UPD detection using homozygosity profiling with a SNP genotyping microarray

Papenhausen, Peter; Schwartz, Stuart; Risheg, Hiba; Keitges, Elisabeth A.; Gadi, Inder K.; Burnside, Rachel D.; Jaswaney, Vikram; Pappas, John; Pasion, Romela; Friedman, Kenneth J.; Tepperberg, James

doi:10.1002/ajmg.a.33939

Cited by 113 publications

(135 citation statements)

References 21 publications

(22 reference statements)

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“…This is somewhat surprising and contrary to theoretical expectations that single-chromosome ROHs reflective of UPD would be more frequent at subtelomeric regions and signify true illegitimate meiotic recombination. 4 There does not seem to be an easy explanation for this somewhat discrepant observation and our findings need further support from additional large studies. Future studies complemented by molecular confirmation of suspected UPD cases will be valuable.…”

Section: Discussioncontrasting

confidence: 58%

“…Depending on chromosomal distribution and cumulative extent, it may indicate background ancestral homozygosity, uniparental disomy (UPD) or parental consanguinity. [1][2][3][4] Small random ROHs exist in all populations, including outbred cosmopolitan ones, and are believed to be a reflection of recombination rates and population history. A recent study using HapMap trios aimed at determining the prevalence of UPD in the general population suggested the existence of segmental UPD in 1 per 173 births (B0.6%) in the random population.…”

Section: Introductionmentioning

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: Discussioncontrasting

confidence: 58%

Section: Introductionmentioning

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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“…11 This group analyzed long contiguous stretches of homozygosity (LCSH) in patients with DD, autism or congenital anomalies. A threshold for possible UPD correlation was set at 13.5 Mb for isolated LCSH and 15 Mb if two LCSH in a single chromosome were found.…”

Section: Discussionmentioning

confidence: 99%

“…Current techniques for UPD detection (eg, methylation-specific PCR, methylation-specific MLPA and microsatellite analysis) are limited by number of markers and are generally restricted to distinct genomic regions or well-known imprinting syndromes. The usability of SNP microarrays for UPD detection has been proven and requires child-parent trio and special software for correct subclassification of UPDs [10][11][12] or parental exclusions from microsatellite analysis. UPD detection from trio experiments exceeds standard analysis that infers isodisomy from loss of heterozygosity 13 and requires specialized bioinformatic tools that automatically analyze occurrences of inheritance errors (Mendelian errors (MEs)) in large cohorts.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide UPD screening in patients with intellectual disability

et al. 2014

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Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. It may occur as isodisomy, heterodisomy or a combination of both and may involve only chromosome segments. UPD can affect each chromosome. The incidence is estimated to be around 1:3500 in live births. Some parts of chromosomes are subject to 'parent-of-origin imprinting' and the phenotypic effect in UPD syndromes is mainly due to functional imbalance of imprinted genes. Isodisomy can result in mutation homozygosity in autosomal-recessive inherited diseases. UPD causes several well-defined imprinting syndromes associated with intellectual disability (ID). Although knowledge on frequency and size of UPDs in patients with unexplained ID remains largely unknown as no efficient genome-wide screening technique was available for detection of both isodisomic and heterodisomic UPDs. SNP microarrays have been proven to be capable to detect UPDs through Mendelian errors. The correct subclassification of UPD requires child-parent trio experiments. To further elucidate the role of UPD in patients with unexplained ID, we analyzed a total of 322 child-parent trios. We were not able to detect UPDs (isodisomies and heterodisomies) within our cohort spanning whole chromosomes or chromosomal segments. We conclude that UPD is rare in patients with unexplained ID.

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Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders

Lee

Deignan

Dorrani

et al. 2014

JAMA

847

737

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Importance Clinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders. Objective To report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types. Design, Setting, and Participants Clinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available. Main outcomes and Measures Clinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES. Results Of the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants. Conclusions and Relevance In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.

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UPD detection using homozygosity profiling with a SNP genotyping microarray

Cited by 113 publications

References 21 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

Genome-wide UPD screening in patients with intellectual disability

Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders

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