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Callaway J.L.A.,Wessex Regional Genetics Laboratory | Shaffer L.G.,Genetic Veterinary science Inc | Chitty L.S.,University College London | Rosenfeld J.A.,Perkin Elmer Corporation | And 2 more authors.
Prenatal Diagnosis | Year: 2013

The clinical utility of microarray technologies when used in the context of prenatal diagnosis lies in the technology's ability to detect submicroscopic copy number changes that are associated with clinically significant outcomes. We have carried out a systematic review of the literature to calculate the utility of prenatal microarrays in the presence of a normal conventional karyotype. Amongst 12362 cases in studies that recruited cases from all prenatal ascertainment groups, 295/12362 (2.4%) overall were reported to have copy number changes with associated clinical significance (pCNC), 201/3090 (6.5%) when ascertained with an abnormal ultrasound, 50/5108 (1.0%) when ascertained because of increased maternal age and 44/4164 (1.1%) for all other ascertainment groups (e.g. parental anxiety and abnormal serum screening result). When additional prenatal microarray studies are included in which ascertainment was restricted to fetuses with abnormal ultrasound scans, 262/3730 (7.0%) were reported to have pCNCs. © 2013 John Wiley & Sons, Ltd.

Shaffer L.G.,Genetic Veterinary science Inc | Rosenfeld J.A.,Perkin Elmer Corporation
Expert Review of Molecular Diagnostics | Year: 2013

The goal of prenatal cytogenetic testing is to provide reassurance to the couple seeking testing for their pregnancy, identify chromosome abnormalities in the fetus, if present, and provide treatments and medical management for affected babies. Cytogenetic analysis of banded chromosomes has been the standard for identifying chromosome abnormalities in the fetus for over 40 years. With chromosome analysis, whole chromosome aneuploidies and large structural rearrangements can be identified. The sequencing of the human genome has provided the resources to develop molecular tools that allow higher resolution observations of human chromosomes. The future holds the promise of sequencing that may identify chromosomal imbalances and deleterious single nucleotide variants. This review will focus on the use of genomic microarrays for the testing and identification of chromosome anomalies in prenatal diagnosis and will discuss the future directions of fetal testing. © 2013 Informa UK Ltd.

Simons A.,Radboud University Nijmegen | Shaffer L.G.,Genetic Veterinary science Inc | Hastings R.J.,University of Oxford
Cytogenetic and Genome Research | Year: 2013

The latest edition of the International System for Human Cytogenetic Nomenclature, ISCN 2013, has recently been published following a thorough revision of the 2009 issue and the incorporation of suggestions from the community by the current standing committee. This review will highlight the multiple nomenclature changes in the respective chapters of the 2013 version compared to the previous version of the ISCN published in 2009. These highlights are meant as a guide for the cytogeneticist to assist in the transition in the use of this updated nomenclature for describing cytogenetic and molecular cytogenetic findings in both clinical and research reports. © 2013 S. Karger AG, Basel.

Antonacci F.,University of Bari | Dennis M.Y.,University of Washington | Huddleston J.,University of Washington | Huddleston J.,Howard Hughes Medical Institute | And 20 more authors.
Nature Genetics | Year: 2014

Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into the instability of this region, we sequenced it in affected individuals, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 Mb. These configurations arose recently (â 1/40.5-0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons - a â 1/414-kb primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage and independent structural changes in apes. The significant clustering (P = 0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting the evolutionary and disease-related instability of chromosome 15. © 2014 Nature America, Inc. All rights reserved.

Rosenfeld J.A.,Perkin Elmer Corporation | Coe B.P.,University of Washington | Eichler E.E.,University of Washington | Eichler E.E.,Howard Hughes Medical Institute | And 3 more authors.
Genetics in Medicine | Year: 2013

Purpose: Although an increasing number of copy-number variations are being identified as susceptibility loci for a variety of pediatric diseases, the penetrance of these copy-number variations remains mostly unknown. This poses challenges for counseling, both for recurrence risks and prenatal diagnosis. We sought to provide empiric estimates for penetrance for some of these recurrent, disease-susceptibility loci.Methods:We conducted a Bayesian analysis, based on the copy-number variation frequencies in control populations (n = 22,246) and in our database of >48,000 postnatal microarray-based comparative genomic hybridization samples. The background risk for congenital anomalies/ developmental delay/intellectual disability was assumed to be ∼5%. Copy-number variations studied were 1q21.1 proximal duplications, 1q21.1 distal deletions and duplications, 15q11.2 deletions, 16p13.11 deletions, 16p12.1 deletions, 16p11.2 proximal and distal deletions and duplications, 17q12 deletions and duplications, and 22q11.21 duplications.Results:Estimates for the risk of an abnormal phenotype ranged from 10.4% for 15q11.2 deletions to 62.4% for distal 16p11.2 deletions.Conclusion:This model can be used to provide more precise estimates for the chance of an abnormal phenotype for many copy-number variations encountered in the prenatal setting. By providing the penetrance, additional, critical information can be given to prospective parents in the genetic counseling session. © American College of Medical Genetics and Genomics.

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