Variability in laboratory reporting practices for regions of homozygosity indicating parental relatedness as identified by SNP microarray testing

Grote, Lauren; Myers, Melanie F.; Lovell, Anne M.; Saal, Howard M.; Sund, Kristen L.

doi:10.1038/gim.2012.83

Cited by 21 publications

(28 citation statements)

References 20 publications

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“…Currently, there is no consensus regarding the threshold for identification of runs or ROHs in constitutional cases. 10 The choice of 5 Mb as the cutoff value for identification of ROHs is primarily derived from study of European populations, demonstrating that outbred individuals rarely carried ROHs over 4 Mb in size. 6 However, the cutoff value for other populations is likely to be different.…”

Section: Discussionmentioning

confidence: 99%

“…study of European populations and recent data from other laboratories. 6,10 To avoid underestimation of the amount of ROH, the screening threshold was often varied so as not to miss ROHs just below the 5 Mb cutoff. ROH was reported as the presence of one segment of homozygosity 410 Mb or at least two ROHs 45 Mb in each region (with two or more segments on two or more chromosomes classified as IBD; and all segment(s) within one chromosome classified as possible UPD).…”

Section: Materials and Methods Patientsmentioning

confidence: 99%

“…Another study of over 13 000 samples with developmental delay focused on the study of UPD only, with identification of 16 cases with isoUPD, 19 cases with hetero-isoUPD and 3 cases with segmental UPD. 4 There was no clinical study that provided an overall review of the finding of ROHs for all these three categories, that is, parental relatedness, autosomal recessive disorders and UPD, and this may be because of a huge variation for the threshold for reporting ROHs between laboratories, 10 and a lack of recommendations regarding the standards and guidelines for documenting suspected consanguinity. 11 In this study, the largest and most comprehensive series reported so far, we report the finding of 832 (6%) cases with ROH from 805 families from 14 574 clinical cases referred to our laboratory: 651 (78%) cases with multiple ROHs and likely due to parental relatedness, and 181 (22%) cases with single-chromosome involvement.…”

Section: Introductionmentioning

confidence: 99%

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Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility

et al. 2014

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Copy neutral segments with allelic homozygosity, also known as regions of homozygosity (ROHs), are frequently identified in cases interrogated by oligonucleotide single-nucleotide polymorphism (oligo-SNP) microarrays. Presence of ROHs may be because of parental relatedness, chromosomal recombination or rearrangements and provides important clues regarding ancestral homozygosity, consanguinity or uniparental disomy. In this study of 14 574 consecutive cases, 832 (6%) were found to harbor one or more ROHs over 10 Mb, of which 651 cases (78%) had multiple ROHs, likely because of identity by descent (IBD), and 181 cases (22%) with ROHs involving a single chromosome. Parental relatedness was predicted to be first degree or closer in 5%, second in 9% and third in 19%. Of the 181 cases, 19 had ROHs for a whole chromosome revealing uniparental isodisomy (isoUPD). In all, 25 cases had significant ROHs involving a single chromosome; 5 cases were molecularly confirmed to have a mixed iso-and heteroUPD15 and 1 case each with segmental UPD9pat and segmental UPD22mat; 17 cases were suspected to have a mixed iso-and heteroUPD including 2 cases with small supernumerary marker and 2 cases with mosaic trisomy. For chromosome 15, 12 (92%) of 13 molecularly studied cases had either Prader-Willi or Angelman syndrome. Autosomal recessive disorders were confirmed in seven of nine cases from eight families because of the finding of suspected gene within a ROH. This study demonstrates that ROHs are much more frequent than previously recognized and often reflect parental relatedness, ascertain autosomal recessive diseases or unravel UPD in many cases.

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Section: Discussionmentioning

confidence: 99%

Section: Materials and Methods Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility

et al. 2014

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“…In the survey administered by Grote et al [20] , laboratories reported varying approaches related to size thresholds used in the ROH calculation. Multiple laboratories used a pre-determined size threshold without consideration for the number of ROH found throughout the genome (the most common size threshold was >10 Mb, followed by >5 Mb; one laboratory used >8 Mb).…”

Section: Current Practices Of Clinical Laboratoriesmentioning

confidence: 99%

“…A survey was administered during that time to ascertain the practices of these clinical laboratories regarding the reporting of homozygosity [20] . Those practices are summarized here with respect to the main ideas discussed in the ACMG guidelines.…”

Section: Current Practices Of Clinical Laboratoriesmentioning

confidence: 99%

Detection and Reporting of Homozygosity Associated with Consanguinity in the Clinical Laboratory

Sund

Rehder

2014

Hum Hered

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The detection of consanguinity by the presence of multiple regions of homozygosity (ROH) is not an uncommon occurrence in clinical laboratories performing SNP microarray analysis. Reporting practices amongst laboratories are highly variable, due in part to differences in testing platforms, threshold parameters, language utilized, and laboratory policies. While guidance documents have provided a framework for detection and reporting practices, and will doubtless serve to harmonize the field, there are still many facets of the testing that remain at the discretion of the performing laboratory. Clinician and patient education remain a high priority. In the clinical laboratory, these homozygous segments are often examined to identify genes associated with a phenotype that matches that of the proband and autosomal recessive inheritance. While the detection of these ROH is possible with whole genome sequencing, it currently requires special algorithms be utilized, an uncommon practice in most clinical laboratories currently performing this type of testing.

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Variable approaches to genetic counseling for microarray regions of homozygosity associated with parental relatedness

Grote

Myers

Lovell

et al. 2013

American J of Med Genetics Pt A

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SNP microarrays are capable of detecting regions of homozygosity (ROH) which can suggest parental relatedness. This study was designed to describe pre- and post-test counseling practices of genetics professionals regarding ROH, explore perceived comfort and ethical concerns in the follow-up of such results, demonstrate awareness of laws surrounding duty to report consanguinity and incest, and allow respondents to share their personal experiences with results suggesting a parental relationship. A 35 question survey was administered to 240 genetic counselors and geneticists who had ordered or counseled for SNP microarray. The results are presented using descriptive statistics. There was variation in both pre- and post-test counseling practices of genetics professionals. Twenty-five percent of respondents reported pre-test counseling that ROH can indicate parental relatedness. The most commonly reported ethical concern was disclosure of findings suggesting parental relatedness to parents of the patient; only 48.4% reported disclosing parental relatedness when indicated. Fifty-seven percent felt comfortable receiving results suggesting parental consanguinity while 17% felt comfortable receiving results suggesting parental incest. Twenty percent of respondents were extremely/moderately familiar with the laws about duty to report incest. Personal experiences in post-test counseling included both parental acknowledgement and denial of relatedness. This study highlights the differences in genetics professionals' pre- and post-test counseling practices, comfort, and experiences surrounding parental relatedness suggested by SNP microarray results. It identifies a need for professional organizations to offer guidance to genetics professionals about how to respond to and counsel for molecular results suggesting parental consanguinity or incest.

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Variability in laboratory reporting practices for regions of homozygosity indicating parental relatedness as identified by SNP microarray testing

Cited by 21 publications

References 20 publications

Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility

Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility

Detection and Reporting of Homozygosity Associated with Consanguinity in the Clinical Laboratory

Variable approaches to genetic counseling for microarray regions of homozygosity associated with parental relatedness

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