Cold Spring Harbor Molecular Case Studies最新文献

{"title":"Health supervision for children and adolescents with 16p11.2 deletion syndrome.","authors":"Wendy K Chung, Faranak F Herrera","doi":"10.1101/mcs.a006316","DOIUrl":"10.1101/mcs.a006316","url":null,"abstract":"<p><p>Rare genetic conditions are challenging for the primary care provider to manage without proper guidelines. This clinical review is designed to assist the pediatrician, family physician, or internist in the primary care setting to manage the complexities of 16p11.2 deletion syndrome. A multidisciplinary medical home with the primary care provider leading the care and armed with up-to-date guidelines will prove most helpful to the rare genetic patient population. A special focus on technology to fill gaps in deficits, review of case studies on novel medical treatments, and involvement with the educational system for advocacy with an emphasis on celebrating diversity will serve the rare genetic syndrome population well.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10815286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138482092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The importance of escalating molecular diagnostics in patients with low-grade pediatric brain cancer.","authors":"Majd Al Assaad, Gunes Gundem, Benjamin Liechty, Andrea Sboner, Juan Medina, Elli Papaemmanuil, Cora N Sternberg, Asher Marks, Mark M Souweidane, Jeffrey P Greenfield, Ivy Tran, Matija Snuderl, Olivier Elemento, Marcin Imielinski, David J Pisapia, Juan Miguel Mosquera","doi":"10.1101/mcs.a006275","DOIUrl":"10.1101/mcs.a006275","url":null,"abstract":"<p><p>Pilocytic astrocytomas are the most common pediatric brain tumors, typically presenting as low-grade neoplasms. We report two cases of pilocytic astrocytoma with atypical tumor progression. Case 1 involves a 12-yr-old boy with an unresectable suprasellar tumor, negative for <i>BRAF</i> rearrangement but harboring a <i>BRAF</i> p.V600E mutation. He experienced tumor size reduction and stable disease following dabrafenib treatment. Case 2 describes a 6-yr-old boy with a thalamic tumor that underwent multiple resections, with no actionable driver detected using targeted next-generation sequencing. Whole-genome and RNA-seq analysis identified an internal tandem duplication in <i>FGFR1</i> and RAS pathway activation. Future management options include FGFR1 inhibitors. These cases demonstrate the importance of escalating molecular diagnostics for pediatric brain cancer, advocating for early reflexing to integrative whole-genome sequencing and transcriptomic profiling when targeted panels are uninformative. Identifying molecular drivers can significantly impact treatment decisions and improve patient outcomes.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10815291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10129379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leukemic presentation and progressive genomic alterations of MCD/C5 diffuse large B-cell lymphoma (DLBCL).","authors":"Patricia M Kim, Reza Nejati, Pin Lu, Devang Thakkar, Nicholas Mackrides, Vanessa Dupoux, Shazia Nakhoda, Don A Baldwin, Jianming Pei, Sandeep S Dave, Y Lynn Wang, Mariusz A Wasik","doi":"10.1101/mcs.a006283","DOIUrl":"10.1101/mcs.a006283","url":null,"abstract":"<p><p>Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of lymphoid malignancies. Based on gene expression profiling, it has been subdivided into germinal center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies have further refined the subclassification of DLBCL, based on recurrent genetic abnormalities. Here, we describe a distinct case of DLBCL that presented in leukemic form. DNA sequencing targeting 275 genes revealed pathogenically relevant mutations of <i>CD79B</i>, <i>MyD88</i>, <i>TP53</i>, <i>TBL1XR1</i>, and <i>PIM1</i> genes, indicating that this lymphoma would be best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Specifically, the recurrent tumor developed loss of <i>TP53</i> heterozygosity (LOH) and additional chromosomal changes central to ABC DLBCL pathogenesis, such as <i>PRDM1</i> loss. Acquired resistance to ibrutinib and rituxan was indicated by the emergence of <i>BTK</i> and <i>FOXO1</i> mutations, respectively, as well as apparent activation of alternative cell-activation pathways, through copy-number alterations (CNAs), detected by high-resolution chromosomal microarrays. In vitro, studies of relapsed lymphoma cells confirmed resistance to standard BTK inhibitors but sensitivity to vecabrutinib, a noncovalent inhibitor active against both wild-type as well as mutated BTK. In summary, we provide in-depth molecular characterization of a de novo leukemic DLBCL and discuss mechanisms that may have contributed to the lymphoma establishment, progression, and development of drug resistance.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10815299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and functional analysis of the germline <i>TP53</i> p.K164E acetylation site variant.","authors":"Emilia Modolo Pinto, Enilze M S F Ribeiro, Jinling Wang, Aaron H Phillips, Richard W Kriwacki, Gerard P Zambetti","doi":"10.1101/mcs.a006290","DOIUrl":"10.1101/mcs.a006290","url":null,"abstract":"<p><p><i>TP53</i> plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline <i>TP53</i> p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify <i>TP53</i> p.K164E as a likely pathogenic variant.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10815290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138482091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel pathogenic <i>PDX1</i> gene variant in a Korean family with maturity-onset diabetes of the young.","authors":"Hyunji Kim, Hwa Young Kim, Jae Hyun Kim, Soo Hyun Seo, Kyung Un Park","doi":"10.1101/mcs.a006305","DOIUrl":"10.1101/mcs.a006305","url":null,"abstract":"<p><p>The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a mutation in a single gene, is often uncertain until genetic testing is performed. We report a 13-yr-old Korean boy who was initially diagnosed with type 2 diabetes (T2DM). MODY was suspected because of his nonobese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina). Sanger sequencing was performed using blood samples from the parents, siblings, and other relatives. A frameshift variant in the 3' region of the last exon of <i>PDX1</i> was detected in the patient and his family members with diabetes. PP1_Moderate criterion was applied and this variant was confirmed to be the genetic cause of diabetes in the family and classified as likely pathogenic. The study highlights the importance of genetic testing for nonobese, early-onset diabetic patients with multiple affected family members. Increased awareness and aggressive genetic testing for MODY are needed.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10815283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10131533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid genome diagnosis of alveolar capillary dysplasia leading to treatment in a child with respiratory and cardiac failure.","authors":"Dana R Tower, Ronald W Day, Tighe Marrone, Rachel Palmquist, Lincoln D Nadauld, Joshua L Bonkowsky, Sabrina Malone Jenkins","doi":"10.1101/mcs.a006292","DOIUrl":"10.1101/mcs.a006292","url":null,"abstract":"<p><p>Alveolar capillary dysplasia (ACD) is a fatal disorder that typically presents in the neonatal period with refractory hypoxemia and pulmonary hypertension. Lung biopsy is traditionally required to establish the diagnosis. We report a 22-mo-old male who presented with anemia, severe pulmonary hypertension, and right heart failure. He had a complicated hospital course resulting in cardiac arrest and requirement for extracorporeal membrane oxygenation. Computed tomography of the chest showed a heterogenous pattern of interlobular septal thickening and pulmonary edema. The etiology of his condition was unknown, lung biopsy was contraindicated because of his medical fragility, and discussions were held to move to palliative care. Rapid whole-genome sequencing (rWGS) was performed. In 2 d it resulted, revealing a novel <i>FOXF1</i> gene pathogenic variant that led to the presumptive diagnosis of atypical ACD. Cases of atypical ACD have been reported with survival in patients using medical therapy or lung transplantation. Based on the rWGS diagnosis and more favorable potential of atypical ACD, aggressive medical treatment was pursued. The patient was discharged home after 67 d in the hospital; he is currently doing well more than 30 mo after his initial presentation with only one subsequent hospitalization and no requirement for lung transplantation. Our case reveals the potential for use of rWGS in a critically ill child in which the diagnosis is unknown. rWGS and other advanced genetic tests can guide clinical management and expand our understanding of atypical ACD and other conditions.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10815270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10016684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>ITPR1</i>-associated spinocerebellar ataxia with craniofacial features-additional evidence for germline mosaicism.","authors":"Robert Kleyner, Nathaniel Ung, Mohammad Arif, Elaine Marchi, Karen Amble, Maureen Gavin, Ricardo Madrid, Gholson Lyon","doi":"10.1101/mcs.a006303","DOIUrl":"10.1101/mcs.a006303","url":null,"abstract":"<p><p>Inositol 1,4,5-triphosphate receptor type 1 (<i>ITPR1</i>) is an endoplasmic reticulum-bound intracellular inositol triphosphate receptor involved in the regulation of intracellular calcium. Pathogenic variants in <i>ITPR1</i> are associated with spinocerebellar ataxia (SCA) types 15/16 and 29 and have recently been implicated in a facial microsomia syndrome. In this report, we present a family with three affected individuals found to have a heterozygous missense c.800C > T (predicted p.Thr267Met) who present clinically with a SCA29-like syndrome. All three individuals presented with varying degrees of ataxia, developmental delay, and apparent intellectual disability, as well as craniofacial involvement-an uncommon finding in patients with SCA29. The variant was identified using clinical exome sequencing and validated with Sanger sequencing. It is presumed to be inherited via parental germline mosaicism. We present our findings to provide additional evidence for germline mosaic inheritance of SCA29, as well as to expand the clinical phenotype of the syndrome.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10815276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41193558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep molecular tracking over the 12-yr development of endometrial cancer from hyperplasia in a single patient.","authors":"Katherine Reid, Olga Camacho-Vanegas, Deep Pandya, Sandra Catalina Camacho, Rui Fang Qiao, Tamara Kalir, Maria M Padron-Rhenals, Ann-Marie Beddoe, Peter Dottino, John A Martignetti","doi":"10.1101/mcs.a006311","DOIUrl":"10.1101/mcs.a006311","url":null,"abstract":"<p><p>Although the progressive histologic steps leading to endometrial cancer (EndoCA), the most common female reproductive tract malignancy, from endometrial hyperplasia are well-established, the molecular changes accompanying this malignant transformation in a single patient have never been described. We had the unique opportunity to investigate the paired histologic and molecular features associated with the 12-yr development of EndoCA in a postmenopausal female who could not undergo hysterectomy and instead underwent progesterone treatment. Using a specially designed 58-gene next-generation sequencing panel, we analyzed a total of 10 sequential biopsy samples collected over this time frame. A total of eight pathogenic/likely pathogenic mutations in seven genes, <i>APC</i>, <i>ARID1A</i>, <i>CTNNB1</i>, <i>CDKN2A</i>, <i>KRAS</i>, <i>PTEN</i>, and <i>TP53</i>, were identified. A <i>PTEN</i> nonsense mutation p.W111* was present in all samples analyzed except histologically normal endometrium. Apart from this <i>PTEN</i> mutation, the only other recurrent mutation was <i>KRAS</i> G12D, which was present in six biopsy samplings, including histologically normal tissue obtained at the patient's first visit but not detectable in the cancer. The <i>PTEN</i> p.W111* mutant allele fractions were lowest in benign, inactive endometrial glands (0.7%), highest in adenocarcinoma (36.9%), and, notably, were always markedly reduced following progesterone treatment. To our knowledge, this report provides the first molecular characterization of EndoCA development in a single patient. A single <i>PTEN</i> mutation was present throughout the 12 years of cancer development. Importantly, and with potential significance toward medical and nonsurgical management of EndoCA, progesterone treatments were consistently noted to markedly decrease <i>PTEN</i> mutant allele fractions to precancerous levels.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10815295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41232865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>FKBP14</i> kyphoscoliotic Ehlers-Danlos syndrome misdiagnosed as Larsen syndrome: a case report.","authors":"Amy Wiegand, Rama Kastury, Arpita Neogi, Arya Mani, Allen Bale, Allison Cox","doi":"10.1101/mcs.a006281","DOIUrl":"10.1101/mcs.a006281","url":null,"abstract":"<p><p>Hereditary connective tissue disorders have overlapping phenotypes, particularly in regard to musculoskeletal features. This contributes to the challenge of phenotype-based clinical diagnoses. However, some hereditary connective tissue disorders have distinct cardiovascular manifestations that require early intervention and specific management. Molecular testing has increased the ability to categorize and diagnose distinct hereditary connective tissue disorders. A 42-yr-old female with a clinical diagnosis of Larsen syndrome from birth presented for genetic testing based on her recent diagnosis of premenopausal breast cancer. She had a past medical history of multiple carotid dissections. As she never had confirmatory molecular genetic testing for Larsen syndrome, whole-exome sequencing was utilized to assess both hereditary cancer predisposition syndromes and connective tissue disorders. A homozygous pathogenic variant in the <i>FKBP14</i> gene was identified associated with <i>FKBP14</i> kyphoscoliotic Ehlers-Danlos syndrome. We recommend that patients with a clinical diagnosis of Larsen syndrome undergo broad-based molecular sequencing for multiple hereditary connective tissue disorders. Molecular diagnosis is particularly crucial for all individuals who have a history of significant vascular events in the setting of a clinical diagnosis only. Early diagnosis of a hereditary connective tissue disorder with vascular features allows for screening and subsequent prevention of cardiovascular events.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"9 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9920968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of hypereosinophilia in a case of <i>FLT3</i>-mutant acute myeloid leukemia treated with gilteritinib.","authors":"Leslie N Martinez-Gutierrez, Blake C Burgher, Manuel J Glynias, Daniel Alvarado, Elizabeth A Griffiths, Sean T Glenn, Pamela J Sung","doi":"10.1101/mcs.a006279","DOIUrl":"10.1101/mcs.a006279","url":null,"abstract":"<p><p>Acute myeloid leukemias (AMLs) frequently harbor activating mutations in <i>Fms-like tyrosine kinase 3</i> (<i>FLT3</i>). The use of FLT3 inhibitors (FLT3i) is the standard of care for treatment of newly diagnosed and relapsed patients with AML. Differentiation responses including clinical differentiation syndrome have been previously reported with FLT3i when used as single agents in relapsed disease. We present a case of hypereosinophilia in a patient on FLT3i therapy with persistent <i>FLT3</i> polymerase chain reaction (PCR) positivity in peripheral blood. We sorted mature leukocytes by lineage to determine if the eosinophils were leukemia-derived. <i>FLT3</i> PCR and next-generation sequencing analysis demonstrated monocytic differentiation of the <i>FLT3-ITD</i> leukemic clone with reactive hypereosinophilia that was derived from a preleukemic <i>SF3B1</i>, <i>FLT3</i> wild-type clone. Our case is the first to definitively demonstrate the emergence of clonal <i>FLT3-ITD</i> monocytes with FLT3i and the first to demonstrate a differentiation response following decitabine, venetoclax, and gilteritinib triplet therapy.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"9 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5f/97/MCS006279Mar.PMC10393187.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9926720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}