Cold Spring Harbor Molecular Case Studies最新文献

{"title":"Two mutations in the <i>SBDS</i> gene reveal a diagnosis of Shwachman-Diamond syndrome in a patient with atypical symptoms.","authors":"María Noel Spangenberg, Sofia Grille, Camila Simoes, Nicolás Dell'Oca, Matilde Boada, Cecilia Guillermo, Victor Raggio, Lucía Spangenberg","doi":"10.1101/mcs.a006237","DOIUrl":"10.1101/mcs.a006237","url":null,"abstract":"<p><p>We present the case of a 53-yr-old woman with an inherited bone marrow failure coexisting with uncommon extrahematological symptoms, such as cirrhosis and skin abnormalities. Whole-exome sequencing revealed a diagnosis of Shwachman-Diamond syndrome (SDS) with an atypical presentation. Unexpected was the age of disease expression, normally around the pediatric age, with a predominantly median survival age of 36 yr. To our knowledge, she was the first adult patient with a molecular diagnosis of Shwachman-Diamond in Uruguay. The patient was referred to our service when she was 43-yr-old with a history of bone marrow failure with anemia and thrombocytopenia. All secondary causes of pancytopenia were excluded. Bone marrow aspirate and biopsy specimens were hypocellular for the patient's age. Numerous dysplastic features were observed in the three lineages. She had a normal karyotype and normal chromosomal fragility. A diagnosis of low-risk hypoplastic MDS was made. Dermatological examination revealed reticulate skin pigmentation with hypopigmented macules involving the face, neck, and extremities; nail dystrophy; premature graying; and thin hair. Extrahematological manifestations were present (e.g., learning difficulties, short stature). Last, she was diagnosed with cryptogenic liver cirrhosis CHILD C. This rules out all other possible causes of chronic liver disease. This clinical presentation initially oriented the diagnosis toward telomeropathy, so we did a telomeropathy NGS panel that came up negative. Finally, we did an exome sequencing that confirmed the diagnosis of SDS. Using whole-exome sequencing, we were able to find two compound heterozygous mutations in the <i>SBDS</i> gene that were responsible for the phenotype of a patient that was undiagnosed for 10 years. An earlier genetic diagnosis could have influenced our patient's outcome.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 7","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7b/44/MCS006237Spa.PMC9808556.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10809077","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 sequencing identifies a novel de novo <i>SNAP25</i> variant for neonatal congenital myasthenic syndrome.","authors":"Hayley M Reynolds, Ting Wen, Andrew Farrell, Rong Mao, Barry Moore, Steven E Boyden, Pinar Bayrak-Toydemir, Thomas J Nicholas, Shawn Rynearson, Carson Holt, Christine Miller, Katherine Noble, Dawn Bentley, Rachel Palmquist, Betsy Ostrander, Stephanie Manberg, Joshua L Bonkowsky, Brian J Shayota, Sabrina Malone Jenkins","doi":"10.1101/mcs.a006242","DOIUrl":"10.1101/mcs.a006242","url":null,"abstract":"<p><p>Congenital myasthenic syndrome (CMS) is a group of 32 disorders involving genetic dysfunction at the neuromuscular junction resulting in skeletal muscle weakness that worsens with physical activity. Precise diagnosis and molecular subtype identification are critical for treatment as medication for one subtype may exacerbate disease in another (Engel et al., <i>Lancet Neurol</i> 14: 420 [2015]; Finsterer, <i>Orphanet J Rare Dis</i> 14: 57 [2019]; Prior and Ghosh, <i>J Child Neurol</i> 36: 610 [2021]). The <i>SNAP25-</i>related CMS subtype (congenital myasthenic syndrome 18, CMS18; MIM #616330) is a rare disorder characterized by muscle fatigability, delayed psychomotor development, and ataxia. Herein, we performed rapid whole-genome sequencing (rWGS) on a critically ill newborn leading to the discovery of an unreported pathogenic de novo <i>SNAP25</i> c.529C > T; p.Gln177Ter variant. In this report, we present a novel case of CMS18 with complex neonatal consequence. This discovery offers unique insight into the extent of phenotypic severity in CMS18, expands the reported <i>SNAP25</i> variant phenotype, and paves a foundation for personalized management for CMS18.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 7","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/20/40/MCS006242Rey.PMC9808558.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10686638","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":"Identification of a novel large multigene deletion and a frameshift indel in <i>PDE6B</i> as the underlying cause of early-onset recessive rod-cone degeneration.","authors":"Riccardo Sangermano, Pooja Biswas, Lori S Sullivan, Emily M Place, Shyamanga Borooah, Juerg Straubhaar, Eric A Pierce, Stephen P Daiger, Kinga M Bujakowska, Radha Ayaggari","doi":"10.1101/mcs.a006247","DOIUrl":"10.1101/mcs.a006247","url":null,"abstract":"<p><p>A family, with two affected identical twins with early-onset recessive inherited retinal degeneration, was analyzed to determine the underlying genetic cause of pathology. Exome sequencing revealed a rare and previously reported causative variant (c.1923_1969delinsTCTGGG; p.Asn643Glyfs*29) in the <i>PDE6B</i> gene in the affected twins and their unaffected father. Further investigation, using genome sequencing, identified a novel ∼7.5-kb deletion (Chr 4:670,405-677,862del) encompassing the <i>ATP5ME</i> gene, part of the 5' UTR of <i>MYL5</i>, and a 378-bp (Chr 4:670,405-670,782) region from the 3' UTR of <i>PDE6B</i> in the affected twins and their unaffected mother. Both variants segregated with disease in the family. Analysis of the relative expression of <i>PDE6B</i>, in peripheral blood cells, also revealed a significantly lower level of <i>PDE6B</i> transcript in affected siblings compared to a normal control. <i>PDE6B</i> is associated with recessive rod-cone degeneration and autosomal dominant congenital stationary night blindness. Ophthalmic evaluation of these patients showed night blindness, fundus abnormalities, and peripheral vision loss, which are consistent with <i>PDE6B</i>-associated recessive retinal degeneration. These findings suggest that the loss of <i>PDE6B</i> transcript resulting from the compound heterozygous pathogenic variants is the underlying cause of recessive rod-cone degeneration in the study family.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 7","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f1/fc/MCS006247San.PMC9808551.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9652591","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":"A missense, loss-of-function <i>YARS1</i> variant in a patient with proximal-predominant motor neuropathy.","authors":"Megan E Forrest, Alayne P Meyer, Stephanie M Laureano Figueroa, Anthony Antonellis","doi":"10.1101/mcs.a006246","DOIUrl":"10.1101/mcs.a006246","url":null,"abstract":"<p><p>Aminoacyl-tRNA synthetases (ARSs) are essential enzymes with a critical role in protein synthesis: charging tRNA molecules with cognate amino acids. Heterozygosity for variants in five genes (<i>AARS1</i>, <i>GARS1</i>, <i>HARS1</i>, <i>WARS1</i>, and <i>YARS1</i>) encoding cytoplasmic, dimeric ARSs have been associated with autosomal dominant neurological phenotypes, including axonal Charcot-Marie-Tooth disease (CMT). Missense variants in the catalytic domain of <i>YARS1</i> were previously linked to dominant intermediate CMT type C (DI-CMTC). Here, we report a patient with a missense variant of unknown significance predicted to modify residue 308 in the anticodon binding domain of <i>YARS1</i> (p.Asp308Tyr). Interestingly, p.Asp308Tyr is associated with proximal-predominant motor neuropathy, which has not been reported in patients with pathogenic <i>YARS1</i> variants. We demonstrate that this allele causes a loss-of-function effect in yeast complementation assays when modeled in <i>YARS1</i> and the yeast ortholog <i>TYS1</i>; structural modeling of this variant further supports a loss-of-function effect. Taken together, this study raises the possibility that certain <i>YARS1</i> variants cause proximal-prominent motor neuropathy and indicates that patients with this phenotype should be screened for genetic lesions in <i>YARS1</i>.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 7","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0e/04/MCS006246For.PMC9808560.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10633645","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":"Genetic diagnosis for adult patients at a genetic clinic.","authors":"Kitiwan Rojnueangnit, Pimjai Anthanont, Thanitchet Khetkham, Sukita Puttamanee, Chupong Ittiwut","doi":"10.1101/mcs.a006235","DOIUrl":"10.1101/mcs.a006235","url":null,"abstract":"<p><p>Clinical utility of genetic testing has rapidly increased in the past decade to identify the definitive diagnosis, etiology, and specific management. The majority of patients receiving testing are children. There are several barriers for genetic tests in adult patients; barriers may arise from either patients or clinicians. Our study aims to realize the detection rate and the benefits of genetic tests in adults. We conducted a prospective study of 10 adult patients who were referred to a genetic clinic. Exome sequencing (ES) was pursued in all cases, and chromosomal microarray (CMA) was performed for six cases. Our result is impressive; six cases (60%) received likely pathogenic and pathogenic variants. Four definitive diagnosis cases had known pathogenic variants in <i>KCNJ2</i>, <i>TGFBR1</i>, <i>SCN1A</i>, and <i>FBN1</i>, whereas another two cases revealed novel likely pathogenic and pathogenic variants in <i>GNB1</i> and <i>DNAH9.</i> Our study demonstrates the success in genetic diagnosis in adult patients: four cases with definitive, two cases with possible, and one case with partial diagnosis. The advantage of diagnosis is beyond obtaining the diagnosis itself, but also relieving any doubt for the patient regarding any previous questionable diagnosis, guide for management, and recurrence risk in their children or family members. Therefore, this supports the value of genetic testing in adult patients.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 7","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4c/55/MCS006235Roj.PMC9808555.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10632378","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":"Characterization of a novel deep-intronic variant in <i>DYNC2H1</i> identified by whole-exome sequencing in a patient with a lethal form of a short-rib thoracic dysplasia type III.","authors":"Muqsit Buchh, Patrick J Gillespie, Kayla Treat, Marco A Abreu, Tae-Hwi Linus Schwantes-An, Benjamin M Helm, Fang Fang, Xiaoling Xuei, Lili Mantcheva, Kristen R Suhrie, Brett H Graham, Erin Conboy, Francesco Vetrini","doi":"10.1101/mcs.a006254","DOIUrl":"10.1101/mcs.a006254","url":null,"abstract":"<p><p>Biallelic pathogenic variants in <i>DYNC2H1</i> are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the <i>DYNC2H1</i> gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in <i>DYNC2H1</i> was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited <i>DYNC2H1</i> deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of <i>DYNCH2H1</i> mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 7","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d8/dc/MCS006254Buc.PMC9808550.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10631243","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":"Whole-genome characterization of myoepithelial carcinomas of the soft tissue.","authors":"Joanna Cyrta,&nbsp;Joel Rosiene,&nbsp;Rohan Bareja,&nbsp;Sarah Kudman,&nbsp;Wael Al Zoughbi,&nbsp;Samaneh Motanagh,&nbsp;David C Wilkes,&nbsp;Kenneth Eng,&nbsp;Tuo Zhang,&nbsp;Evan Sticca,&nbsp;Susan Mathew,&nbsp;Mark A Rubin,&nbsp;Andrea Sboner,&nbsp;Olivier Elemento,&nbsp;Brian P Rubin,&nbsp;Marcin Imielinski,&nbsp;Juan Miguel Mosquera","doi":"10.1101/mcs.a006227","DOIUrl":"https://doi.org/10.1101/mcs.a006227","url":null,"abstract":"<p><p>Myoepithelial carcinomas (MECs) of soft tissue are rare and aggressive tumors affecting young adults and children, but their molecular landscape has not been comprehensively explored through genome sequencing. Here, we present the whole-exome sequencing (WES), whole-genome sequencing (WGS), and RNA sequencing findings of two MECs. Patients 1 and 2 (P1, P2), both male, were diagnosed at 27 and 37 yr of age, respectively, with shoulder (P1) and inguinal (P2) soft tissue tumors. Both patients developed metastatic disease, and P2 died of disease. P1 tumor showed a rhabdoid cytomorphology and a complete loss of INI1 (SMARCB1) expression, associated with a homozygous <i>SMARCB1</i> deletion. The tumor from P2 showed a clear cell/small cell morphology, retained INI1 expression and strong S100 positivity. By WES and WGS, tumors from both patients displayed low tumor mutation burdens, and no targetable alterations in cancer genes were detected. P2's tumor harbored an <i>EWSR1::KLF15</i> rearrangement, whereas the tumor from P1 showed a novel <i>ASCC2::GGNBP2</i> fusion. WGS evidenced a complex genomic event involving mainly Chromosomes 17 and 22 in the tumor from P1, which was consistent with chromoplexy. These findings are consistent with previous reports of <i>EWSR1</i> rearrangements (50% of cases) in MECs and provide a genetic basis for the loss of SMARCB1 protein expression observed through immunohistochemistry in 10% of 40% of MEC cases. The lack of additional driver mutations in these tumors supports the hypothesis that these alterations are the key molecular events in MEC evolution. Furthermore, the presence of complex structural variant patterns, invisible to WES, highlights the novel biological insights that can be gained through the application of WGS to rare cancers.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 7","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/17/5b/MCS006227Cyr.PMC9808553.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10634746","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":"Germline mosaicism in a family with <i>MBD5</i> haploinsufficiency.","authors":"Mehak Bhatia,&nbsp;Gianpiero L Cavalleri,&nbsp;Maire White,&nbsp;Norman Delanty,&nbsp;Brian J Sweeney,&nbsp;Daniel J Costello,&nbsp;Marie T Greally,&nbsp;Katherine A Benson","doi":"10.1101/mcs.a006253","DOIUrl":"https://doi.org/10.1101/mcs.a006253","url":null,"abstract":"<p><p>Haploinsufficiency of the methyl-CpG-binding domain protein 5 (<i>MBD5</i>) gene causes a neurodevelopmental disorder that includes intellectual disability, developmental delay, speech impairment, seizures, sleep disturbances, and behavioral difficulties. Microdeletion of 2q23.1 is the most common cause of haploinsufficiency, although <i>MBD5</i> haploinsufficiency may also cause this genetic disorder. We report a family harboring a heterozygous loss-of-function variant in <i>MBD5</i> (NM_018328.5:c.728delC; p.Pro243His<i>fs</i>*26), which includes three affected siblings with varying phenotypic features. Both parents were phenotypically normal but deep coverage sequencing of the parents showed germline mosaicism in the mother.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 7","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fe/8f/MCS006253Bha.PMC9808559.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9187649","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":"A novel biallelic loss-of-function variant in <i>DAND5</i> causes heterotaxy syndrome.","authors":"Mythily Ganapathi,&nbsp;Christie M Buchovecky,&nbsp;Fernando Cristo,&nbsp;Priyanka Ahimaz,&nbsp;Carrie Ruzal-Shapiro,&nbsp;Karen Wou,&nbsp;José M Inácio,&nbsp;Alejandro Iglesias,&nbsp;José A Belo,&nbsp;Vaidehi Jobanputra","doi":"10.1101/mcs.a006248","DOIUrl":"https://doi.org/10.1101/mcs.a006248","url":null,"abstract":"<p><p>The majority of heterotaxy cases do not obtain a molecular diagnosis, although pathogenic variants in more than 50 genes are known to cause heterotaxy. A heterozygous missense variant in <i>DAND5</i>, a nodal inhibitor, which functions in early development for establishment of right-left patterning, has been implicated in heterotaxy. Recently, the first case was reported of a <i>DAND5</i> biallelic loss-of-function (LoF) variant in an individual with heterotaxy. Here, we describe a second unrelated individual with heterotaxy syndrome and a homozygous frameshift variant in <i>DAND5</i> (NM_152654.2:c.197del [p.Leu66ArgfsTer22]). Using an in vitro assay, we demonstrate that the <i>DAND5</i> c.197del variant is unable to inhibit nodal signaling when compared with the wild-type expression construct. This work strengthens the genetic and functional evidence for biallelic LoF variants in <i>DAND5</i> causing an autosomal recessive heterotaxy syndrome.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 7","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/13/6a/MCS006248Gan.PMC9808554.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10686591","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":"Lorlatinib and compound mutations in ALK+ large-cell neuroendocrine lung carcinoma: a case report.","authors":"Christiane Wiedemann,&nbsp;Daniel Kazdal,&nbsp;Jelena Cvetkovic,&nbsp;Julia Kunz,&nbsp;David Fisch,&nbsp;Martina Kirchner,&nbsp;Mark Kriegsmann,&nbsp;Holger Sültmann,&nbsp;Claus-Peter Heussel,&nbsp;Helge Bischoff,&nbsp;Michael Thomas,&nbsp;Albrecht Stenzinger,&nbsp;Petros Christopoulos","doi":"10.1101/mcs.a006234","DOIUrl":"https://doi.org/10.1101/mcs.a006234","url":null,"abstract":"<p><p>Large-cell neuroendocrine lung carcinoma (LCNEC) is a high-grade neoplasm with median survival of 1 year and limited therapeutic options. Here, we report the unusual case of a 47-yr-old female smoker with stage IV LCNEC featuring <i>EML4</i>-<i>ALK</i> variant 2 (E20:A20), wild-type <i>TP53/RB1</i>, and low tumor mutational burden of 3.91 mut/Mb. Despite early progression within 3 mo under crizotinib, a durable response was achieved with alectinib. Oligoprogression in the left breast 10 mo later was treated by surgery, followed by a switch to ceritinib upon multifocal progression and detection of <i>ALK</i>:p.V1180L in the mastectomy specimen, but without success. Another rebiopsy revealed <i>ALK</i>:p.L1196M, but the tumor did not respond to brigatinib or carboplatin/pemetrexed, before stabilization under lorlatinib. Diffuse progression 8 mo later with detection of <i>ALK</i> <i>:</i>p.L1196M/p.G1202R and p.L1196M/ p.D1203N evolving from the previous p.L1196M did not respond to chemoimmunotherapy, and the patient succumbed with an overall survival (OS) of 37 mo. This case illustrates the importance of molecular profiling for LCNEC regardless of smoking status, and the superiority of next-generation ALK inhibitors compared to crizotinib for ALK+ cases. Lorlatinib retained efficacy in the heavily pretreated setting, whereas its upfront use could possibly have prevented the stepwise emergence of compound <i>ALK</i> mutations. Furthermore, the disease course was more aggressive and OS shorter compared to the V2/<i>TP53</i>wt ALK+ lung adenocarcinoma, whereas crizotinib, ceritinib, and brigatinib did not confer the benefit expected according to next-generation sequencing results, which also underline the need for more potent drugs against ALK in the high-risk setting of neuroendocrine histology.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 6","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9632356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10623982","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}