Małgorzata Rydzanicz1, Pawel Olszewski2, Darek Kedra2, Hanna Davies3, Natalia Filipowicz2, Bozena Bruhn-Olszewska3, Marco Cavalli3, Krzysztof Szczałuba1, Marlena Młynek4, Marcin M Machnicki5,6, Piotr Stawiński1, Grażyna Kostrzewa7, Paweł Krajewski7, Dariusz Śladowski8, Krystyna Chrzanowska4, Jan P Dumanski2,3, Rafał Płoski1. 1. Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland. 2. Faculty of Pharmacy and 3P Medicine Laboratory, International Research Agendas Programme, Medical University of Gdańsk, Gdańsk, Poland. 3. Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. 4. Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland. 5. Department of Immunology, Medical University of Warsaw, Warsaw, Poland. 6. Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland. 7. Department of Forensic Medicine, Medical University of Warsaw, Warsaw, Poland. 8. Department of Transplantology and Central Tissue Bank, Centre for Biostructure, Medical University of Warsaw, Warsaw, Poland.
Abstract
BACKGROUND: Phenotypically discordant monozygotic twins (PDMZTs) offer a unique opportunity to study post-zygotic genetic variation and provide insights into the linkage between genotype and phenotype. We report a comprehensive analysis of a pair of PDMZTs. METHODS: Dysmorphic features and delayed neuro-motor development were observed in the proband, whereas her twin sister was phenotypically normal. Four tissues (blood, skin, hair follicles, and buccal mucosa) from both twins were studied using four complementary methods, including whole-exome sequencing, karyotyping, array CGH, and SNP array. RESULTS: In the proband, tetrasomy 18p affecting all studied tissues except for blood was identified. Karyotyping of fibroblasts revealed isochromosome 18p [i(18p)] in all metaphases. The corresponding analysis of the phenotypically normal sister surprisingly revealed low-level mosaicism (5.4%) for i(18p) in fibroblasts. CONCLUSION: We emphasize that when mosaicism is suspected, multiple tissues should be studied and we highlight the usefulness of non-invasive sampling of hair follicles and buccal mucosa as a convenient source of non-mesoderm-derived DNA, which complements the analysis of mesoderm using blood. Moreover, low-level mosaic tetrasomy 18p is well tolerated and such low-level mosaicism, readily detected by karyotyping, can be missed by other methods. Finally, mosaicism for low-level tetrasomy 18p might be more common in the general population than it is currently recognized, due to detection limitations.
BACKGROUND: Phenotypically discordant monozygotic twins (PDMZTs) offer a unique opportunity to study post-zygotic genetic variation and provide insights into the linkage between genotype and phenotype. We report a comprehensive analysis of a pair of PDMZTs. METHODS:Dysmorphic features and delayed neuro-motor development were observed in the proband, whereas her twin sister was phenotypically normal. Four tissues (blood, skin, hair follicles, and buccal mucosa) from both twins were studied using four complementary methods, including whole-exome sequencing, karyotyping, array CGH, and SNP array. RESULTS: In the proband, tetrasomy 18p affecting all studied tissues except for blood was identified. Karyotyping of fibroblasts revealed isochromosome 18p [i(18p)] in all metaphases. The corresponding analysis of the phenotypically normal sister surprisingly revealed low-level mosaicism (5.4%) for i(18p) in fibroblasts. CONCLUSION: We emphasize that when mosaicism is suspected, multiple tissues should be studied and we highlight the usefulness of non-invasive sampling of hair follicles and buccal mucosa as a convenient source of non-mesoderm-derived DNA, which complements the analysis of mesoderm using blood. Moreover, low-level mosaic tetrasomy 18p is well tolerated and such low-level mosaicism, readily detected by karyotyping, can be missed by other methods. Finally, mosaicism for low-level tetrasomy 18p might be more common in the general population than it is currently recognized, due to detection limitations.
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