Browsing by Author "Douzgou, Sofia"

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    Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
    (Springer Nature, 2023) Palmer, Elizabeth E.; Pusch, Michael; Picollo, Alessandra; Forwood, Caitlin; Nguyen, Matthew H.; Suckow, Vanessa; Gibbons, Jessica; Hoff, Alva; Sigfrid, Lisa; Megarbane, Andre; Nizon, Mathilde; Cogné, Benjamin; Beneteau, Claire; Alkuraya, Fowzan S.; Chedrawi, Aziza; Hashem, Mais O.; Stamberger, Hannah; Weckhuysen, Sarah; Vanlander, Arnaud; Ceulemans, Berten; Rajagopalan, Sulekha; Nunn, Kenneth; Arpin, Stéphanie; Raynaud, Martine; Motter, Constance S.; Ward-Melver, Catherine; Janssens, Katrien; Meuwissen, Marije; Beysen, Diane; Dikow, Nicola; Grimmel, Mona; Haack, Tobias B.; Clement, Emma; McTague, Amy; Hunt, David; Townshend, Sharron; Ward, Michelle; Richards, Linda J.; Simons, Cas; Costain, Gregory; Dupuis, Lucie; Mendoza-Londono, Roberto; Dudding-Byth, Tracy; Boyle, Jackie; Saunders, Carol; Fleming, Emily; El Chehadeh, Salima; Spitz, Marie-Aude; Piton, Amelie; Gerard, Bénédicte; Warde, Marie-Thérèse Abi; Rea, Gillian; McKenna, Caoimhe; Douzgou, Sofia; Banka, Siddharth; Akman, Cigdem; Bain, Jennifer M.; Sands, Tristan T.; Wilson, Golder N.; Silvertooth, Erin J.; Miller, Lauren; Lederer, Damien; Sachdev, Rani; Macintosh, Rebecca; Monestier, Olivier; Karadurmus, Deniz; Collins, Felicity; Carter, Melissa; Rohena, Luis; Willemsen, Marjolein H.; Ockeloen, Charlotte W.; Pfundt, Rolph; Kroft, Sanne D.; Field, Michael; Laranjeira, Francisco E. R.; Fortuna, Ana M.; Soares, Ana R.; Michaud, Vincent; Naudion, Sophie; Golla, Sailaja; Weaver, David D.; Bird, Lynne M.; Friedman, Jennifer; Clowes, Virginia; Joss, Shelagh; Pölsler, Laura; Campeau, Philippe M.; Blazo, Maria; Bijlsma, Emilia K.; Rosenfeld, Jill A.; Beetz, Christian; Powis, Zöe; McWalter, Kirsty; Brandt, Tracy; Torti, Erin; Mathot, Mikaël; Mohammad, Shekeeb S.; Armstrong, Ruth; Kalscheuer, Vera M.; Medical and Molecular Genetics, School of Medicine
    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.
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    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 Medicine
    Next-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.