Variable degree of mosaicism for tetrasomy 18p in phenotypically discordant monozygotic twins—Diagnostic implications

Rydzanicz, Małgorzata; Olszewski, Paweł; Kedra, Darek; Davies, Hanna; Filipowicz, Natalia; Bruhn-Olszewska, Bożena; Cavalli, Marco; Szczałuba, Krzysztof; Młynek, Marlena; Machnicki, Marcin M.; Stawiński, Piotr; Kostrzewa, Grażyna; Krajewski, Paweł; Śladowski, Dariusz; Chrzanowska, K; Dumanski, Jan P.; Płoski, Rafał

doi:10.1002/mgg3.1526

Cited by 10 publications

(12 citation statements)

References 35 publications

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“…Interestingly, in most reports, blood is the source of DNA for genetic testing, thus relative scarcity of reported genetic differences between monozygotic twins may be due to blood chimerism caused by vascular anastomoses in monochorionic placentas (Chen et al, 2013) which may mask a relevant genetic differences (Armitage et al, 2021; Erlich, 2011). Indeed, in our previous study, we also showed the usefulness of nonblood‐derived DNA (hair follicles and buccal mucosa) in genetic analysis of phenotypically discordant monozygotic twins (Rydzanicz et al, 2021). Thus, we strongly suggest that blood may not be the optimal tissue to search for genetic differences between monozygotic twins.…”

Section: Introductionmentioning

confidence: 80%

“…DNA from 30 hair follicles (I‐2 and I‐3) and buccal mucosa (III‐5) was extracted using the DNA IQ™ Casework Pro‐Kit for Maxwell® 16 (Promega, Madison, WI). Twins (I‐2, I‐3) monozygosity was confirmed using a forensic STR panel as previously described (Rydzanicz et al, 2021). Whole exome sequencing (WES) was performed for I‐2, I‐3, and III‐3 using 50 ng of genomic DNA extracted from hair follicles (I‐2, I‐3) or blood (III‐3) with SureSelectQXT Reagent Kit combined with SureSelectXT Human All Exon v5 (Agilent Technologies, Cedar Creek, TX).…”

Section: Methodsmentioning

confidence: 99%

“…DNA from 30 hair follicles (I-2 and I-3) and buccal mucosa (III-5) was extracted using the DNA IQ™ Casework Pro-Kit for Maxwell ® 16 (Promega, Madison, WI). Twins (I-2, I-3) monozygosity was confirmed using a forensic STR panel as previously described (Rydzanicz et al, 2021).…”

Section: Genetic Testingmentioning

confidence: 99%

“…Enriched libraries were paired-end sequenced (2 Â 100 bp) on HiSeq1500 (Illumina, San Diego, CA). Reads were aligned to the GRCh38 (hg38) reference genome and analyzed as previously described (Rydzanicz et al, 2021). The mean sequencing depth was 99Â, 111Â and 51Â, respectively for I-2, I-3, and III-2.…”

Section: Genetic Testingmentioning

confidence: 99%

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Postzygotic mosaicism of a novel PTPN11 mutation in monozygotic twins discordant for metachondromatosis

Rydzanicz

Glinkowski

Walczak

et al. 2022

American J of Med Genetics Pt A

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Genetic mosaicism caused by postzygotic mutations is of a great interest due to its role in human disease. Monozygotic twins arising from a single zygote are considered as genetically identical, and any differences likely to be caused by postzygotic events. Thus, phenotypically discordant monozygotic twins offer a unique opportunity to study genotype–phenotype correlation. Here, we present a three‐generation family starting from a pair of monozygotic twins discordant for metachondromatosis due to postzygotic p.(Gln175His) variant in the PTPN11 gene. Both phenotypically discordant monozygotic twins harbor p.(Gln175His), however significant differences in mosaic ratio is observed not only between twins, but also within different tissue types within one individual. Phenotypic manifestation of p.(Gln175His) in examined family clearly depends on allele variant fraction (VAF). Individuals harboring constitutional mutation (VAF 50%) present typical metachondromatosis. Milder phenotype is observed in twin harboring high‐level mosaicism in the tissue of ectodermal origin (VAF 45%), but not in a blood (VAF 5%). Finally, her twin sister harboring low‐level mosaicism in blood (VAF 2%) and nonblood (VAF 12%) tissues is phenotypically normal. Our results provide insights into biological role of mosaicism in disease and further support the usefulness of nonblood tissues as an optimal source of DNA for the identification of postzygotic mutations in phenotypically discordant monozygotic twins.

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Section: Introductionmentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Genetic Testingmentioning

confidence: 99%

Section: Genetic Testingmentioning

confidence: 99%

See 2 more Smart Citations

Postzygotic mosaicism of a novel PTPN11 mutation in monozygotic twins discordant for metachondromatosis

Rydzanicz

Glinkowski

Walczak

et al. 2022

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

show abstract

“…Genotyping data was analyzed using Nexus Copy Number software version 10.0 (BioDiscovery). Quality control of samples was performed as described previously 14,50 . Briefly, samples with Log R Ratio (LRR) sd >0.2 were flagged as poor quality and excluded from the analysis.…”

Section: Snp Array Genotyping Was Performed For Um and Pt Samples On An Illumina Infiniummentioning

confidence: 99%

High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing

Kostecka

Nowikiewicz

Olszewski

et al. 2021

Preprint

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The mammary gland undergoes hormonally stimulated cycles of proliferation, lactation and involution. We hypothesized that these factors increase the mutational burden in glandular tissue and may explain high cancer incidence rate in the general population and recurrent disease. Hence, we investigated the DNA sequence variants in the normal mammary gland, tumor and peripheral blood from 52 reportedly sporadic breast cancer patients, including breast-conserving surgery cases. Targeted resequencing of 542 cancer associated genes revealed mosaic somatic pathogenic variants of: PIK3CA, TP53, AKT1, MAP3K1, CDH1, RB1, NCOR1, MED12, CBFB, TBX3 and TSHR in the normal mammary gland, at considerable allelic frequencies (9x10-2 to 5.2x10-1) indicating clonal expansion. Further evaluation of the frequently damaged PIK3CA and TP53 genes by ultra-sensitive duplex sequencing demonstrated a diversified picture of multiple low level-mosaic (in 10-2 to 10-4 alleles) hotspot pathogenic variants. Our results raise a question about the oncogenic potential in non-tumor mammary gland tissue of breast-conserving surgery patients.

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Comparing saliva and blood for the detection of mosaic genomic abnormalities that cause syndromic intellectual disability

et al. 2022

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We aimed to determine whether SNP-microarray genomic testing of saliva had a greater diagnostic yield than blood for pathogenic copy number variants (CNVs). We selected patients who underwent CMA testing of both blood and saliva from 23,289 blood and 21,857 saliva samples. Our cohort comprised 370 individuals who had testing of both, 224 with syndromic intellectual disability (ID) and 146 with isolated ID. Mosaic pathogenic CNVs or aneuploidy were detected in saliva but not in blood in 20/370 (4.4%). All 20 individuals had syndromic ID, accounting for 9.1% of the syndromic ID sub-cohort. Pathogenic CNVs were large in size (median of 46 Mb), and terminal in nature, with median mosaicism of 27.5% (not exceeding 40%). By contrast, non-mosaic pathogenic CNVs were 100% concordant between blood and saliva, considerably smaller in size (median of 0.65 Mb), and predominantly interstitial in location. Given that salivary microarray testing has increased diagnostic utility over blood in individuals with syndromic ID, we recommend it as a first-tier testing in this group.

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Variable degree of mosaicism for tetrasomy 18p in phenotypically discordant monozygotic twins—Diagnostic implications

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 10 publications

References 35 publications

Postzygotic mosaicism of a novel PTPN11 mutation in monozygotic twins discordant for metachondromatosis

Postzygotic mosaicism of a novel PTPN11 mutation in monozygotic twins discordant for metachondromatosis

High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing

Comparing saliva and blood for the detection of mosaic genomic abnormalities that cause syndromic intellectual disability

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