Browsing by Author "Payne, Katelyn"
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Item Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum(Elsevier, 2020-09-03) Motta, Marialetizia; Pannone, Luca; Pantaleoni, Francesca; Bocchinfuso, Gianfranco; Radio, Francesca Clementina; Cecchetti, Serena; Ciolfi, Andrea; Di Rocco, Martina; Elting, Mariet W.; Brilstra, Eva H.; Boni, Stefania; Mazzanti, Laura; Tamburrino, Federica; Walsh, Larry; Payne, Katelyn; Fernández-Jaén, Alberto; Ganapathi, Mythily; Chung, Wendy K.; Grange, Dorothy K.; Dave-Wala, Ashita; Reshmi, Shalini C.; Bartholomew, Dennis W.; Mouhlas, Danielle; Carpentieri, Giovanna; Bruselles, Alessandro; Pizzi, Simone; Bellacchio, Emanuele; Piceci-Sparascio, Francesca; Lißewski, Christina; Brinkmann, Julia; Waclaw, Ronald R.; Waisfisz, Quinten; van Gassen, Koen; Wentzensen, Ingrid M.; Morrow, Michelle M.; Álvarez, Sara; Martínez-García, Mónica; De Luca, Alessandro; Memo, Luigi; Zampino, Giuseppe; Rossi, Cesare; Seri, Marco; Gelb, Bruce D.; Zenker, Martin; Dallapiccola, Bruno; Stella, Lorenzo; Prada, Carlos E.; Martinelli, Simone; Flex, Elisabetta; Tartaglia, Marco; Medical and Molecular Genetics, School of MedicineSignal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.Item Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes(Elsevier, 2018-02-01) Martinelli, Simone; Krumbach, Oliver H.F.; Pantaleoni, Francesca; Coppola, Simona; Amin, Ehsan; Pannone, Luca; Nouri, Kazem; Farina, Luciapia; Dvorsky, Radovan; Lepri, Francesca; Bucholzer, Marcel; Konopatzki, Raphael; Walsh, Laurence; Payne, Katelyn; Pierpont, Mary Ella; Vergano, Samantha Schrier; Langley, Katherine G.; Larsen, Douglas; Farwell, Kelly D.; Tang, Sha; Mroske, Cameron; Gallotta, Ivan; Schiavi, Elia Di; della Monica, Matteo; Lugli, Licia; Rossi, Cesare; Seri, Marco; Cocchi, Guido; Henderson, Lindsay; Baskin, Berivan; Alders, Mariëlle; Mendoza-Londono, Roberto; Dupuis, Lucie; Nickerson, Deborah A.; Chong, Jessica X.; Meeks, Naomi; Brown, Kathleen; Causey, Tahnee; Cho, Megan T.; Demuth, Stephanie; Digilio, Maria Cristina; Gelb, Bruce D.; Bamshad, Michael J.; Zenker, Martin; Ahmadian, Mohammad Reza; Hennekam, Raoul C.; Tartaglia, Marco; Mirzaa, Ghayda M.; Neurology, School of MedicineExome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.Item Genetic Testing for Parkinson Disease: Are We Ready?(American Academy of Neurology, 2021-02) Cook, Lola; Schulze, Jeanine; Kopil, Catherine; Hastings, Tara; Naito, Anna; Wojcieszek, Joanne; Payne, Katelyn; Alcalay, Roy N.; Klein, Christine; Saunders-Pullman, Rachel; Simuni, Tatyana; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicinePurpose of review: With the advent of precision medicine and demand for genomic testing information, we may question whether it is time to offer genetic testing to our patients with Parkinson disease (PD). This review updates the current genetic landscape of PD, describes what genetic testing may offer, provides strategies for evaluating whom to test, and provides resources for the busy clinician. Recent findings: Patients with PD and their relatives, in various settings, have expressed an interest in learning their PD genetic status; however, physicians may be hesitant to widely offer testing due to the perceived low clinical utility of PD genetic test results. The rise of clinical trials available for patients with gene-specific PD and emerging information on genotype-phenotype correlations are starting to shift this discussion about testing. Summary: By learning more about the various genetic testing options for PD and utility of results for patients and their care, clinicians may become more comfortable with widespread PD genetic testing in the research and clinical setting.Item Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood(Elsevier, 2017-08-03) Edvardson, Simon; Nicolae, Claudia M.; Agrawal, Pankaj B.; Mignot, Cyril; Payne, Katelyn; Prasad, Asuri Narayan; Prasad, Chitra; Sadler, Laurie; Nava, Caroline; Mullen, Thomas E.; Begtrup, Amber; Baskin, Berivan; Powis, Zöe; Shaag, Avraham; Keren, Boris; Moldovan, George-Lucian; Elpeleg, Orly; Pediatrics, School of MedicineRibosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5'- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.Item Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity(Wiley, 2019-10-23) Cheng, Hanyin; Capponi, Simona; Wakeling, Emma; Marchi, Elaine; Li, Quan; Zhao, Mengge; Weng, Chunhua; Piatek, Stefan G.; Ahlfors, Helena; Kleyner, Robert; Rope, Alan; Lumaka, Aimé; Lukusa, Prosper; Devriendt, Koenraad; Vermeesch, Joris; Posey, Jennifer E.; Palmer, Elizabeth E.; Murray, Lucinda; Leon, Eyby; Diaz, Jullianne; Worgan, Lisa; Mallawaarachchi, Amali; Vogt, Julie; de Munnik, Sonja A.; Dreyer, Lauren; Baynam, Gareth; Ewans, Lisa; Stark, Zornitza; Lunke, Sebastian; Gonçalves, Ana R.; Soares, Gabriela; Oliveira, Jorge; Fassi, Emily; Willing, Marcia; Waugh, Jeff L.; Faivre, Laurence; Riviere, Jean-Baptiste; Moutton, Sebastien; Mohammed, Shehla; Payne, Katelyn; Walsh, Laurence; Begtrup, Amber; Guillen Sacoto, Maria J.; Douglas, Ganka; Alexander, Nora; Buckley, Michael F.; Mark, Paul R.; Adès, Lesley C.; Sandaradura, Sarah A.; Lupski, James R.; Roscioli, Tony; Agrawal, Pankaj B.; Kline, Antonie D.; Wang, Kai; Timmers, T. Marc; Lyon, Gholson J.; Neurology, School of MedicineWe recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X.Item Novel Homozygous Deletion in STRADA Gene Associated With Polyhydramnios, Megalencephaly, and Epilepsy in 2 Siblings: Implications for Diagnosis and Treatment(Sage, 2018) Nelson, Katherine; Bell, Jennifer; Jackman, Christopher; Shih, Chie-Schin; Payne, Katelyn; Dlouhy, Stephen; Walsh, Laurence; Neurology, School of MedicineMutations in the STE20-related kinase adaptor α (STRADA) gene have been reported to cause an autosomal recessive neurodevelopmental disorder characterized by infantile-onset epilepsy, developmental delay, and craniofacial dysmorphisms. To date, there have been 17 reported individuals diagnosed with STRADA mutations, 16 of which are from a single Old Order Mennonite cohort and share a deletion of exons 9-13. The remaining individual is of consanguineous Indian descent and has a homozygous single–base pair duplication. We report a novel STRADA gene deletion of exons 7-9 in 2 sisters from nonconsanguineous parents, as well as an improvement in seizure control in 1 sibling following treatment with sirolimus, an m-Tor inhibitor of potential benefit to patients with this genetic mutation.Item De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder(Elsevier, 2018-06-07) Reijnders, Margot R.F.; Miller, Kerry A.; Alvi, Mohsan; Goos, Jacqueline A.C.; Lees, Melissa M.; de Burca, Anna; Henderson, Alex; Kraus, Alison; Mikat, Barbara; de Vries, Bert B.A.; Isidor, Bertrand; Kerr, Bronwyn; Marcelis, Carlo; Schluth-Bolard, Caroline; Deshpande, Charu; Ruivenkamp, Claudia A.L.; Wieczorek, Dagmar; Baralle, Diana; Blair, Edward M.; Engels, Hartmut; Lüdecke, Hermann-Josef; Eason, Jacqueline; Santen, Gijs W.E.; Clayton-Smith, Jill; Chandler, Kate; Tatton-Brown, Katrina; Payne, Katelyn; Helbig, Katherine; Radtke, Kelly; Nugent, Kimberly M.; Cremer, Kirsten; Strom, Tim M.; Bird, Lynne M.; Sinnema, Margje; Bitner-Glindzicz, Maria; van Dooren, Marieke F.; Alders, Marielle; Koopmans, Marije; Brick, Lauren; Kozenko, Mariya; Harline, Megan L.; Klaassens, Merel; Steinraths, Michelle; Cooper, Nicola S.; Edery, Patrick; Yap, Patrick; Terhal, Paulien A.; van der Spek, Peter J.; Lakeman, Phillis; Taylor, Rachel L.; Littlejohn, Rebecca O.; Pfundt, Rolph; Mercimek-Andrews, Saadet; Stegmann, Alexander P.A.; Kant, Sarina G.; McLean, Scott; Joss, Shelagh; Swagemakers, Sigrid M.A.; Douzgou, Sofia; Wall, Steven A.; Küry, Sebastian; Calpena, Eduardo; Koelling, Nils; McGowan, Simon J.; Twigg, Stephen R.F.; Mathijssen, Irene M.J.; Nellaker, Christoffer; Brunner, Han G.; Wilkie, Andrew O.M.; Medical and Molecular Genetics, School of MedicineNext-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.Item Phenotypic expansion of POGZ-related intellectual disability syndrome (White-Sutton syndrome)(Wiley, 2020-01) Batzir, Nurit Assia; Posey, Jennifer E.; Song, Xiaofei; Akdemir, Zeynep Coban; Rosenfeld, Jill A.; Brown, Chester W.; Chen, Emily; Holtrop, Shannon G.; Mizerik, Elizabeth; Moreno, Margarita Nieto; Payne, Katelyn; Raas-Rothschild, Annick; Scott, Richard; Vernon, Hilary J.; Zadeh, Neda; Lupski, James R.; Sutton, V. Reid; Neurology, School of MedicineWhite-Sutton syndrome (WHSUS) is a recently-identified genetic disorder resulting from de novo heterozygous pathogenic variants in POGZ. Thus far, over 50 individuals have been reported worldwide, however phenotypic characterization and data regarding the natural history are still incomplete. Here we report the clinical features of 22 individuals with 21 unique loss of function POGZ variants. We observed a broad spectrum of intellectual disability and/or developmental delay with or without autism, and speech delay in all individuals. Other common problems included ocular abnormalities, hearing loss and gait abnormalities. A validated sleep disordered breathing questionnaire identified symptoms of obstructive sleep apnea in 4/12 (33%) individuals. A higher-than-expected proportion of cases also had gastrointestinal phenotypes, both functional and anatomical, as well as genitourinary anomalies. In line with previous publications, we observed an increased body mass index (BMI) z-score compared to the general population (mean 0.59, median 0.9; p 0.0253). Common facial features included microcephaly, broad forehead, midface hypoplasia, triangular mouth, broad nasal root and flat nasal bridge. Analysis of the Baylor Genetics clinical laboratory database revealed that POGZ variants were implicated in approximately 0.14% of cases who underwent clinical exome sequencing for neurological indications with or without involvement of other body systems. This study describes a greater allelic series and expands the phenotypic spectrum of this new syndromic form of intellectual disability and autism.Item An Unexplained Case of Progressive Spastic Paraparesis in an Individual with Known DiGeorge Syndrome(Karger, 2020-06-09) Dhoot, Roshni; Payne, Katelyn; Fink, John K.; Pascuzzi, Robert M.; Neurology, School of MedicineDiGeorge syndrome (22q11.2 deletion) is associated with several neurologic disorders including structural abnormalities involving brain and spine, movement disorders, and epilepsy. Progressive spastic paraparesis has not been reported with DiGeorge syndrome. We report an individual in which DiGeorge syndrome was associated with progressive spastic paraparesis. This report extends the clinical phenotype of DiGeorge syndrome and presents the differential diagnosis of progressive spastic paraparesis in individuals with DiGeorge syndrome which provides insight into the clinical evaluation of such individuals.Item WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features(Elsevier, 2017-07-06) Skraban, Cara M.; Wells, Constance F.; Markose, Preetha; Cho, Megan T.; Nesbitt, Addie I.; Au, P.Y. Billie; Begtrup, Amber; Bernat, John A.; Bird, Lynne M.; Cao, Kajia; de Brouwer, Arjan P.M.; Denenberg, Elizabeth H.; Douglas, Ganka; Gibson, Kristin M.; Grand, Katheryn; Goldenberg, Alice; Innes, A. Micheil; Juusola, Jane; Kempers, Marlies; Kinning, Esther; Markie, David M.; Owens, Martina M.; Payne, Katelyn; Person, Richard; Pfundt, Rolph; Stocco, Amber; Turner, Claire L.S.; Verbeek, Nienke E.; Walsh, Laurence E.; Warner, Taylor C.; Wheeler, Patricia G.; Wieczorek, Dagmar; Wilkens, Alisha B.; Zonneveld-Huijssoon, Evelien; Deciphering Developmental Disorders Study; Kleefstra, Tjitske; Robertson, Stephen P.; Santani, Avni; van Gassen, Koen L.I.; Deardorf, Matthew A.; Pediatrics, School of MedicineWe report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.