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Additive Diagnostic Yield of Homozygosity Regions Identified During Chromosomal microarray Testing in Children with Developmental Delay, Dysmorphic Features or Congenital Anomalies

  • Mohamed A. M. AliEmail author
  • Abdelrahman M. Hassan
  • Mosaab A. Saafan
  • Adel A. Abdelmagid
Original Article
  • 65 Downloads

Abstract

Chromosomal microarray (CMA) has emerged as a robust tool for identifying microdeletions and microduplications, termed copy number variants (CNVs). Nevertheless, data regarding its utility in different patient populations with developmental delay (DD), dysmorphic features (DF) and congenital anomalies (CA), is a matter of dense debate. Although regions of homozygosity (ROH) are not diagnostic of a specific condition, they may have pathogenic implications. Certain CNVs and ROH have ethnically specific occurrences and frequencies. We aimed to determine whether CMA testing offers additional diagnostic information over classical cytogenetics for identifying genomic imbalances in a pediatric cohort with idiopathic DD, DF, or CA. One hundred sixty-nine patients were offered cytogenetics and CMA simultaneously for etiological diagnosis of DD (n = 67), DF (n = 52) and CA (n = 50). CMA could identify additional, clinically significant anomalies as compared with cytogenetics. CMA detected 61 CNVs [21 (34.4%) pathogenic CNVs, 37 (60.7%) variants of uncertain clinical significance and 3 (4.9%) benign CNVs] in 44 patients. CMA identified one or more ROH in 116/169 (68.6%) patients. When considering pathogenic CNVs and aneuploidies as positive findings, 9/169 (5.3%) received a genetic diagnosis from cytogenetics, while 25/169 (14.8%) could have a genetic diagnosis from CMA. The identification of ROH was clinically significant in two cases (2/169), thereby, adding 1.2% to the diagnostic yield of CMA (16% vs. 5.3%, p < 0.001). CMA uncovers additional genetic diagnoses over cytogenetics, thereby, offering a much higher diagnostic yield. Our findings convincingly demonstrate the additive diagnostic value of clinically significant ROH identified during CMA testing, highlighting the need for careful clinical interpretation of these ROH.

Keywords

Chromosomal microarray Loss of heterozygosity Developmental delay Dysmorphology Multiple congenital anomalies 

Notes

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the local ethical committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10528_2019_9931_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 18 kb)
10528_2019_9931_MOESM2_ESM.docx (109 kb)
Supplementary material 2 (DOCX 108 kb)
10528_2019_9931_MOESM3_ESM.docx (68 kb)
Supplementary material 3 (DOCX 67 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mohamed A. M. Ali
    • 1
    Email author
  • Abdelrahman M. Hassan
    • 2
  • Mosaab A. Saafan
    • 3
  • Adel A. Abdelmagid
    • 3
  1. 1.Department of Biochemistry, Faculty of ScienceAin Shams UniversityCairoEgypt
  2. 2.Human Cytogenetics DepartmentNational Research CenterCairoEgypt
  3. 3.Cytogenetics UnitAl Borg Medical LaboratoriesJeddahKingdom of Saudi Arabia

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