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ORIGINAL RESEARCH ARTICLE ©American College of Medical Genetics and Genomics Regions of homozygosity identified bySN P microarray analysis aid in the diagnosis of autosomal recessive disease and incidentally detect parental blood relationships Kristen Lipscomb Sund, PhD, MS1, Sarah L. Zimmerman, PhD1, Cameron Thomas, MD2, Anna L. Mitchell, MD, PhD3, Carlos E. Prada, MD1, Lauren Grote, BS1, Liming Bao, MD, PhD1, Lisa J. Martin, PhD1 and Teresa A. Smolarek, PhD1 Purpose: The purpose of this study was to document the ability of was suspected in the parents of at least 11 patients with regions of single-nucleotide polymorphism microarray to identify copy-neutral homozygosity covering >21.3% of their autosome. In four patients regions of homozygosity, demonstrate clinical utility of regions of from two families, homozygosity mapping discovered a candidate homozygosity, and discuss ethical/legal implications when regions of gene that was sequenced to identify a clinically significant mutation. homozygosity are associated with a parental blood relationship. Conclusion: This study demonstrates clinical utility in the identifica- Methods: Study data were compiled from consecutive samples tion of regions of homozygosity, as these regions may aid in diagnosis sent to our clinical laboratory over a 3-year period. A cytogenetics of the patient. This study establishes the need for careful reporting, database identified patients with at least two regions of homozygosity thorough pretest counseling, and careful electronic documentation, >10 Mb on two separate chromosomes. A chart review was conduct- as microarray has the capability of detecting previously unknown/ ed on patients who met the criteria. unreported relationships. Results: Of 3,217 single-nucleotide polymorphism microarrays, Genet Med 2013:15(1):70–78 59 (1.8%) patients met inclusion criteria. The percentage of homozygosity ranged from 0.9 to 30.1%, indicating parental rela- Key Words: consanguinity; heterozygosity; homozygosity; incest; tionships from distant to first-degree relatives. First-degree kinship microarray. INTRODUCTION malformations and a 4.4% increased risk for prereproduc- Genome-wide copy-number analysis by microarray is a front- tive mortality.12 Close consanguineous unions, mostly first- line test for the diagnosis of microdeletion/microduplication cousin marriages, occur in up to 60% of relationships in some syndromes.1,2 Single-nucleotide polymorphism (SNP) microar- parts of the world13 but fall in the range of 0.1–1.5% in rays can also detect regions of homozygosity (ROH) through- North America.14–17 out the genome. Depending on the genomic context, constitu- Although several laboratories perform SNP microarray, and tional ROH may indicate ancestral homozygosity, uniparental reviews are available to describe the capability of these arrays disomy, or parental consanguinity.3–5 Short ROH (up to 5 Mb) to detect ROH,3–5 literature describing patients with ROH due are considered ancestral markers of an outbred population.3,4,6,7 to parental consanguinity in a clinical setting is limited.11,18 As The presence of a single large ROH or a couple of large ROH more laboratories incorporate this test, it becomes increasingly on the same chromosome most likely indicates uniparental dis- important to discuss the advantages and disadvantages of the omy, especially if the ROH is telomeric.4 Multiple large ROH technology. Our report highlights the ability of SNP microar- spread across different chromosomes is representative of a ray to detect parental consanguinity in a patient population and parental blood relationship.3,6,8,9 uses select cases to illustrate the utility of this tool in clinical Clinically, ROH of any size can aid in diagnosis of auto- diagnosis. somal recessive disease through homozygosity mapping and selection of a candidate gene for sequence analysis.10,11 In con- METHODS sanguineous families, the risk for autosomal recessive disease Patient population is directly proportional to the degree of parental relation- Study data were compiled from consecutive samples sent to ship.3 As a guide, it is estimated that offspring of first cous- our clinical laboratory between May 2008 and July 2011 for ins have an additional 1.7–2.8% increased risk for congenital SNP microarray analysis. Patient indications were chosen 1Division of Human Genetics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; 2Division of Neurology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; 3University Hospitals Case Medical Center, Departments of Genetics and Pediatrics, Cleveland, Ohio, USA. Correspondence: Kristen Sund ([email protected]) Submitted 26 January 2012; accepted 26 June 2012; advance online publication 2 August 2012. doi:10.1038/gim.2012.94 70 Volume 15 | Number 1 | January 2013 | GENETICS in MEDICINE Regions of homozygosity and SNP microarray | SUND et al ORIGINAL RESEARCH ARTICLE by referring physicians from a broad range of specialties. the Omni1-Quad. This calculation, adapted from McQuillan Ethnicity/race was extracted from the patient medical record. et al.,6 excludes mitochondrial DNA and sex chromosomes: This study included patients with at least two ROH on two L separate chromosomes, each >10 Mb. The 10 Mb cutoff was = å rohauto 19 Froh based on the suggestion by Kirin et al. that ROH >10 Mb Lauto are rarely seen in cosmopolitan populations; the suggestion by Kearney et al.5 that conservative clinical thresholds for ROH Separate calculations were performed on female patients to are between 3 and 10 Mb; and the exclusion of patients from evaluate the impact of the X chromosome on total homozygos- uniparental disomy analysis by Papenhausen et al.4 when a ity. ROH >5 Mb were summed across the entire covered female second chromosome had an ROH >10 Mb, indicating identity genome (Lroh genome), including the X chromosome, and divided by descent. by the total number of base pairs in the genome (Lgenome). The When multiple family members were submitted simulta- sum of the covered female genomes was 2,843,859,790 bps neously, only one was included in the study as the proband. for the 370-duo, 2,843,756,902 bps for the 610-Quad, and Percentage of homozygosity was determined for the other sib- 2,851,012,420 bps for the Omni1-Quad: lings but not included in the cohort summary. Retrospective chart reviews were done in accordance with the institutional åLrohgenome Females: F = review board policies at Cincinnati Children’s Hospital roh Lgenome Medical Center. DNA extraction and SNP microarray analysis Classification of degree of consanguinity based on the DNA was extracted using MagnaPure Compact kits (Roche, ­­proportion of ROH Indianapolis, IN) following the manufacturer’s instructions. On the basis of theoretical coefficients of inbreeding, the Between May and September of 2008, microarray analysis expected degree of homozygosity in offspring of consan- identified ROH in three patients using the Illumina Human guineous matings is 25, 12.5, 6.25, 3.125, and 1.5625% for CNV 370-duo DNA Analysis BeadChip platform (Illumina, first-, second-, third-, fourth-, and fifth-degree relatives, San Diego, CA). Mean spacing of SNPs on this platform is respectively.20,21 However, estimates of homozygosity in any 7.7 kb; median spacing is 5 kb. Between September 2008 one individual may vary by chance. Therefore, to molecularly and October 2010, microarray analysis identified ROH in 32 classify degrees of consanguinity, we determined the 95% con- patients using the Illumina Human610-DUO Quad v1.0 DNA fidence intervals for expected proportions of first- through Analysis BeadC chip platform. Mean spacing of SNPs is 4.7 fifth-degree relatives. To calculate confidence intervals on kb; median spacing is 2.7kb. Between October 2010 and July expected degree of homozygosity, we assumed that degree of 2011, microarray analysis identified ROH in 24 patients using homozygosity was based on an underlying binary distribu- the Illumina HumanOmni1-Quad. Mean spacing of SNPs is tion (homozygosity for any one region scored as yes/no). Of 2.4 kb; median spacing is 1.2 kb. The Illumina Infinium Assay note, the distribution of degree of homozygosity could also be was performed as described by the manufacturer on 250 ng viewed as a continuous trait, but as this trait exhibits a multi- DNA. B-allele frequency and log2R ratio were analyzed with modal distribution, calculation of confidence intervals would Illumina Genome Studio V2009.2 software (Illumina, San be extremely challenging. Calculation of confidence inter- Diego, CA). DNA copy-number changes were prioritized vals was based on autosome coverage on the Omni1-Quad using cnvPartition Plug-in v2.3.4. The software identifies (Supplementary Table S3 online). To calculate confidence ROH based on the presence of homozygosity in the B-allele intervals, the effective number of regions (n) across the auto- frequency but no change in the log2R ratio, to exclude regions some must be determined. Determining this is complicated that are hemizygous due to deletion. ROH interrupted by because the autosome is not linear, is not captured completely homozygous deletions or genotyping errors were manually by current SNP chips, and is not completely independent. To adjusted. address nonlinearity, the analysis was performed following breakdown of each chromosome into its respective p and q Calculation of percentage of homozygosity arms. To address incomplete capture, only regions
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