 | 9p22.3p13.1(14,800,000–39,200,000), ×2 hmz | 24.4 | Consistently | VUS | |
9q21.11q21.13(71,100,000–78,500,000), ×2 hmz | 7.4 | Additional findings | VUS | ||||||
‘109 | amniotic fluid | advanced maternal age | 7q32.3q36.1(132,165,146–151,810,715)×2 hmz | 19.6 | 7q32.3q34(132,300,000–142,000,000), ×2 hmz | 9.7 | Consistently | VUS | Silver–Russell syndrome |
7q34q36.1(143,100,000–151,500,000), ×2 hmz | 8.4 | Consistently | VUS |
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Lü, Y.; Jiang, Y.; Zhou, X.; Hao, N.; Lü, G.; Guo, X.; Guo, R.; Liu, W.; Xu, C.; Chang, J.; et al. Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis. Diagnostics 2023, 13, 560. https://doi.org/10.3390/diagnostics13030560
Lü Y, Jiang Y, Zhou X, Hao N, Lü G, Guo X, Guo R, Liu W, Xu C, Chang J, et al. Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis. Diagnostics. 2023; 13(3):560. https://doi.org/10.3390/diagnostics13030560
Chicago/Turabian StyleLü, Yan, Yulin Jiang, Xiya Zhou, Na Hao, Guizhen Lü, Xiangxue Guo, Ruidong Guo, Wenjie Liu, Chenlu Xu, Jiazhen Chang, and et al. 2023. "Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis" Diagnostics 13, no. 3: 560. https://doi.org/10.3390/diagnostics13030560
APA StyleLü, Y., Jiang, Y., Zhou, X., Hao, N., Lü, G., Guo, X., Guo, R., Liu, W., Xu, C., Chang, J., Li, M., Zhang, H., Zhou, J., Zhang, W., & Qi, Q. (2023). Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis. Diagnostics, 13(3), 560. https://doi.org/10.3390/diagnostics13030560