Molecular Case Studies

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ISSN / EISSN : 2373-2865 / 2373-2873
Published by: Cold Spring Harbor Laboratory (10.1101)
Total articles ≅ 400
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Subit Barua, Sara Berger, Elaine M. Pereira, Vaidehi Jobanputra
Molecular Case Studies, Volume 8; https://doi.org/10.1101/mcs.a006195

Abstract:
Vacuolar ATPases (V-ATPases) are large multisubunit proton pumps conserved among all eukaryotic cells that are involved in diverse functions including acidification of membrane-bound intracellular compartments. The ATP6AP1 gene encodes an accessory subunit of the vacuolar (V)-ATPase protein pump. Pathogenic variants in ATP6AP1 have been described in association with a congenital disorder of glycosylation (CDG), which are highly variable, but often characterized by immunodeficiency, hepatopathy, and neurologic manifestations. Although the most striking and common clinical feature is hepatopathy, the phenotypic and genotypic spectrum of ATP6AP1-CDG continues to expand. Here, we report identical twins who presented with acute liver failure and jaundice. Prenatal features included cystic hygroma, atrial septal defect, and ventriculomegaly. Postnatal features included pectus carinatum, connective tissue abnormalities, and hypospadias. Whole-exome sequencing (WES) revealed a novel de novo in-frame deletion in the ATP6AP1 gene (c.230_232delACT;p.Tyr77del). Although both twins have the commonly reported clinical feature of hepatopathy seen in other individuals with ATP6AP1-CDG-related disorder, they do not have neurological sequelae. This report expands the phenotypic spectrum of ATP6AP1-CDG-related disorder with both probands exhibiting unique prenatal and postnatal features, including fetal ventriculomegaly, umbilical hernia, pectus carinatum, micropenis, and hypospadias. Furthermore, this case affirms that neurological features described in the initial case series on ATP6AP1-CDG do not appear to be central, whereas the prenatal and connective tissue manifestations may be more common than previously thought. This emphasizes the importance of long-term clinical follow-up and variant interpretation using current updated recommendations.
Muhammad Kohailan, Omayma Al-Saei, Sujitha Padmajeya, Waleed Aamer, Najwa Elbashir, Ammira Al-Shabeeb Akil, Abdul-Rauf Kamboh, Khalid Fakhro
Molecular Case Studies, Volume 8; https://doi.org/10.1101/mcs.a006206

Abstract:
Mandibulofacial dysostosis with microcephaly (MFDM) is a rare genetic disorder inherited in an autosomal dominant pattern. Major characteristics include developmental delay, craniofacial malformations such as malar and mandibular hypoplasia, and ear anomalies. Here, we report a 4.5-yr-old female patient with symptoms fitting MFDM. Using whole-genome sequencing, we identified a de novo start-codon loss (c.3G > T) in the EFTUD2. We examined EFTUD2 expression in the patient by RNA sequencing and observed a notable functional consequence of the variant on gene expression in the patient. We identified a novel variant for the development of MFDM in humans. To the best of our knowledge, this is the first report of a start-codon loss in EFTUD2 associated with MFDM.
Abdulrahman Allaf, Berta Victoria, Rosa Rosario, Carly Misztal, Sakir Humayun Gultekin, Christine T. Dinh, Cristina Fernandez-Valle
Molecular Case Studies, Volume 8; https://doi.org/10.1101/mcs.a006178

Abstract:
Schwannomatosis is a rare genetic disorder that predisposes individuals to development of multiple schwannomas mainly in spinal and peripheral nerves and to debilitating chronic pain often unrelated to any schwannoma. Pathogenic variants of two genes, SMARCB1 and LZTR1, are causal in familial cases. However, many schwannomatosis patients lack mutations in these genes. Surgery is the standard treatment for schwannomas but leaves patients with increasing neurological deficits. Pain management is a daily struggle controlled by the use of multiple analgesic and anti-inflammatory drugs. There is a need for both nonsurgical treatment to manage tumor growth and nonaddictive, nonsedative pain control. Because standard clinical trials are exceedingly difficult for patients with rare disorders, precision medicine approaches offer the possibility of bespoke therapeutic regimens to control tumor growth. As a proof of principle, we obtained a bio-specimen of paraspinal schwannoma from a schwannomatosis patient with a germline point mutation in the SMARCB1/INI gene. We created an hTERT immortalized cell line and tested the ability of targeted small molecules with efficacy in neurofibromatosis type 2–related schwannomas to reduce cell viability and induce cell death. We identified WP1066, a STAT3 inhibitor, currently in phase 2 clinical trials for pediatric and adult brain tumors as a lead compound. It reduced cell viability and STAT-3 phosphorylation and induced expression of markers for both necroptosis and caspase-dependent cell death. The results demonstrate feasibility in creating patient-derived cell lines for use in precision medicine studies.
Dingani Nkosi, Caroline A. Miller, Audrey N. Jajosky,
Molecular Case Studies, Volume 8; https://doi.org/10.1101/mcs.a006201

Abstract:
Liquid biopsy is considered an alternative to standard next-generation sequencing (NGS) of solid tumor samples when biopsy tissue is inadequate for testing or when testing of a peripheral blood sample is preferred. A common assumption of liquid biopsies is that the NGS data obtained on circulating cell-free DNA is a high-fidelity reflection of what would be found by solid tumor testing. Here, we describe a case that challenges this widely held assumption. A patient diagnosed with lung carcinoma showed pathogenic IDH1 and TP53 mutations by liquid biopsy NGS at an outside laboratory. Subsequent in-house NGS of a metastatic lymph node fine-needle aspiration (FNA) sample revealed two pathogenic EGFR mutations. Morphologic and immunophenotypic assessment of the patient's blood sample identified acute myeloid leukemia, with in-house NGS confirming and identifying pathogenic IDH1, TP53, and BCOR mutations, respectively. This case, together with a few similar reports, demonstrates that caution is needed when interpreting liquid biopsy NGS results, especially if they are inconsistent with the presumptive diagnosis. Our case suggests that routine parallel sequencing of peripheral white blood cells would substantially increase the fidelity of the obtained liquid biopsy results.
Julia P Pereira, Juliana R Ferreira, Anna Paula A Botelho, Marcelo M Melo, Glauber Monteiro Dias
Molecular Case Studies; https://doi.org/10.1101/mcs.a006215

Abstract:
Aortic diseases arising in Marfan Syndrome (MFS), such as in aneurysms and dissections of the thoracic aorta, are related to genetic alterations in the FBN1 gene. Databases, such as Universal Mutations-FBN1, ClinVar and The Human Gene Mutation, contain more than a thousand FBN1 mutations associated with MFS. The FBN1 gene, which encodes fibrillin-1, is responsible for the integral production of different protein domains. Possible genetic changes may lead to a weakening of blood vessels, leading to the development of aortopathies. In this study, we present the association of a novel FBN1 variant with MFS. The proband is a man who presented ascending aortic aneurysm and dissection (TAAD) at 42-yr-old, which was surgically treated. Clinical investigations were performed in all family members enrolled in the study. Marfan signs were observed in the proband, daughters and granddaughter. Direct sequencing of the FBN1 gene in the proband identified a novel truncation variant p.(Glu2019Ter) and a cascade screening were done. The variant was classified as pathogenic and causal for MFS according to the American College of Medical Genetics and Genomics (ACMG) criteria and revised Ghent nosology for MFS diagnosis, respectively. Proband's daughter and granddaughter harbor the variant, however without aortic alteration. This work reports for the first time a patient with the FBN1-p.(Glu2019Ter) variant and its association with MFS/TAAD.
Maeson S Latsko, Daniel C Koboldt, Samuel J Franklin, Scott E Hickey, Rachel K Williamson, Shannon Garner, , Kristy Lee, , Richard K Wilson
Molecular Case Studies; https://doi.org/10.1101/mcs.a006172

Abstract:
De novo variants are increasingly recognized as a common cause of early infantile epileptic encephalopathies. We present a 4-year-old male with epileptic encephalopathy characterized by seizures, autism spectrum disorder, and global developmental delay. Whole genome sequencing of the proband and his unaffected parents revealed a novel de novo missense variant in GRIA2 (c.1589A>T; p.Lys530Met; ENST00000264426.14). Variants in the GRIA2 gene were recently reported to cause an autosomal dominant neurodevelopmental disorder with language impairments and behavioral abnormalities (OMIM; MIM #618917), a condition characterized by intellectual disability and developmental delay in which seizures are a common feature. The de novo variant identified in our patient maps to the edge of a key ligand binding domain of the AMPA receptor and has not been previously reported in gnomAD or other public databases, making it novel. Our findings provided a long-sought diagnosis for this patient and support the link between GRIA2 and a dominant neurodevelopmental disorder.
Kosuke Shimizu, Takeshi Sano, Kei Mizuno, Takuro Sunada, Noriyuki Makita, Hiroki Hagimoto, Takayuki Goto, Atsuro Sawada, Masakazu Fujimoto, Kentaro Ichioka, et al.
Molecular Case Studies, Volume 8; https://doi.org/10.1101/mcs.a006194

Abstract:
Defective DNA mismatch repair genes can lead to microsatellite instability (MSI)-high status in prostate cancer (PC). Accumulation of replication errors in DNA leads to the production of abundant neoantigens, which could be targets for immune checkpoint inhibitors (CPIs). However, the incidence of MSI-high PC is low, and not all patients show a satisfactory therapeutic response to CPIs. Here, we present the case of a patient with MSI-high castration-resistant PC who showed a remarkable and durable response to pembrolizumab. The patient was resistant to abiraterone, docetaxel, and cabazitaxel and was suffering from multiple tumor-associated or treatment-related complications, such as urinary tract infection, infective endocarditis, and uncontrollable prostatic hemorrhage. Soon after the start of pembrolizumab therapy, the patient showed a dramatic decrease in prostate-specific antigen from 35.67 ng/mL to an undetectable level and a remarkable reduction in the size of a massive prostate mass and lymph node metastases, with an absence of treatment-related complications. Specimens from the transurethral resection of prostate cancer during cabazitaxel treatment for control of prostate bleeding and also that from the prostate biopsy at initial diagnosis revealed MSI-high status. Immunohistochemistry showed loss of MSH2 and MSH6, and whole-exome sequencing revealed an approximate tumor mutation burden of 61 mutations/Mb as well as biallelic loss of MSH2. Pembrolizumab could show a significant effect even in a heavily treated patient with MSI-high advanced PC. Accumulation of detailed clinical and genomic information of cases of MSI-high PC treated with pembrolizumab is necessary for optimal patient selection.
Marlene Richter Jensen, Ulrik Stoltze, Thomas Van Overeem Hansen, , Astrid Sehested, Catherine Rechnitzer, René Mathiasen, , Karen Bonde Larsen, Tina Elisabeth Olsen, et al.
Molecular Case Studies, Volume 8; https://doi.org/10.1101/mcs.a006164

Abstract:
Germline pathogenic variants in CDKN2A predispose to various cancers, including melanoma, pancreatic cancer, and neural system tumors, whereas CDKN2B variants are associated with renal cell carcinoma. A few case reports have described heterozygous germline deletions spanning both CDKN2A and CDKN2B associated with a cancer predisposition syndrome (CPS) that constitutes a risk of cancer beyond those associated with haploinsufficiency of each gene individually, indicating an additive effect or a contiguous gene deletion syndrome. We report a young woman with a de novo germline 9p21 microdeletion involving the CDKN2A/CDKN2B genes, who developed six primary cancers since childhood, including a very rare extraskeletal osteosarcoma (eOS) at the age of 8. To our knowledge this is the first report of eOS in a patient with CDKN2A/CDKN2B deletion.
Feng Xu, Erfan Aref-Eshghi, Jinhua Wu, Jeffrey Schubert, Gerald Wertheim, Tricia Bhatti, Jennifer Pogoriler, Maha Patel, Kajia Cao, Ariel Long, et al.
Molecular Case Studies; https://doi.org/10.1101/mcs.a006181

Abstract:
Li-Fraumeni syndrome (LFS) is one of the most common cancer predisposition syndromes that affects both children and adults. Individuals with LFS are at an increased risk of developing various types of cancer over their lifetime including soft tissue sarcomas, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. Heterozygous germline pathogenic variants in the tumor suppressor gene TP53 are the known causal genetic defect for LFS. Single nucleotide variants (SNVs) including missense substitutions that occur in the highly conserved DNA binding domain of the protein are the most common alterations, followed by nonsense and splice site variants. Gross copy number changes in TP53 are rare and account for less than 1% of all variants. Using next-generation sequencing (NGS) panels, we identified a paternally inherited germline intragenic duplication of TP53 in a child with metastatic osteosarcoma who later developed acute myeloid leukemia (AML). Transcriptome sequencing (RNA-Seq) demonstrated the duplication was tandem, encompassing exons 2-6 and 28 nucleotides of the untranslated region (UTR) upstream of the start codon in exon 2. The inclusion of the 28 nucleotides is expected to result in a frameshift with a stop codon 18 codons downstream of the exon 6, leading to a loss-of-function allele. This case highlights the significance of simultaneous identification of both significant copy number variants as well as SNVs/indels using NGS panels.
, Laura A Tseng, Clara Dm van Karnebeek
Molecular Case Studies; https://doi.org/10.1101/mcs.a006197

Abstract:
Pyridoxine dependent epilepsy due to mutations in ALDH7A1 (PDH-ALDH7A1) is a highly treatable developmental and epileptic encephalopathy. Pharmacologic doses of pyridoxine are associated with dramatic clinical seizure improvement and most patient achieve adequate seizure control with pyridoxine alone. Unfortunately, patients with PDE-ALDH7A1 have died prior to diagnosis and subsequent treatment with pyridoxine highlighting the importance of a timely diagnosis. Although critical for seizure control, pyridoxine treatment alone is not sufficient for normal outcomes as most patients suffer intellectual and developmental delay. Adjunct lysine reduction therapies are associated with significant developmental improvements although these treatments have limited efficacy if delayed after the first few months of life. Recently two biomarkers were identified that overcome previous technical hurdles for newborn screening. Herein we provide commentary that PDE-ALDH7A1 meets both current and historic criteria for newborn screening, and that a neonatal diagnosis and treatment can both reduce mortality from uncontrolled seizures and significantly improve the cognitive delay that is pervasive in this treatable disorder.
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