Browsing by Author "Bernier, Raphael A."

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Characterizing the autism spectrum phenotype in DYRK1A-related syndrome
    (Wiley, 2023) Kurtz-Nelson, Evangeline C.; Rea, Hannah M.; Petriceks, Aiva C.; Hudac, Caitlin M.; Wang, Tianyun; Earl, Rachel K.; Bernier, Raphael A.; Eichler, Evan E.; Neuhaus, Emily; Pediatrics, School of Medicine
    Likely gene-disrupting (LGD) variants in DYRK1A are causative of DYRK1A syndrome and associated with autism spectrum disorder (ASD) and intellectual disability (ID). While many individuals with DYRK1A syndrome are diagnosed with ASD, they may present with a unique profile of ASD traits. We present a comprehensive characterization of the ASD profile in children and young adults with LGDs in DYRK1A. Individuals with LGD variants in DYRK1A (n = 29) were compared to children who had ASD with no known genetic cause, either with low nonverbal IQ (n = 14) or average or above nonverbal IQ (n = 41). ASD was assessed using the ADOS-2, ADI-R, SRS-2, SCQ, and RBS-R. Quantitative score comparisons were conducted, as were qualitative analyses of clinicians' behavioral observations. Diagnosis of ASD was confirmed in 85% and ID was confirmed in 89% of participants with DYRK1A syndrome. Individuals with DYRK1A syndrome showed broadly similar social communication behaviors to children with idiopathic ASD and below-average nonverbal IQ, with specific challenges noted in social reciprocity and nonverbal communication. Children with DYRK1A syndrome also showed high rates of sensory-seeking behaviors. Phenotypic characterization of individuals with DYRK1A syndrome may provide additional information on mechanisms contributing to co-occurring ASD and ID and contribute to the identification of genetic predictors of specific ASD traits.
  • Thumbnail Image
    Item
    De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders
    (American Association for the Advancement of Science, 2022) Jia, Xiangbin; Zhang, Shujie; Tan, Senwei; Du, Bing; He, Mei; Qin, Haisong; Chen, Jia; Duan, Xinyu; Luo, Jingsi; Chen, Fei; Ouyang, Luping; Wang, Jian; Chen, Guodong; Yu, Bin; Zhang, Ge; Zhang, Zimin; Lyu, Yongqing; Huang, Yi; Jiao, Jian; Chen, Jin Yun (Helen); Swoboda, Kathryn J.; Agolini, Emanuele; Novelli, Antonio; Leoni, Chiara; Zampino, Giuseppe; Cappuccio, Gerarda; Brunetti-Pierri, Nicola; Gerard, Benedicte; Ginglinger, Emmanuelle; Richer, Julie; McMillan, Hugh; White-Brown, Alexandre; Hoekzema, Kendra; Bernier, Raphael A.; Kurtz-Nelson, Evangeline C.; Earl, Rachel K.; Meddens, Claartje; Alders, Marielle; Fuchs, Meredith; Caumes, Roseline; Brunelle, Perrine; Smol, Thomas; Kuehl, Ryan; Day-Salvatore, Debra-Lynn; Monaghan, Kristin G.; Morrow, Michelle M.; Eichler, Evan E.; Hu, Zhengmao; Yuan, Ling; Tan, Jieqiong; Xia, Kun; Shen, Yiping; Guo, Hui; Pediatrics, School of Medicine
    Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in UBAP2L, which encodes an essential regulator of SG assembly. Ubap2l haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes (G3BP1, G3BP2, and UBAP2L) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRIN1, disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.
  • Thumbnail Image
    Item
    Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders
    (BMC, 2021-04-19) Gillentine, Madelyn A.; Wang, Tianyun; Hoekzema, Kendra; Rosenfeld, Jill; Liu, Pengfei; Guo, Hui; Kim, Chang N.; De Vries, Bert B.A.; Vissers, Lisenka E.L.M.; Nordenskjold, Magnus; Kvarnung, Malin; Lindstrand, Anna; Nordgren, Ann; Gecz, Jozef; Iascone, Maria; Cereda, Anna; Scatigno, Agnese; Maitz, Silvia; Zanni, Ginevra; Bertini, Enrico; Zweier, Christiane; Schuhmann, Sarah; Wiesener, Antje; Pepper, Micah; Panjwani, Heena; Torti, Erin; Abid, Farida; Anselm, Irina; Srivastava, Siddharth; Atwal, Paldeep; Bacino, Carlos A.; Bhat, Gifty; Cobian, Katherine; Bird, Lynne M.; Friedman, Jennifer; Wright, Meredith S.; Callewaert, Bert; Petit, Florence; Mathieu, Sophie; Afenjar, Alexandra; Christensen, Celenie K.; White, Kerry M.; Elpeleg, Orly; Berger, Itai; Espineli, Edward J.; Fagerberg, Christina; Brasch-Andersen, Charlotte; Hansen, Lars Kjærsgaard; Feyma, Timothy; Hughes, Susan; Thiffault, Isabelle; Sullivan, Bonnie; Yan, Shuang; Keller, Kory; Keren, Boris; Mignot, Cyril; Kooy, Frank; Meuwissen, Marije; Basinger, Alice; Kukolich, Mary; Philips, Meredith; Ortega, Lucia; Drummond-Borg, Margaret; Lauridsen, Mathilde; Sorensen, Kristina; Lehman, Anna; Lopez-Range, Elena; Levy, Paul; Lessel, Davor; Lotze, Timothy; Madan-Khetarpal, Suneeta; Sebastian, Jessica; Vento, Jodie; Vats, Divya; Benman, L. Manace; Mckee, Shane; Mirzaa, Ghayda M.; Muss, Candace; Pappas, John; Peeters, Hilde; Romano, Corrado; Elia, Maurizio; Galesi, Ornella; Simon, Marleen E.H.; Van Gassen, Koen L.I.; Simpson, Kara; Stratton, Robert; Syed, Sabeen; Thevenon, Julien; Palafoll, Irene Valenzuela; Vitobello, Antonio; Bournez, Marie; Faivre, Laurence; Xia, Kun; Earl, Rachel K.; Nowakowski, Tomasz; Bernier, Raphael A.; Eichler, Evan E.; Pediatrics, School of Medicine
    Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.
  • Thumbnail Image
    Item
    Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions
    (Springer Nature, 2024-04-15) Neuhaus, Emily; Rea, Hannah; Jones, Elizabeth; Benavidez, Hannah; Miles, Conor; Whiting, Alana; Johansson, Margaret; Eayrs, Curtis; Kurtz‑Nelson, Evangeline C.; Earl, Rachel; Bernier, Raphael A.; Eichler, Evan E.; Pediatrics, School of Medicine
    Background: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice. In this paper, we evaluate behavioral features within three gene groups associated with ID and ASD - ADNP, CHD8, and DYRK1A - with two aims: (1) characterize phenotypes across behavioral domains of anxiety, depression, ADHD, and challenging behavior; and (2) understand whether age and early developmental milestones are associated with later mental health outcomes. Methods: Phenotypic data were obtained for youth with disruptive variants in ADNP, CHD8, or DYRK1A (N = 65, mean age = 8.7 years, 40% female) within a long-running, genetics-first study. Standardized caregiver-report measures of mental health features (anxiety, depression, attention-deficit/hyperactivity, oppositional behavior) and developmental history were extracted and analyzed for effects of gene group, age, and early developmental milestones on mental health features. Results: Patterns of mental health features varied by group, with anxiety most prominent for CHD8, oppositional features overrepresented among ADNP, and attentional and depressive features most prominent for DYRK1A. For the full sample, age was positively associated with anxiety features, such that elevations in anxiety relative to same-age and same-sex peers may worsen with increasing age. Predictive utility of early developmental milestones was limited, with evidence of early language delays predicting greater difficulties across behavioral domains only for the CHD8 group. Conclusions: Despite shared associations with autism and intellectual disability, disruptive variants in ADNP, CHD8, and DYRK1A may yield variable psychiatric phenotypes among children and adolescents. With replication in larger samples over time, efforts such as these may contribute to improved clinical care for affected children and adolescents, allow for earlier identification of emerging mental health difficulties, and promote early intervention to alleviate concerns and improve quality of life.