ISABEL FURQUIM PINHEIRO
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conferenceObject Buccal cell whole exome sequencing improves the diagnostic yield in a Cornelia de Lange Syndrome Brazilian cohort(2024) NUNES, Beatriz Carvalho; FAVILLA, Bianca Pereira; VILELLA, Thaina; PINHEIRO, Isabel; AOI, Haromi; SEYAMA, Rie; MATSUMOTO, Naomichi; BELLUCCO, Fernanda Teixeira; KIM, Chong; MELARAGNO, Maria IsabelconferenceObject A 43 years-old patient with Cornelia de Lange Syndrome with NIPBL gene mutation and a mild phenotype(2024) VILELLA, Thaina; NUNES, Beatriz Carvalho; PINHEIRO, Isabel; AOI, Haromi; MATSUMOTO, Naomichi; KIM, Chong; MELARAGNO, Maria Isabel- Pathogenic variants detected by RNA sequencing in Cornelia de Lange syndrome(2022) SEYAMA, Rie; UCHIYAMA, Yuri; CERONI, Jose Ricard Magliocco; KIM, Veronica Eun Hue; FURQUIM, Isabel; HONJO, Rachel Sayuri; CASTRO, Matheus Augusto Araujo; PIRES, Lucas Vieira Lacerda; AOI, Hiromi; IWAMA, Kazuhiro; HAMANAKA, Kohei; FUJITA, Atsushi; TSUCHIDA, Naomi; KOSHIMIZU, Eriko; MISAWA, Kazuharu; MIYATAKE, Satoko; MIZUGUCHI, Takeshi; MAKINO, Shintaro; ITAKURA, Atsuo; BERTOLA, Debora R.; KIM, Chong Ae; MATSUMOTO, NaomichiRecent studies suggest that transcript isoforms significantly overlap (approximately 60%) between brain tissue and Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs). Interestingly, 14 cohesion-related genes with variants that cause Cornelia de Lange Syndrome (CdLS) are highly expressed in the brain and LCLs. In this context, we first performed RNA sequencing of LCLs from 22 solved (with pathogenic variants) and 19 unsolved (with no confirmed variants) CdLS cases. Next, an RNA sequencing pipeline was developed using solved cases with two different methods: short variant analysis (for single-nucleotide and indel variants) and aberrant splicing detection analysis. Then, 19 unsolved cases were subsequently applied to our pipeline, and four pathogenic variants in NIPBL (one inframe deletion and three intronic variants) were newly identified. Two of three intronic variants were located at Alu elements in deep-intronic regions, creating cryptic exons. RNA sequencing with LCLs was useful for identifying hidden variants in exome-negative cases.
- Imagawa-Matsumoto syndrome: SUZ12-related overgrowth disorder(2023) IMAGAWA, Eri; SEYAMA, Rie; AOI, Hiromi; UCHIYAMA, Yuri; MARCARINI, Bruno Guimaraes; FURQUIM, Isabel; HONJO, Rachel Sayuri; BERTOLA, Debora Romeo; KIM, Chong Ae; MATSUMOTO, NaomichiThe SUZ12 gene encodes a subunit of polycomb repressive complex 2 (PRC2) that is essential for development by silencing the expression of multiple genes. Germline heterozygous variants in SUZ12 have been found in Imagawa-Matsumoto syndrome (IMMAS) characterized by overgrowth and multiple dysmorphic features. Similarly, both EZH2 and EED also encode a subunit of PRC2 each and their pathogenic variants cause Weaver syndrome and Cohen-Gibson syndrome, respectively. Clinical manifestations of these syndromes significantly overlap, although their different prevalence rates have recently been noted: generalized overgrowth, intellectual disability, scoliosis, and excessive loose skin appear to be less prevalent in IMMAS than in the other two syndromes. We could not determine any apparent genotype-phenotype correlation in IMMAS. The phenotype of neurofibromatosis type 1 arising from NF1 deletion was also shown to be modified by the deletion of SUZ12, 560 kb away. This review deepens our understanding of the clinical and genetic characteristics of IMMAS together with other overgrowth syndromes related to PRC2. We also report on a novel IMMAS patient carrying a splicing variant (c.1023+1G>C) in SUZ12. This patient had a milder phenotype than other previously reported IMMAS cases, with no macrocephaly or overgrowth phenotypes, highlighting the clinical variation in IMMAS.