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

Biochem Genet. 2020 Feb;58(1):74-101. doi: 10.1007/s10528-019-09931-3. Epub 2019 Jul 4.


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; Developmental delay; Dysmorphology; Loss of heterozygosity; Multiple congenital anomalies.

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Chromosome Breakage
  • Cohort Studies
  • DNA Copy Number Variations
  • Developmental Disabilities / genetics
  • Down Syndrome / diagnosis*
  • Down Syndrome / genetics
  • Female
  • Homozygote*
  • Humans
  • Infant
  • Infant, Newborn
  • Klinefelter Syndrome / diagnosis*
  • Klinefelter Syndrome / genetics
  • Male
  • Oligonucleotide Array Sequence Analysis / methods
  • Trisomy 13 Syndrome / diagnosis*
  • Trisomy 13 Syndrome / genetics
  • Trisomy 18 Syndrome / diagnosis*
  • Trisomy 18 Syndrome / genetics
  • Turner Syndrome / diagnosis*
  • Turner Syndrome / genetics