Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Prenatal diagnosis of fetuses with region of homozygosity detected by single nucleotide polymorphism array: a retrospective cohort study

Journal of Human Genetics volume 67, pages 629–638 (2022)Cite this article

Subjects

Abstract

Region of homozygosity (ROH) is classified as uniparental disomy (UPD) or identity by descent, depending on its origin. To explore the clinical relevance of ROH in prenatal diagnoses, we reviewed 5063 fetal samples subjected to single nucleotide polymorphism array at our center over 5 years. ROH cases meeting our reporting threshold were further analyzed. ROHs were detected in 22 fetuses (0.43%, 22/5063), of which, 77.3% (17/22) showed a ROH on a single chromosome and 22.7% (5/22) showed multiple ROHs on different chromosomes. Among 5063 fetuses undergoing invasive prenatal diagnoses owing to various indications, five cases were identified as UPDs with a rate of ~1/1000. We observed clinically relevant UPDs in two cases related to Prader–Willi syndrome and transient neonatal diabetes mellitus. Of note, one case showed 50% mosaicism for trisomy 2 in amniotic fluid, whereas a complete UPD (2) was observed in umbilical cord blood. Trio whole-exome sequencing was performed for three cases. Clinically relevant variants were identified in two cases, one of which, NM_000302:c.2071_2072insCC (p.R693Qfs*122) in PLOD1 located in the ROH, may be related to Ehlers-Danlos syndrome, kyphoscoliotic type, 1. Overall, 72.7% (16/22) of the ROH carriers showed ultrasound abnormalities, of whom eight (50%, 8/16) had adverse perinatal outcomes. Our study demonstrates that the clinical relevance of ROHs should be examined regarding fetuses with ROHs occurring on imprinted chromosomes or those derived from consanguineous parents in prenatal diagnoses; imprinting disorders and/or autosomal recessive diseases attributed to ROHs should be considered during genetic counseling.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Kearney HM, Kearney JB, Conlin LK. Diagnostic implications of excessive homozygosity detected by SNP-based microarrays: consanguinity, uniparental disomy, and recessive single-gene mutations. Clin Lab Med. 2011;31:595–613.

    Article  Google Scholar 

  2. Del Gaudio D, Shinawi M, Astbury C, Tayeh MK, Deak KL, Raca G, ACMG Laboratory Quality Assurance Committee. Diagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22:1133–41.

    Article  Google Scholar 

  3. Rehder CW, David KL, Hirsch B, Toriello HV, Wilson CM, Kearney HM. American College of Medical Genetics and Genomics: standards and guidelines for documenting suspected consanguinity as an incidental finding of genomic testing. Genet Med: Off J Am Coll Med Genet. 2013;15:150–2.

    Article  Google Scholar 

  4. Niida Y, Ozaki M, Shimizu M, Ueno K, Tanaka T. Classification of Uniparental Isodisomy Patterns That Cause Autosomal Recessive Disorders: Proposed Mechanisms of Different Proportions and Parental Origin in Each Pattern. Cytogenetic Genome Res. 2018;154:137–46.

    Article  Google Scholar 

  5. Hansen WF, Bernard LE, Langlois S, Rao KW, Chescheir NC, Aylsworth AS, et al. Maternal uniparental disomy of chromosome 2 and confined placental mosaicism for trisomy 2 in a fetus with intrauterine growth restriction, hypospadias, and oligohydramnios. Prenat Diagn. 1997;17:443–50.

    Article  CAS  Google Scholar 

  6. Scheuvens R, Begemann M, Soellner L, Meschede D, Raabe-Meyer G, Elbracht M, et al. Maternal uniparental disomy of chromosome 16 [upd(16)mat]: clinical features are rather caused by (hidden) trisomy 16 mosaicism than by upd(16)mat itself. Clin Genet. 2017;92:45–51.

    Article  CAS  Google Scholar 

  7. Spence JE, Perciaccante RG, Greig GM, Willard HF, Ledbetter DH, Hejtmancik JF, et al. Uniparental disomy as a mechanism for human genetic disease. Am J Hum Genet. 1988;42:217–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Vetro A, Goidin D, Lesende I, Limongelli I, Ranzani GN, Novara F, et al. Diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence and copy number as well as LOH. Clin Genet. 2018;93:545–56.

    Article  CAS  Google Scholar 

  9. Guo T, Tan ZP, Chen HM, Zheng DY, Liu L, Huang XG, et al. An effective combination of whole-exome sequencing and runs of homozygosity for the diagnosis of primary ciliary dyskinesia in consanguineous families. Sci Rep. 2017;7:7905.

    Article  Google Scholar 

  10. Xiao B, Wang L, Liu H, Fan Y, Xu Y, Sun Y, et al. Uniparental isodisomy caused autosomal recessive diseases: NGS-based analysis allows the concurrent detection of homogenous variants and copy-neutral loss of heterozygosity. Mol Genet Genomic Med. 2019;7:e00945.

    Article  Google Scholar 

  11. Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST, Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13:680–5.

    Article  Google Scholar 

  12. Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22:245–57.

    Article  Google Scholar 

  13. Schroeder C, Sturm M, Dufke A, Mau-Holzmann U, Eggermann T, Poths S, et al. UPDtool: a tool for detection of iso- and heterodisomy in parent-child trios using SNP microarrays. Bioinformatics. 2013;29:1562–4.

    Article  CAS  Google Scholar 

  14. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–23.

    Article  Google Scholar 

  15. McQuillan R, Leutenegger AL, Abdel-Rahman R, Franklin CS, Pericic M, Barac-Lauc L, et al. Runs of homozygosity in European populations. Am J Hum Genet. 2008;83:359–72.

    Article  CAS  Google Scholar 

  16. Hoppman N, Rumilla K, Lauer E, Kearney H, Thorland E. Patterns of homozygosity in patients with uniparental disomy: detection rate and suggested reporting thresholds for SNP microarrays. Genet Med. 2018;20:1522–7.

    Article  CAS  Google Scholar 

  17. Inoue T, Yagasaki H, Nishioka J, Nakamura A, Matsubara K, Narumi S, et al. Molecular and clinical analyses of two patients with UPD(16)mat detected by screening 94 patients with Silver-Russell syndrome phenotype of unknown aetiology. J Med Genet. 2019;56:413–8.

    Article  Google Scholar 

  18. Kotzot D, Utermann G. Uniparental disomy (UPD) other than 15: phenotypes and bibliography updated. Am J Med Genet A. 2005;136:287–305.

    Article  Google Scholar 

  19. Eggermann T. Prenatal Detection of Uniparental Disomies (UPD): Intended and Incidental Finding in the Era of Next Generation Genomics. Genes (Basel). 2020;11:1454.

    Article  CAS  Google Scholar 

  20. Nakka P, Pattillo Smith S, O’Donnell-Luria AH, McManus KF. 23andMe Research Team, Mountain JL, et al. Characterization of Prevalence and Health Consequences of Uniparental Disomy in Four Million Individuals from the General Population. Am J Hum Genet. 2019;105:921–32.

    Article  CAS  Google Scholar 

  21. Matsubara K, Murakami N, Nagai T, Ogata T. Maternal age effect on the development of Prader-Willi syndrome resulting from upd(15)mat through meiosis 1 errors. J Hum Genet. 2011;56:566–71.

    Article  Google Scholar 

  22. Robinson WP, Christian SL, Kuchinka BD, Peñaherrera MS, Das S, Schuffenhauer S, et al. Somatic segregation errors predominantly contribute to the gain or loss of a paternal chromosome leading to uniparental disomy for chromosome 15. Clin Genet. 2000;57:349–58.

    Article  CAS  Google Scholar 

  23. Bittles A. Consanguinity and its relevance to clinical genetics. Clin Genet. 2001;60:89–98.

    Article  CAS  Google Scholar 

  24. Yingjun X, Zhiyang H, Linhua L, Fangming S, Linhuan H, Jinfeng T. Chromosomal uniparental disomy 16 and fetal intrauterine growth restriction. Eur J Obstet Gynecol Reprod Biol. 2017;211:1–7.

    Article  Google Scholar 

  25. Kotzot D. Prenatal testing for uniparental disomy: indications and clinical relevance. Ultrasound Obstet Gynecol. 2008;31:100–5.

    Article  CAS  Google Scholar 

  26. Wilkins-Haug L, Quade B, Morton CC. Confined placental mosaicism as a risk factor among newborns with fetal growth restriction. Prenat Diagn. 2006;26:428–32.

    Article  Google Scholar 

Download references

Acknowledgements

We deeply thank the patients and family members who participated in this study.

Funding

This work was supported by grant from Fujian Provincial Health Technology Project (grant no. 2020GGB018); Fujian Provincial Maternity and Child Health Hospital (grant no. YCXM 19–15); Fujian Provincial Natural Science Foundation (grant no. 2019J01509); and Joints Funds for the Innovation of Science and Technology, Fujian Province (grant no. 2020Y9159).

Author information

Author notes

  1. These authors contributed equally: Bin Liang, Donghong Yu.

Authors and Affiliations

  1. Medical Genetic Diagnosis and Therapy Center, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 350001, Fuzhou, China

    Bin Liang, Yan Wang, Xinrui Wang, Xiaoqing Wu, Lingji Chen, Meihuan Chen, Min Zhang, Xuemei Chen, Na Lin, Hailong Huang & Liangpu Xu

  2. Fujian Obstetrics and Gynecology Hospital, Fuzhou, 350011, Fujian, China

    Donghong Yu & Wantong Zhao

  3. Medical Research Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China

    Donghong Yu & Xinrui Wang

Authors
  1. Bin Liang
    View author publications

    Search author on:PubMed Google Scholar

  2. Donghong Yu
    View author publications

    Search author on:PubMed Google Scholar

  3. Wantong Zhao
    View author publications

    Search author on:PubMed Google Scholar

  4. Yan Wang
    View author publications

    Search author on:PubMed Google Scholar

  5. Xinrui Wang
    View author publications

    Search author on:PubMed Google Scholar

  6. Xiaoqing Wu
    View author publications

    Search author on:PubMed Google Scholar

  7. Lingji Chen
    View author publications

    Search author on:PubMed Google Scholar

  8. Meihuan Chen
    View author publications

    Search author on:PubMed Google Scholar

  9. Min Zhang
    View author publications

    Search author on:PubMed Google Scholar

  10. Xuemei Chen
    View author publications

    Search author on:PubMed Google Scholar

  11. Na Lin
    View author publications

    Search author on:PubMed Google Scholar

  12. Hailong Huang
    View author publications

    Search author on:PubMed Google Scholar

  13. Liangpu Xu
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Na Lin, Hailong Huang or Liangpu Xu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liang, B., Yu, D., Zhao, W. et al. Prenatal diagnosis of fetuses with region of homozygosity detected by single nucleotide polymorphism array: a retrospective cohort study. J Hum Genet 67, 629–638 (2022). https://doi.org/10.1038/s10038-022-01062-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s10038-022-01062-9

This article is cited by

Search

Advanced search

Quick links