Molecular Case Studies

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ISSN / EISSN : 2373-2865 / 2373-2873
Published by: Cold Spring Harbor Laboratory (10.1101)
Total articles ≅ 368
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Claire Mallard, Michael Johnston, Anna Bobyn, Ana Nikolic, Bob Argiropoulos, Jennifer Chan, Gregory Guilcher,
Molecular Case Studies; https://doi.org/10.1101/mcs.a006157

Abstract:
B-cell acute lymphoblastic leukemia (B-ALL) is often driven by chromosome translocations that result in recurrent and well-studied gene fusions. Currently, fluorescent in-situ hybridization probes are employed to detect candidate translocations in bone marrow samples from B-ALL patients. Recently Hi-C, a sequencing-based technique originally designed to reconstruct the three-dimensional architecture of the nuclear genome, was shown to effectively recognize structural variants. Here, we demonstrate that Hi-C can be used as a genome-wide assay to detect translocations and other structural variants of potential clinical interest. Structural variants were identified in both bone marrow and peripheral blood samples, including an ETV6-RUNX1 translocation present in one pediatric B-ALL patient. Our report provides proof-of-principle that Hi-C could be an effective strategy to globally detect driver structural variants in B-ALL peripheral blood specimens, reducing the need for invasive bone marrow biopsies and candidate-based clinical tests.
Tamara J. Hagoel, Eduardo Cortez Gomez, Ajay Gupta, Clare J. Twist, Rafal Kozielski, Jeffrey C Martin, Lingui Gao, Joseph Kuechle, Prashant K Singh, Miranda Lynch, et al.
Molecular Case Studies; https://doi.org/10.1101/mcs.a005942

Abstract:
Undifferentiated soft tissue sarcomas (UDSTS ) are a group of mesenchymal tumors that remain a diagnostic challenge due to their morphologic heterogeneity and unclear histologic origin (Peters et al. 2015b). In this case report, we present the first multi-omics molecular signature for a BCOR-CCNB3 sarcoma (BCS) that includes mutation analysis, gene expression, DNA methylation, and mi-RNA expression. We identify a paucity of additional mutations in this tumor and detail that there is significant dysregulation of gene expression of epigeneic remodeling agents including key members of the PRC, Sin3A/3b, NuRD, and NcoR/SMRT complexes and the DNA methyltransferases DNMT1, DNMT3a, and DNMT3b. This is accompanied by significant DNA methylation changes and dysregulation of multiple miRNA with known links to tumorigenesis. This study significantly increases our understanding of the BCOR effects on fusion positive undifferentiated sarcomas at both the genomic and epigenomic level and suggests that as better-tailored and more refined treatment algorithms continue to evolve, epigenetic modifying agents should be further evaluated for their efficacy against these tumors.
Kamal Hassan, Amal Robay, AlJazi Al-Maraghi, Nuha Nimeri, Asmaa Azzam, Alya Al Shakaki, Eman Hamid, Ronald Crystal, Khalid Fakhro
Molecular Case Studies; https://doi.org/10.1101/mcs.a006103

Abstract:
Microvillus inclusion disease (MVID, MIM♯ 251850), also known as congenital microvil-lus atrophy, was first described by Davidson et al. in 1978. It is a rare au-tosomal recessive disease that presents with an intractable life-threatening watery diarrhea either within the first days of life (early-onset form) or at several months of life (late-onset form) . The hallmarks of MVID are a lack of microvilli on the surface of villous enterocytes, occurrence of microvillous inclusions and the cytoplasmic accumulation of periodic acid-schiff-positive vesicles. In 2008, Muller et al showed that mutations in MYO5B (MIM ♯ 606540), en-coding the unconventional type Vb myosin motor protein, were associated with MVID in an ex-tended Turkish kindred. Since then, more mutations were described in different populations . In this report we describe a novel mutation in two unrelated Syrian patients with MVID.
Nicole Baca, Pedro Sanchez-Lara, Celeste Eno, Rhona Schreck, Fataneh Majlessipour
Molecular Case Studies; https://doi.org/10.1101/mcs.a006126

Abstract:
Trisomy 21 is a common congenital disorder with well documented clinical manifestations, including an increased risk for transient myeloproliferative disorder as a neonate and leukemia in childhood and adolescence. Children with mosaic trisomy 21 can have a similar risk for hematological malignancies. We present a non-dysmorphic neonate, with negative noninvasive prenatal screening of maternal blood for trisomy 21, who came to medical attention because of ruddy skin. He was found to have mild polycythemia, thrombocytopenia and developed peripheral blasts. His clinical presentation was concerning for transient myeloproliferative disorder, which is only seen in trisomy 21 patients. Cytogenetic studies were positive for mosaic trisomy 21.
Kayla J Muirhead, Amanda R Clause, Zinayida Schlachetzki, Holly Dubbs, Denise L Perry, Tanner Hagelstrom, Ryan J Taft, Adeline Vanderver
Molecular Case Studies; https://doi.org/10.1101/mcs.a006143

Abstract:
Undiagnosed genetic disease imposes significant burden on families and healthcare resources, especially in cases with a complex phenotype. Here we present a child with suspected leukodystrophy in the context of additional features, including hearing loss, clinodactyly, rotated thumbs, tapered fingers, and simplified palmar crease. Trio genome sequencing (GS) identified three molecular diagnoses in this individual: compound heterozygous missense variants associated with Pol III-related leukodystrophy, a 4 Mb de novo copy number loss including the MYCN gene associated with Feingold syndrome, and a mosaic single nucleotide variant (SNV) associated with COL2A1-related disorders. These variants fully account for the individual's features, but also illustrate the potential for superimposed and unclear contributions of multiple diagnoses to a individual's overall presentation. This report demonstrates the advantage of GS in detection of multiple variant types, including low-level mosaic variants, and emphasizes the need for comprehensive genetic analysis and detailed clinical phenotyping to provide individuals and their families with the maximum benefit for clinical care and genetic counseling.
Hilary A Scott, Anna Larson, , Sudeep Mehrotra, Rossano Butcher, Katherine R Chao, Janey Wiggs, Emily M. Place, ,
Molecular Case Studies; https://doi.org/10.1101/mcs.a006131

Abstract:
Rod cone dystrophy (RCD), also known as retinitis pigmentosa, is an inherited condition leading to vision loss, affecting 1/3500 people. Over 270 genes are known to be implicated in the inherited retinal degenerations (IRDs), yet genetic diagnosis for ~30% IRD of patients remains elusive despite advances in sequencing technologies. The goal of this study was to determine the genetic causality in a family with Rod-cone dystrophy (RCD). Family members were given a full ophthalmic exam at the Retinal Service at MEE and consented to genetic testing. Whole exome sequencing (WES) was performed and variants of interest were Sanger validated. Functional assays were conducted in zebrafish along with splicing assays in relevant cell lines to determine the impact on retinal function. WES identified variants in two potential candidate genes that segregated with disease: GNL3 (G Protein Nucleolar 3) c.1187+3A>C and c.1568-8C>A; and PDE4DIP (Phosphodiester 4D Interacting Protein) c.3868G>A (p.Glu1290Lys) and c.4603G>A (p.Ala1535Thr). Both genes were promising candidates based on their retinal involvement (development and interactions with IRD-associated proteins), however the functional assays did not validate either gene. Subsequent WES reanalysis with an updated bioinformatics pipeline and widened search parameters led to the detection of a 94bp duplication in PRPF31 (pre-mRNA Processing Factor 31) c.73_266dup (p.Asp56GlyfsTer33) as the causal variant. Our study demonstrates the importance of thorough functional characterization of new disease candidate genes, and the value of reanalyzing NGS sequence data, which in our case led to identification of a hidden pathogenic variant in a known IRD gene.
Marilena Melas, Mariam T Mathew, , Vijayakumar Jayaraman, Sarah A Wilson, Cortlandt Martin, Amanda E Jacobson-Kelly, Ben J Kelly, Vincent Magrini, , et al.
Molecular Case Studies; https://doi.org/10.1101/mcs.a006135

Abstract:
The methodologic approach used in next-generation sequencing (NGS) affords a high depth of coverage in genomic analysis. Inherent in the nature of genomic testing, there exists potential for identifying genomic findings that are incidental or secondary to the indication for clinical testing, with the frequency dependent on the breadth of analysis and the tissue sample under study. The interpretation and management of clinically meaningful incidental genomic findings is a pressing issue particularly in the pediatric population. Our study describes a 16-month old male who presented with Dandy-Walker malformation, metopic craniosynostosis and developmental delay. Clinical exome sequencing (ES) trio analysis revealed the presence of two variants in the proband. The first was a de novo variant in the PPP2R1A gene (c.773G>A, p.Arg258His), which is associated with autosomal dominant (AD) intellectual disability, accounting for the proband's clinical phenotype. The second was a recurrent hotspot variant in the CBL gene (c.1111T>C, p.Tyr371His), which was present at a variant allele fraction of 11%, consistent with somatic variation in the peripheral blood sample. Germline pathogenic variants in CBL are associated with AD Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (JMML). Molecular analyses using a different tissue source, buccal epithelial cells, suggest that the CBL alteration may represent a clonal population of cells restricted to leukocytes. This report highlights the laboratory methodologic and interpretative processes and clinical considerations in the setting of acquired variation detected during clinical ES in a pediatric patient.
Robert Kleyner, Arif Mohammad, Elaine Marchi, Naomi Horowitz, Andrea Haworth, Brian King, Karen Amble, Maureen Gavin, Milen Velinov,
Molecular Case Studies; https://doi.org/10.1101/mcs.a006137

Abstract:
An SLC30A9 associated cerebro renal syndrome was first reported in consanguineous Bedouin kindred by Perez et al in 2017. While the function of the gene has not yet been fully elucidated, it may be implicated in Wnt signaling, nuclear regulation, as well as cell and mitochondrial zinc regulation. In this research report, we present a female proband with two distinct, inherited autosomal recessive loss of function SLC30A9 variants from unrelated parents. To our knowledge, this is the first reported case of a possible SLC30A9 associated cerebro renal syndrome in a nonconsanguineous family. Furthermore, a limited statistical analysis was conducted to identify possible allele frequency differences between populations. Our findings provide further support for an SLC30A9 associated cerebro renal syndrome and may help further clarify the function of this gene.
Felicia Hernandez, Blair Rene Conner, Marcy E. Richardson, , Elizabeth Chao, ,
Molecular Case Studies; https://doi.org/10.1101/mcs.a006152

Abstract:
MUTYH-associated polyposis (MAP) is an autosomal recessive disorder characterized by the development of multiple adenomatous colonic polyps and an increased lifetime risk of colorectal cancer. Germline biallelic pathogenic variants in MUTYH are responsible for MAP. The MUTYH c.934-2A>G (NM_001128425.1) variant, which is also known as c.850-2A>G for NM_001048174.2, has been identified in our laboratory in more than 800 patients, including homozygous and compound heterozygote carriers. The variant was initially classified as a variant of uncertain significance (VUS) due to lack of a MAP phenotype in biallelic carriers. In two unrelated female patients who were heterozygous carriers of this variant, further testing by RNA sequencing identified an aberrant transcript with a deletion of 9 nucleotides at the start of exon 11 (MUTYH r.934_942del9). This event is predicted to lead to an in-frame loss of 3 amino acids in a non-critical domain of the protein. This was the only splice defect identified in these patients which was not present in the controls and the aberrant transcript is derived exclusively from the variant allele, strongly supporting the cause of this splice defect as being the intronic variant, MUTYH c.934-2A>G. The splicing analysis demonstrating a small in-frame skipping of 3 amino acids in a non-critical domain along with the absence of a MAP phenotype in our internal cohort of biallelic carriers provides evidence that the variant is likely benign and not of clinical significance.
Kelly A Duffy, Evan R Hathaway, Steven D Klein, Arupa Ganguly,
Molecular Case Studies; https://doi.org/10.1101/mcs.a006115

Abstract:
Beckwith-Wiedemann syndrome (BWS) is a rare overgrowth disorder caused by epigenetic alterations on chromosome 11p15.5. Most molecular changes are sporadic and are thought to occur in a mosaic pattern. Thereby, the distribution of affected cells differs between tissues for each individual which can complicate genotype-phenotype correlations. In two of the BWS molecular subtypes, tissue mosaicism has been demonstrated; however, mosaicism has not been specifically studied in the most common cause of BWS, loss of methylation at KCNQ1OT1:TSS DMR (IC2 LOM). The increased prevalence of twinning associated with the IC2 LOM subtype and the discordant phenotypes between the twins previously led to the proposal of diffused epigenetic mosaicism leading to asymmetric distribution of affected cells during embryonic development. In this study, we evaluated the level of methylation detected in 64 samples collected from 30 patients affected by IC2 LOM. We demonstrate that the IC2 LOM defect can occur in mosaic and non-mosaic patterns, and tissues from the same patient can show variable patterns, which suggests this asymmetric distribution during development. We further suggest that the clinical phenotype in patients with BWS IC2 LOM is correlated with the epigenetic burden of affected cells in each tissue type. This series is the first report to demonstrate tissue mosaicism within the IC2 LOM epigenotype and consideration of this mosaicism is necessary to understanding the pathogenesis of BWS.
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