Scientific Publications

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Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics

Hopkins CE, Brock T, Caulfield TR, Bainbridge M.

Mol Aspects Med. 2022 Nov 18:101153. doi: 10.1016/j.mam.2022.101153. Online ahead of print. ABSTRACT Precision medicine strives for highly individualized treatments for disease under the notion that each individual’s unique genetic makeup and environmental exposures imprints upon them not only a disposition to illness, but also an optimal therapeutic approach. In the realm of rare disorders, genetic predisposition is often the predominant mechanism driving disease presentation. For such, mostly, monogenic disorders, a causal gene to phenotype association is likely. As a result, it becomes important to query the patient’s genome for the presence of pathogenic variations that are likely to cause the disease. Determining whether a variant is pathogenic or not is critical to these analyses and can be challenging, as many disease-causing variants are novel and, ergo, have no available functional data to help categorize them. This problem is exacerbated by the need for rapid evaluation of pathogenicity, since many genetic diseases present in young children who will experience increased morbidity and mortality without rapid diagnosis and therapeutics. Here, we discuss the utility of animal models, with a focus mainly on C. elegans, as a contrast to tissue culture and in silico approaches, with emphasis on how these systems are used in determining pathogenicity of variants with uncertain significance and then used to screen for novel therapeutics. PMID:36411139 DOI:10.1016/j.mam.2022.101153

November 18, 2022

Rapid Whole Genome Sequencing in Critically Ill Neonates Enables Precision Medicine Pipeline

Beaman M, Fisher K, McDonald M, Tan QKG, Jackson D, Cocanougher BT, Landstrom AP, Hobbs CA, Cotten M, Cohen JL.

J Pers Med. 2022 Nov 18;12(11):1924. doi: 10.3390/jpm12111924. ABSTRACT Rapid genome sequencing in critically ill infants is increasingly identified as a crucial test for providing targeted and informed patient care. We report the outcomes of a pilot study wherein eight critically ill neonates received rapid whole genome sequencing with parental samples in an effort to establish a prompt diagnosis. Our pilot study resulted in a 37.5% diagnostic rate by whole genome sequencing alone and an overall 50% diagnostic rate for the cohort. We describe how the diagnoses led to identification of additional affected relatives and a change in management, the limitations of rapid genome sequencing, and some of the challenges with sample collection. Alongside this pilot study, our site simultaneously established a research protocol pipeline that will allow us to conduct research-based genomic testing in the cases for which a diagnosis was not reached by rapid genome sequencing or other available clinical testing. Here we describe the benefits, limitations, challenges, and potential for rapid whole genome sequencing to be incorporated into routine clinical evaluation in the neonatal period. PMID:36422100 DOI:10.3390/jpm12111924

November 18, 2022

Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities

Cali E, Suri M, Scala M, Ferla MP, Alavi S, Faqeih EA, Bijlsma EK, Wigby KM, Baralle D, Mehrjardi MYV, Schwab J, Platzer K, Steindl K, Hashem M, Jones M, Niyazov DM, Jacober J, Littlejohn RO, Weis D, Zadeh N, Rodan L, Goldenberg A, Lecoquierre F, Dutra-Clarke M, Horvath G, Young D, Orenstein N, Bawazeer S, Vulto-van Silfhout AT, Herenger Y, Dehghani M, Seyedhassani SM, Bahreini A, Nasab ME, Ercan-Sencicek AG, Firoozfar Z, Movahedinia M, Efthymiou S, Striano P, Karimiani EG, Salpietro V, Taylor JC, Redman M, Stegmann APA, Laner A, Abdel-Salam G, Li M, Bengala M, Müller AJ, Digilio MC, Rauch A, Gunel M, Titheradge H, Schweitzer DN, Kraus A, Valenzuela I, McLean SD, Phornphutkul C, Salih M, Begtrup A, Schnur RE, Torti E, Haack TB, Prada CE, Alkuraya FS, Houlden H, Maroofian R.

Genet Med. 2022 Nov 17:S1098-3600(22)00954-6. doi: 10.1016/j.gim.2022.09.016. Online ahead of print. ABSTRACT PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities. PMID:36399134 DOI:10.1016/j.gim.2022.09.016

November 17, 2022

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Palmer EE, Pusch M, Picollo A, Forwood C, Nguyen MH, Suckow V, Gibbons J, Hoff A, Sigfrid L, Megarbane A, Nizon M, Cogné B, Beneteau C, Alkuraya FS, Chedrawi A, Hashem MO, Stamberger H, Weckhuysen S, Vanlander A, Ceulemans B, Rajagopalan S, Nunn K, Arpin S, Raynaud M, Motter CS, Ward-Melver C, Janssens K, Meuwissen M, Beysen D, Dikow N, Grimmel M, Haack TB, Clement E, McTague A, Hunt D, Townshend S, Ward M, Richards LJ, Simons C, Costain G, Dupuis L, Mendoza-Londono R, Dudding-Byth T, Boyle J, Saunders C, Fleming E, El Chehadeh S, Spitz MA, Piton A, Gerard B, Abi Warde MT, Rea G, McKenna C, Douzgou S, Banka S, Akman C, Bain JM, Sands TT, Wilson GN, Silvertooth EJ, Miller L, Lederer D, Sachdev R, Macintosh R, Monestier O, Karadurmus D, Collins F, Carter M, Rohena L, Willemsen MH, Ockeloen CW, Pfundt R, Kroft SD, Field M, Laranjeira FER, Fortuna AM, Soares AR, Michaud V, Naudion S, Golla S, Weaver DD, Bird LM, Friedman J, Clowes V, Joss S, Pölsler L, Campeau PM, Blazo M, Bijlsma EK, Rosenfeld JA, Beetz C, Powis Z, McWalter K, Brandt T, Torti E, Mathot M, Mohammad SS, Armstrong R, Kalscheuer VM.

Mol Psychiatry. 2022 Nov 16. doi: 10.1038/s41380-022-01852-9. Online ahead of print. ABSTRACT Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis. PMID:36385166 DOI:10.1038/s41380-022-01852-9

November 16, 2022
Genetic Neurologic DiseaseNeurogenomics

Evaluating human mutation databases for “treatability” using patient-customized therapy

Mittal S, Tang I, Gleeson JG. Evaluating human mutation databases for “treatability” using patient-customized therapy. Med (N Y).

Med (N Y). 2022 Nov 11;3(11):740-759. doi: 10.1016/j.medj.2022.08.006. ABSTRACT Genome sequencing in the clinic often allows patients to receive a molecular diagnosis. However, variants are most often evaluated for pathogenicity, neglecting potential treatability and thus often yielding limited clinical benefit. Antisense oligonucleotides (ASOs), among others, offer attractive programmable and relatively safe platforms for customized therapy based upon the causative genetic variant. The landscape of ASO-treatable variants is largely uncharted, with new developments emerging for loss-of-function, haploinsufficient, and gain-of-function effects. ASOs can access the transcriptome to target splice-gain variants, poison exons, untranslated/regulatory regions, and naturally occurring antisense transcripts. Here we assess public variant databases and find that approximately half of pathogenic variants have one or more viable avenues for ASO therapy. The future might see medical teams considering “treatability” when interpreting genomic sequencing results to fully realize benefits for patients. PMID:36370694 DOI:10.1016/j.medj.2022.08.006

November 11, 2022

Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals

Saida K, Maroofian R, Sengoku T, Mitani T, Pagnamenta AT, Marafi D, Zaki MS, O’Brien TJ, Karimiani EG, Kaiyrzhanov R, Takizawa M, Ohori S, Leong HY, Akay G, Galehdari H, Zamani M, Romy R, Carroll CJ, Toosi MB, Ashrafzadeh F, Imannezhad S, Malek H, Ahangari N, Tomoum H, Gowda VK, Srinivasan VM, Murphy D, Dominik N, Elbendary HM, Rafat K, Yilmaz S, Kanmaz S, Serin M, Krishnakumar D, Gardham A, Maw A, Rao TS, Alsubhi S, Srour M, Buhas D, Jewett T, Goldberg RE, Shamseldin H, Frengen E, Misceo D, Strømme P, Magliocco Ceroni JR, Kim CA, Yesil G, Sengenc E, Guler S, Hull M, Parnes M, Aktas D, Anlar B, Bayram Y, Pehlivan D, Posey JE, Alavi S, Madani Manshadi SA, Alzaidan H, Al-Owain M, Alabdi L, Abdulwahab F, Sekiguchi F, Hamanaka K, Fujita A, Uchiyama Y, Mizuguchi T, Miyatake S, Miyake N, Elshafie RM, Salayev K, Guliyeva U, Alkuraya FS, Gleeson JG, Monaghan KG, Langley KG, Yang H, Motavaf M, Safari S, Alipour M, Ogata K, Brown AEX, Lupski JR, Houlden H, Matsumoto N.

Genet Med. 2022 Oct 31:S1098-3600(22)00948-0. doi: 10.1016/j.gim.2022.09.010. Online ahead of print. ABSTRACT PURPOSE: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants. METHODS: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies. RESULTS: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities. CONCLUSION: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders. PMID:36318270 DOI:10.1016/j.gim.2022.09.010

October 31, 2022

Autosomal recessive LRP1-related syndrome featuring cardiopulmonary dysfunction, bone dysmorphology, and corneal clouding

Mark PR, Murray SA, Yang T, Eby A, Lai A, Lu D, Zieba J, Rajasekaran S, VanSickle EA, Rossetti LZ, Guidugli L, Watkins K, Wright MS, Bupp CP, Prokop JW.

Cold Spring Harb Mol Case Stud. 2022 Oct 28;8(6):a006169. doi: 10.1101/mcs.a006169. Print 2022 Oct. ABSTRACT We provide the first study of two siblings with a novel autosomal recessive LRP1-related syndrome identified by rapid genome sequencing and overlapping multiple genetic models. The patients presented with respiratory distress, congenital heart defects, hypotonia, dysmorphology, and unique findings, including corneal clouding and ascites. Both siblings had compound heterozygous damaging variants, c.11420G > C (p.Cys3807Ser) and c.12407T > G (p.Val4136Gly) in LRP1, in which segregation analysis helped dismiss additional variants of interest. LRP1 analysis using multiple human/mouse data sets reveals a correlation to patient phenotypes of Peters plus syndrome with additional severe cardiomyopathy and blood vessel development complications linked to neural crest cells. PMID:36307211 DOI:10.1101/mcs.a006169

October 28, 2022

N-myc mediated translation control is a therapeutic vulnerability in medulloblastoma

Kuzuoglu-Ozturk D, Aksoy O, Schmidt C, Lea R, Larson JD, Phelps RRL, Nasholm N, Holt M, Contreras A, Huang M, Wong-Michalak S, Shao H, Wechsler-Reya R, Phillips JJ, Gestwicki JE, Ruggero D, Weiss WA.

Cancer Res. 2022 Oct 20:CAN-22-0945. doi: 10.1158/0008-5472.CAN-22-0945. Online ahead of print. ABSTRACT Deregulation of N-myc is a leading cause of malignant brain tumors in children. To target N-myc-driven medulloblastoma, most research has focused on identifying genomic alterations or on the analysis of the medulloblastoma transcriptome. Here, we have broadly characterized the translatome of medulloblastoma and shown that N-myc unexpectedly drives selective translation of transcripts that promote protein homeostasis. Cancer cells are constantly exposed to proteotoxic stress associated with alterations in protein production or folding. It remains poorly understood how cancers cope with proteotoxic stress to promote their growth. Here, our data unexpectedly revealed that N-myc regulates the expression of specific components (~5%) of the protein folding machinery at the translational level through the major cap binding protein, eukaryotic initiation factor eIF4E. Reducing eIF4E levels in mouse models of medulloblastoma blocked tumorigenesis. Importantly, targeting Hsp70, a protein folding chaperone translationally regulated by N-myc, suppressed tumor growth in mouse and human medulloblastoma xenograft models. These findings reveal a previously hidden molecular program that promotes medulloblastoma formation and identify new therapies that may have impact in the clinic. PMID:36264168 DOI:10.1158/0008-5472.CAN-22-0945

October 20, 2022

Phenotypic continuum of NFU1-related disorders

Kaiyrzhanov R, Zaki MS, Lau T, Sen S, Azizimalamiri R, Zamani M, Sayin GY, Hilander T, Efthymiou S, Chelban V, Brown R, Thompson K, Scarano MI, Ganesh J, Koneev K, Gülaçar IM, Person R, Sadykova D, Maidyrov Y, Seifi T, Zadagali A, Bernard G, Allis K, Elloumi HZ, Lindy A, Taghiabadi E, Verma S, Logan R, Kirmse B, Bai R, Khalaf SM, Abdel-Hamid MS, Sedaghat A, Shariati G, Issa M, Zeighami J, Elbendary HM, Brown G, Taylor RW, Galehdari H, Gleeson JJ, Carroll CJ, Cowan JA, Moreno-De-Luca A, Houlden H, Maroofian R.

Ann Clin Transl Neurol. 2022 Oct 18. doi: 10.1002/acn3.51679. Online ahead of print. ABSTRACT Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1-related phenotypic continuum. PMID:36256512 DOI:10.1002/acn3.51679

October 18, 2022

Safety and efficacy of intraventricular immunovirotherapy with oncolytic HSV-1 for CNS cancers

Kang KD, Bernstock JD, Totsch SK, Gary SE, Rocco A, Nan L, Li R, Etminan T, Han X, Beierle EA, Eisemann T, Wechsler-Reya RJ, Bae S, Whitley R, Gillespie GY, Markert JM, Friedman GK.

Clin Cancer Res. 2022 Oct 14:CCR-22-1382. doi: 10.1158/1078-0432.CCR-22-1382. Online ahead of print. ABSTRACT PURPOSE: Oncolytic virotherapy with herpes simplex virus-1 (HSV) has shown promise for treatment of pediatric and adult brain tumors; however, completed and ongoing clinical trials have utilized intratumoral/peritumoral oncolytic HSV (oHSV) inoculation due intraventricular/intrathecal toxicity concerns. Intratumoral delivery requires an invasive neurosurgical procedure, limits repeat injections, and precludes direct targeting of metastatic and leptomeningeal disease. To address these limitations, we determined causes of toxicity from intraventricular oHSV and established methods for mitigating toxicity to treat disseminated brain tumors in mice. EXPERIMENTAL DESIGN: HSV-sensitive CBA/J mice received intraventricular vehicle, inactivated oHSV, or treatment doses (1×107 plaque-forming units) of oHSV, and toxicity was assessed by weight loss and immunohistochemistry. Protective strategies to reduce oHSV toxicity, including intraventricular low-dose oHSV or interferon inducer polyinosinic-polycytidylic acid (poly I:C) prior to oHSV treatment dose, were evaluated and then utilized to assess intraventricular oHSV treatment of multiple models of disseminated CNS disease. RESULTS: A standard treatment dose of intraventricular oHSV damaged ependymal cells via virus replication and induction of CD8+ T cells, whereas vehicle or inactivated virus resulted in no toxicity. Subsequent doses of intraventricular oHSV caused little additional toxicity. Interferon induction with phosphorylation of eukaryotic initiation factor-2α (eIF2α) via intraventricular pretreatment with low-dose oHSV or poly I:C mitigated ependyma toxicity. This approach enabled safe delivery of multiple treatment doses of clinically relevant oHSV G207 and prolonged survival in disseminated brain tumor models. CONCLUSIONS: Toxicity from intraventricular oHSV can be mitigated resulting in therapeutic benefit. These data support clinical translation of intraventricular G207. PMID:36239623 DOI:10.1158/1078-0432.CCR-22-1382

October 14, 2022

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