Authors' response to: Meeting the challenge of interpreting high-resolution single nucleotide polymorphism array data: does increased diagnostic power outweigh the dilemma of rare variants

Authors

  • G McGillivray,

    1. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia
    2. Genetic Counselling Service, Royal Women's Hospital, Melbourne, Australia
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  • DL Bruno,

    1. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia
    2. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia
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  • HR Slater,

    1. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia
    2. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia
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  • DJ Amor

    1. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia
    2. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia
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Authors' Reply

Sir,

Hillman et al.[1] agree that high-resolution single nucleotide polymorphism (SNP) microarray analysis has greater sensitivity for detection of pathogenic findings in a high-risk obstetric population; however, they express concern about the more frequent detection of variants of uncertain significance (VOUS) inherent in this approach. Specifically they question whether the major advantage of high-resolution microarrays, the greater sensitivity for pathogenic findings, is outweighed by VOUS detection and the associated increase in costs and more difficult counselling scenarios.

We agree that detection of VOUS presents challenges for laboratory professionals, medical specialists, genetic counsellors and parents. However, we believe that these challenges can be met by a coordinated and combined clinical–laboratory approach, with expertise gained through the use of high-resolution microarrays in the postnatal setting and by the ‘critical assessment of the evidence base current at the time of reporting’.[2]

There are three additional advantages of using high-resolution SNP microarrays in a high-risk obstetric population, beyond the greater sensitivity for pathogenic findings. First, it removes the risk of discrepant results between prenatal and postnatal samples. Second, copy number variations (CNV) (>200 kilobases) from high-resolution SNP microarrays are unambiguous because of dense probe coverage, negating the need for second-step analyses. Third, there is a substantially reduced need to update probe designs as new pathogenic regions or genes are described.

We also believe that patient autonomy is critical and that it should extend, in the context of informed consent, to women having the option of high-resolution microarray testing for prenatal diagnosis for all indications for fetal karyotyping. We have previously addressed the concern that the reporting of VOUS could theoretically result in the termination of a pregnancy for a result that turns out to be benign.[3] This concern can be addressed ethically by viewing the primary role of prenatal diagnosis as giving women the opportunity for informed choice, rather than helping women to have healthy babies.

Finally, some caution is required when comparing detection rates of VOUS between studies because of differing laboratory policies for reporting VOUS and differing views regarding the reclassification of results based on inheritance status.

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