Browsing by Author "Fleming, Emily"

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    Adolescents with Congenital Heart Disease: a Patient and Parental Perspective of Genetic Information and Genetic Risk
    (Cambridge University Press, 2020-02) Crawford, Christopher A.; Vujakovich, Courtney E.; Elmore, Lindsey; Fleming, Emily; Landis, Benjamin J.; Spoonamore, Katie G.; Ware, Stephanie M.; Pediatrics, School of Medicine
    Congenital heart defects (CHDs) occur in 8 of 1000 live-born children, making them common birth defects in the adolescent population. CHDs may have single gene, chromosomal, or multifactorial causes. Despite evidence that patients with CHD want information on heritability and genetics, no studies have investigated the interest or knowledge base in the adolescent population. This information is necessary as patients in adolescence take greater ownership of their health care and discuss reproductive risks with their physicians. The objectives of this survey-based study were to determine adolescents' recall of their own heart condition, to assess patient and parent perception of the genetic contribution to the adolescent's CHD, and to obtain information about the preferred method(s) for education. The results show that adolescent patients had good recall of their type of CHD. Less than half of adolescents and parents believed their CHD had a genetic basis or was heritable; however, adolescents with a positive family history of CHD were more likely to believe that their condition was genetic (p = 0.0005). The majority of patients were interested in receiving additional genetics education and preferred education in-person and in consultation with both parents and a physician. The adolescents who felt most competent to have discussions with their doctors regarding potential causes of their heart defect previously had a school science course which covered topics in genetics. These results provide insight into adolescents' perceptions and understanding about their CHD and genetic risk and may inform the creation and provision of additional genetic education.
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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.