Genomic Investigation of Balanced Chromosomal Rearrangements in Patients with Abnormal Phenotypes

Simioni, Milena; Artiguenave, François; Meyer, Vincent; Sgardioli, Ilária Cristina; Viguetti-Campos, Nilma Lúcia; Monlleó, Isabella Lopes; Maciel‐Guerra, Andréa Trevas; Steiner, Carlos Eduardo

doi:10.1159/000477084

Cited by 8 publications

(6 citation statements)

References 46 publications

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“…In particular, the long insert-size mate-pair (MP) sequencing protocols have been useful for analyzing structural variation, mainly due to its high span coverage which potentially could bridge regions that are hard to map, such as repetitive regions [7, 9]. On the other hand, the higher coverage PCR-free paired-end (PE) libraries enables the use of split reads for exact breakpoint analysis, and highly precise read depth CNV detection [10, 11]. These different protocols provide a flexible framework for analyzing different types of variations and answering different questions.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements

et al. 2019

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Complex chromosomal rearrangements (CCRs) are rearrangements involving more than two chromosomes or more than two breakpoints. Whole genome sequencing (WGS) allows for outstanding high resolution characterization on the nucleotide level in unique sequences of such rearrangements, but problems remain for mapping breakpoints in repetitive regions of the genome, which are known to be prone to rearrangements. Hence, multiple complementary WGS experiments are sometimes needed to solve the structures of CCRs. We have studied three individuals with CCRs: Case 1 and Case 2 presented with de novo karyotypically balanced, complex interchromosomal rearrangements (46,XX,t(2;8;15)(q35;q24.1;q22) and 46,XY,t(1;10;5)(q32;p12;q31)), and Case 3 presented with a de novo, extremely complex intrachromosomal rearrangement on chromosome 1. Molecular cytogenetic investigation revealed cryptic deletions in the breakpoints of chromosome 2 and 8 in Case 1, and on chromosome 10 in Case 2, explaining their clinical symptoms. In Case 3, 26 breakpoints were identified using WGS, disrupting five known disease genes. All rearrangements were subsequently analyzed using optical maps, linked-read WGS, and short-read WGS. In conclusion, we present a case series of three unique de novo CCRs where we by combining the results from the different technologies fully solved the structure of each rearrangement. The power in combining short-read WGS with long-molecule sequencing or optical mapping in these unique de novo CCRs in a clinical setting is demonstrated.

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Section: Introductionmentioning

confidence: 99%

Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements

et al. 2019

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“…В частности, технология высокопроизводительного полногеномного секвенирования (WGS) позволяет расширить границы детекции хромосомного дисбаланса и обеспечить высокоразрешающий анализ кариотипа на молекулярном уровне. Картирование и секвенирование точек разрывов при сбалансированных хромосомных перестройках, анализ мутаций и генной экспрессии позволяют отобразить этиопатогенез вариабельного аномального фенотипа в каждом конкретном случае [16,17].…”

Section: Discussionunclassified

Characterization of genomic imbalance in patients with balanced chromosomal rearrangements and abnormal phenotypes

Миньженкова¹,

Маркова²,

Гусева³

et al. 2020

Nauchno-Prakticheskii Zhurnal «Medicinskaia Genetika»

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Идентификация причин формирования аномалий развития у пациентов со сбалансированными хромосомными перестройками на сегодняшний день является актуальным и не в полной мере изученным направлением в цитогенетической практике, требующим разработки уникального подхода с использованием современных молекулярно-генетических технологий. Целью данного исследования явилась этиологическая диагностика геномного дисбаланса у пациентов со сбалансированными хромосомными перестройками и аномалиями развития. 20 пациентов с аномальным фенотипом и сбалансированными хромосомными перестройками, выявленными при стандартном кариотипировании, были обследованы методами хромосомного микроматричного анализа (ХМА) и FISH. Геномный дисбаланс (CNV) обнаружен в 13 случаях из 20, что составило 65%. Использование ХМА позволило установить, что в 69,2% случаев носительства сбалансированных хромосомных перестроек причиной аномального фенотипа являлось наличие микроделеций/микродупликаций, ассоциированных с точками разрывов при перестройках, а в 20,8% случаев наблюдались микроделеции/микродупликации на хромосомах, не задействованных в аберрациях. Несмотря на то, что ХМА позволил выявить причины аномалий развития в большинстве случаев, 7 пациентам (35%) не удалось установить окончательный молекулярно-цитогенетический диагноз. Более того, у некоторых пациентов выявленные CNVs не полностью отражают генотип-фенотип корреляцию, что требует проведения дополнительных молекулярно-генетических исследований. При отсутствии геномного дисбаланса при ХМА, а также при неполной генотип-фенотип корреляции, диагностика этиологии аномалий развития и патологического фенотипа должна быть продолжена молекулярными методами более высокого разрешения. Identification of genomic imbalances in cases with balanced chromosomal rearrangements and abnormal phenotype is a current trends in cytogenetics practice, requiring the development of unique approach using modern molecular genetic technologies. The aim of this study is diagnostics etiologies of the abnormal phenotype in patients with balanced chromosomal rearrangements. We report the investigations results of 20 patients with abnormal phenotype and balanced chromosomal rearrangements by conventional cytogenetic analysis. Genomic imbalances by microarray studies detected in 13 of 20 cases (65%). Most of CNVs was microdeletion or microduplication at a rearrangement breakpoint (69.2%) and 20.8% microdeletion/microduplication in other chromosomes.

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“…Pada 6% kasus translokasi dan 9,4% kasus inversi yang balans dapat terjadi fenotip abnormal. 27 Kelainan struktur kromosom pada penelitian ini bersifat tidak balans, karena menimbulkan kecacatan dan kelainan yang paling sering adalah delesi, duplikasi dan insersi.…”

Section: Tabel 3 Profil Karyogram Subjek Penelitian Dengan Aberasi Kr...unclassified

Profil Aberasi Kromosom Pasien Malformasi Kongenital Multipel Non-Sindromik

Aswin

Rachmadi

2022

ejki

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Malformasi kongenital multipel (MKM) non-sindromik merupakan penyakit neonatal dengan mortalitas tinggi, menurunkan kualitas hidup anak dan mahalnya biaya perawatan. Untuk mendiagnosis MKM-non-sindromik diperlukan analisis kromosom secara akurat dengan biaya terjangkau yaitu metode G-banding, namun detection rate belum diketahui. Penelitian bertujuan untuk mengetahui proporsi MKM non-sindromik yang dapat didiagnosis dengan metode G-banding. Penelitian ini menggunakan desain potong lintang dengan subjek semua pasien yang datang ke laboratorium sitogenetik Departemen Biologi FKUI pada Juli 2014 sampai dengan Desember 2017. Pasien dilakukan pemeriksaan fisis kemudian dibandingkan dengan basis data Online Mendelian Inheritance in Man (OMIM) untuk menyeleksi pasien MKM sindromik dan non-sindromik. Sebanyak 34 dari 83 subjek (41%) dapat ditegakkan diagnosis klinis menggunakan database fenotip. Sebanyak 49 pasien memenuhi kriteria penelitian kemudian dilakukan analisis kromosom dengan metode G-banding. Terdapat 17 (34,7%) subyek yang menunjukkan aberasi kromosom. Tiga fenotip tersering pada subjek adalah hambatan pertumbuhan, mikrosefali, dan penyakit jantung bawaan. Disimpulkan metode G-banding sebagai pemeriksaan skrining awal pada MKM berperan penting dalam mendiagnosis penyebab genetik. Kata kunci: MKM non-sindromik, basis data fenotip, Indonesia, G-banding. Chromosome Aberration Profiles in Patients with Non-Syndromic Multiple Congenital Malformation Abstract Non-syndromic multiple congenital malformations (MCM) remains a significant problem in Indonesia Chromosome Aberration Profiles in Patients with Non-Syndromic Multiple Congenital Malformation as it causes high mortality and morbidity rate in neonates and infants as well as a significant financial burden for families in caring for patients with non-syndromic MCM. Genetics is the major cause of non-syndromic MCM, and more than 50% is caused by chromosomal abnormalities. Considering the condition in Indonesia, where most families have a low socioeconomic background and where there are limited molecular genetics laboratory facilities, this research aims to study the proportion of non-syndromic MCM that can be detected using G-banding and describe chromosome aberration profiles in non-syndromic MCM patients. The Online Mendelian Inheritance in Man (OMIM) was used to differentiate non-syndromic and syndromic MCM in 83 recruited MCM patients. Thirtyfour patients (41%) were diagnosed using a phenotype database based on clinical signs. The three most common phenotypes were growth failure, microcephaly, and congenital heart diseases. Forty-nine patients were classified with non-syndromic MCM after filtering with OMIM and underwent G-banding. Seventeen out of 49 non-syndromic MCM patients (34.7%) had chromosome aberration after G-banding. This indicates that G-banding remains an effective first-line screening tool for non-syndromic MCM in Indonesia. Keywords: non-syndromic multiple congenital malformation, phenotype database, G-banding, Indonesia.

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Genomic Investigation of Balanced Chromosomal Rearrangements in Patients with Abnormal Phenotypes

Cited by 8 publications

References 46 publications

Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements

Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements

Characterization of genomic imbalance in patients with balanced chromosomal rearrangements and abnormal phenotypes

Profil Aberasi Kromosom Pasien Malformasi Kongenital Multipel Non-Sindromik

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