Browsing by Subject "Chromosome deletion"

Now showing 1 - 5 of 5
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    A familial SAMD9 variant present in pediatric myelodysplastic syndrome
    (Cold Spring Harbor Laboratory, 2023-05-09) Rahim, Mahvish Q.; Rahrig, April; Overholt, Kathleen; Conboy, Erin; Czader, Magdalena; Saraf, Amanda June; Pediatrics, School of Medicine
    Myelodysplastic syndrome (MDS) is a rare pediatric diagnosis characterized by ineffective hematopoiesis with potential to evolve into acute myelogenous leukemia (AML). In this report, we describe a unique case of a 17-yr-old female with an aggressive course of MDS with excess blasts who was found to have monosomy 7 and a SAMD9 germline variant, which has not previously been associated with a MDS phenotype. This case of MDS was extremely rapidly progressing, showing resistance to chemotherapy and stem cell transplant, unfortunately resulting in patient death. It is imperative to further investigate this rare variant to aid in the future care of patients with this variant.
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    Genitourinary Defects Associated with Genomic Deletions in 2p15 Encompassing OTX1
    (Public Library of Science, 2014-09-09) Jorgez, Carolina J.; Rosenfeld, Jill A.; Wilken, Nathan R.; Vangapandu, Hima V.; Sahin, Aysegul; Pham, Dung; Carvalho, Claudia M. B.; Bandholz, Anne; Miller, Amanda; Weaver, David D.; Burton, Barbara; Babu, Deepti; Bamforth, John S.; Wilks, Timothy; Flynn, Daniel P.; Roeder, Elizabeth; Patel, Ankita; Cheung, Sau W.; Lupski, James R.; Lamb, Dolores J.; Medical and Molecular Genetics, School of Medicine
    Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1-4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1∶47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2-7 had large de novo CNVs (2.39-6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia.
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    NAHR-mediated copy-number variants in a clinical population: Mechanistic insights into both genomic disorders and Mendelizing traits
    (Cold Spring Harbor Laboratory, 2013) Dittwald, Piotr; Gambin, Tomasz; Szafranski, Przemyslaw; Li, Jian; Amato, Stephen; Divon, Michael Y.; Rodríguez Rojas, Lisa Ximena; Elton, Lindsay E.; Scott, Daryl A.; Schaaf, Christian P.; Torres-Martinez, Wilfredo; Stevens, Abby K.; Rosenfeld, Jill A.; Agadi, Satish; Francis, David; Kang, Sung-Hae L.; Breman, Amy; Lalani, Seema R.; Bacino, Carlos A.; Bi, Weimin; Milosavljevic, Aleksandar; Beaudet, Arthur L.; Patel, Ankita; Shaw, Chad A.; Lupski, James R.; Gambin, Anna; Cheung, Sau Wai; Stankiewicz, Pawel; Medical and Molecular Genetics, School of Medicine
    We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/velocardiofacial syndrome, 166). In the ∼25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5'-CCNCCNTNNCCNC-3', correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13, were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR-mediated genomic instability and further elucidates the role of NAHR in human disease.
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    Parental origin of chromosome 15 deletion in Prader-Willi syndrome
    (Elsevier, 1983-06-04) Butler, Merlin G.; Palmer, Catherine G.; Medical and Molecular Genetics, School of Medicine
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    Phelan-McDermid syndrome: a classification system after 30 years of experience
    (BMC, 2022-01-29) Phelan, Katy; Boccuto, Luigi; Powell, Craig M.; Boeckers, Tobias M.; van Ravenswaaij‑Arts, Conny; Rogers, R. Curtis; Sala, Carlo; Verpelli, Chiara; Thurm, Audrey; Bennett, William E., Jr.; Winrow, Christopher J.; Garrison, Sheldon R.; Toro, Roberto; Bourgeron, Thomas; Pediatrics, School of Medicine
    Phelan-McDermid syndrome (PMS) was initially called the 22q13 deletion syndrome based on its etiology as a deletion of the distal long arm of chromosome 22. These included terminal and interstitial deletions, as well as other structural rearrangements. Later, pathogenetic variants and deletions of the SHANK3 gene were found to result in a phenotype consistent with PMS. The association between SHANK3 and PMS led investigators to consider disruption/deletion of SHANK3 to be a prerequisite for diagnosing PMS. This narrow definition of PMS based on the involvement of SHANK3 has the adverse effect of causing patients with interstitial deletions of chromosome 22 to "lose" their diagnosis. It also results in underreporting of individuals with interstitial deletions of 22q13 that preserve SHANK3. To reduce the confusion for families, clinicians, researchers, and pharma, a simple classification for PMS has been devised. PMS and will be further classified as PMS-SHANK3 related or PMS-SHANK3 unrelated. PMS can still be used as a general term, but this classification system is inclusive. It allows researchers, regulatory agencies, and other stakeholders to define SHANK3 alterations or interstitial deletions not affecting the SHANK3 coding region.