When genotype is not predictive of phenotype: implications for genetic counseling based on 21,594 chromosomal microarray analysis examinations

Genet Med. 2018 Jan;20(1):128-131. doi: 10.1038/gim.2017.89. Epub 2017 Jul 20.


PurposeTo compare the frequency of copy-number variants (CNVs) of variable penetrance in low-risk and high-risk prenatal samples and postnatal samples.MethodsTwo cohorts were categorized according to chromosomal microarray analysis (CMA) indication: group I, low-risk prenatal-women with uneventful pregnancy (control group); group II, high-risk prenatal-women whose fetuses had congenital malformations; and group III, postnatal-individuals with unexplained developmental delay/intellectual disability, autism spectrum disorders, or multiple congenital anomalies. CNVs were categorized based on clinical penetrance: (i) high (>40%), (ii) moderate (10-40%), and (iii) low (<10%).ResultsFrom 2013 to 2016, 21,594 CMAs were performed. The frequency of high-penetrance CNVs was 0.1% (21/15,215) in group I, 0.9% (26/2,791) in group II, and 2.6% (92/3,588) in group III. Moderate-penetrance CNV frequency was 0.3% (47/15,215), 0.6% (19/2,791), and 1.2% (46/3,588), respectively. These differences were statistically significant. The frequency of low-penetrance CNVs was not significantly different among groups: 0.6% (85/15,215), 0.9% (25/2,791), and 1.0% (35/3,588), respectively.ConclusionHigh-penetrance CNVs might be a major factor in the overall heritability of developmental, intellectual, and structural anomalies. Low-penetrance CNV alone does not seem to contribute to these anomalies. These data may assist pre- and posttest CMA counseling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Aberrations
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • Female
  • Genetic Association Studies*
  • Genetic Counseling
  • Genetic Heterogeneity*
  • Genotype*
  • Humans
  • Infant, Newborn
  • Male
  • Neonatal Screening
  • Penetrance
  • Phenotype*
  • Polymorphism, Single Nucleotide
  • Prenatal Diagnosis
  • Sexism