title: Meeting the challenge of interpreting high-resolution single nucleotide polymorphism array data in prenatal diagnosis: does increased diagnostic power outweigh the dilemma of rare variants?
abstract: OBJECTIVE
  Several studies have already shown the superiority of chromosomal microarray analysis (CMA) compared with conventional karyotyping for prenatal investigation of fetal ultrasound abnormality. This study used very high-resolution single nucleotide polymorphism (SNP) arrays to determine the impact on detection rates of all clinical categories of copy number variations (CNVs), and address the issue of interpreting and communicating findings of uncertain or unknown clinical significance, which are to be expected at higher frequency when using very high-resolution CMA.
  
  
  METHODS
  Prospective validation study.
  
  
  METHODS
  Tertiary clinical genetics centre.
  
  
  METHODS
  Women referred for further investigation of fetal ultrasound anomaly.
  
  
  METHODS
  We prospectively tested 104 prenatal samples using both conventional karyotyping and high-resolution arrays.
  
  
  METHODS
  The detection rates for each clinical category of CNV.
  
  
  RESULTS
  Unequivocal pathogenic CNVs were found in six cases, including one with uniparental disomy (paternal UPD 14). A further four cases had a 'likely pathogenic' finding. Overall, CMA improved the detection of 'pathogenic' and 'likely pathogenic' abnormalities from 2.9% (3/104) to 9.6% (10/104). CNVs of 'unknown' clinical significance that presented interpretational difficulties beyond results from parental investigations were detected in 6.7% (7/104) of samples.
  
  
  CONCLUSIONS
  Increased detection sensitivity appears to be the main benefit of high-resolution CMA. Despite this, in this cohort there was no significant benefit in terms of improving detection of small pathogenic CNVs. A potential disadvantage is the high detection rate of CNVs of 'unknown' clinical significance. These findings emphasise the importance of establishing an evidence-based policy for the interpretation and reporting of CNVs, and the need to provide appropriate pre- and post-test counselling.
authors: VCGS Cytogenetics Laboratory, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia.
authors: D
authors: D
authors: Ganesamoorthy
authors: D L
authors: DL
authors: Bruno
authors: G
authors: G
authors: McGillivray
authors: F
authors: F
authors: Norris
authors: S M
authors: SM
authors: White
authors: S
authors: S
authors: Adroub
authors: D J
authors: DJ
authors: Amor
authors: A
authors: A
authors: Yeung
authors: R
authors: R
authors: Oertel
authors: M D
authors: MD
authors: Pertile
authors: C
authors: C
authors: Ngo
authors: A R
authors: AR
authors: Arvaj
authors: S
authors: S
authors: Walker
authors: P
authors: P
authors: Charan
authors: R
authors: R
authors: Palma-Dias
authors: N
authors: N
authors: Woodrow
authors: H R
authors: HR
authors: Slater
mesh_terms: D018929:Cell Culture Techniques; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D007621:Karyotyping; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D011446:Prospective Studies; D016216:Ultrasonography, Prenatal / Q000379:methods*; D024182:Uniparental Disomy / Q000175:diagnosis*