Browsing by Author "Conboy, Erin"

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    A familial SAMD9 variant present in pediatric myelodysplastic syndrome
    (Cold Spring Harbor Laboratory, 2023-05-09) Rahim, Mahvish Q.; Rahrig, April; Overholt, Kathleen; Conboy, Erin; Czader, Magdalena; Saraf, Amanda June; Pediatrics, School of Medicine
    Myelodysplastic syndrome (MDS) is a rare pediatric diagnosis characterized by ineffective hematopoiesis with potential to evolve into acute myelogenous leukemia (AML). In this report, we describe a unique case of a 17-yr-old female with an aggressive course of MDS with excess blasts who was found to have monosomy 7 and a SAMD9 germline variant, which has not previously been associated with a MDS phenotype. This case of MDS was extremely rapidly progressing, showing resistance to chemotherapy and stem cell transplant, unfortunately resulting in patient death. It is imperative to further investigate this rare variant to aid in the future care of patients with this variant.
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    BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms
    (Elsevier, 2020-12-03) Barish, Scott; Barakat, Tahsin Stefan; Michel, Brittany C.; Mashtalir, Nazar; Phillips, Jennifer B.; Valencia, Alfredo M.; Ugur, Berrak; Wegner, Jeremy; Scott, Tiana M.; Bostwick, Brett; Murdock, David R.; Dai, Hongzheng; Perenthaler, Elena; Nikoncuk, Anita; van Slegtenhorst, Marjon; Brooks, Alice S.; Keren, Boris; Nava, Caroline; Mignot, Cyril; Douglas, Jessica; Rodan, Lance; Nowak, Catherine; Ellard, Sian; Stals, Karen; Lynch, Sally Ann; Faoucher, Marie; Lesca, Gaetan; Edery, Patrick; Engleman, Kendra L.; Zhou, Dihong; Thiffault, Isabelle; Herriges, John; Gass, Jennifer; Louie, Raymond J.; Stolerman, Elliot; Washington, Camerun; Vetrini, Francesco; Otsubo, Aiko; Pratt, Victoria M.; Conboy, Erin; Treat, Kayla; Shannon, Nora; Camacho, Jose; Wakeling, Emma; Yuan, Bo; Chen, Chun-An; Rosenfeld, Jill A.; Westerfield, Monte; Wangler, Michael; Yamamoto, Shinya; Kadoch, Cigall; Scott, Daryl A.; Bellen, Hugo J.; Medical and Molecular Genetics, School of Medicine
    SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.
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    Characterization of a novel deep-intronic variant in DYNC2H1 identified by whole-exome sequencing in a patient with a lethal form of a short-rib thoracic dysplasia type III
    (Cold Spring Harbor Laboratory, 2022-12-28) Buchh, Muqsit; Gillespie, Patrick J.; Treat, Kayla; Abreu, Marco A.; Schwantes-An, Tae-Hwi Linus; Helm, Benjamin M.; Fang, Fang; Xuei, Xiaoling; Mantcheva, Lili; Suhrie, Kristen R.; Graham, Brett H.; Conboy, Erin; Vetrini, Francesco; Medical and Molecular Genetics, School of Medicine
    Biallelic pathogenic variants in DYNC2H1 are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the DYNC2H1 gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in DYNC2H1 was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited DYNC2H1 deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of DYNCH2H1 mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.
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    Diagnostic deserts: Community-level barriers to appropriate genetics services
    (Wiley, 2023-01) Doyle, Tom A.; Conboy, Erin; Halverson, Colin M. E.; Medicine, School of Medicine
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    DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders
    (Elsevier, 2025) Lessel, Ivana; Baresic, Anja; Chinn, Ivan K.; May, Jonathan; Goenka, Anu; Chandler, Kate E.; Posey, Jennifer E.; Afenjar, Alexandra; Averdunk, Luisa; Bedeschi, Maria Francesca; Besnard, Thomas; Brager, Rae; Brick, Lauren; Brugger, Melanie; Brunet, Theresa; Byrne, Susan; de la Calle-Martín, Oscar; Capra, Valeria; Cardenas, Paul; Chappé, Céline; Chong, Hey J.; Cogne, Benjamin; Conboy, Erin; Cope, Heidi; Courtin, Thomas; Deb, Wallid; Dilena, Robertino; Dubourg, Christèle; Elgizouli, Magdeldin; Fernandes, Erica; Fitzgerald, Kristi K.; Gangi, Silvana; George-Abraham, Jaya K.; Gucsavas-Calikoglu, Muge; Haack, Tobias B.; Hadonou, Medard; Hanker, Britta; Hüning, Irina; Iascone, Maria; Isidor, Bertrand; Järvelä, Irma; Jin, Jay J.; Jorge, Alexander A. L.; Josifova, Dragana; Kalinauskiene, Ruta; Kamsteeg, Erik-Jan; Keren, Boris; Kessler, Elena; Kölbel, Heike; Kozenko, Mariya; Kubisch, Christian; Kuechler, Alma; Leal, Suzanne M.; Leppälä, Juha; Luu, Sharon M.; Lyon, Gholson J.; Madan-Khetarpal, Suneeta; Mancardi, Margherita; Marchi, Elaine; Mehta, Lakshmi; Menendez, Beatriz; Morel, Chantal F.; Moyer Harasink, Sue; Nevay, Dayna-Lynn; Nigro, Vincenzo; Odent, Sylvie; Oegema, Renske; Pappas, John; Pastore, Matthew T.; Perilla-Young, Yezmin; Platzer, Konrad; Powell-Hamilton, Nina; Rabin, Rachel; Rekab, Aisha; Rezende, Raissa C.; Robert, Leema; Romano, Ferruccio; Scala, Marcello; Poths, Karin; Schrauwen, Isabelle; Sebastian, Jessica; Short, John; Sidlow, Richard; Sullivan, Jennifer; Szakszon, Katalin; Tan, Queenie K. G.; Undiagnosed Diseases Network; Wagner, Matias; Wieczorek, Dagmar; Yuan, Bo; Maeding, Nicole; Strunk, Dirk; Begtrup, Amber; Banka, Siddharth; Lupski, James R.; Tolosa, Eva; Lessel, Davor; Medical and Molecular Genetics, School of Medicine
    BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.
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    Improving Social Media-Based Support Groups for the Rare Disease Community: Interview Study With Patients and Parents of Children with Rare and Undiagnosed Diseases
    (JMIR, 2024-12-30) Doyle, Tom A.; Vershaw, Samantha L.; Conboy, Erin; Halverson, Colin M. E.; Medical and Molecular Genetics, School of Medicine
    Background: The rarity that is inherent in rare disease (RD) often means that patients and parents of children with RDs feel uniquely isolated and therefore are unprepared or unsupported in their care. To overcome this isolation, many within the RD community turn to the internet, and social media groups in particular, to gather useful information about their RDs. While previous research has shown that social media support groups are helpful for those affected by RDs, it is unclear what these groups are particularly useful or helpful for patients and parents of children with RDs. Objective: This study aimed to identify what specific features of disease-related support groups (DRSGs) the RD community finds particularly useful or supportive and provide a set of recommendations to improve social media-based RD support groups based on this information. Methods: Semistructured qualitative interviews were performed with patients and parents of patients with RDs. Interview participants had to be at least 18 years of age at the time of the interview, be seen by a genetics specialist at a partner health care institution and be proficient in the English language. Social media use was not a prerequisite for participation, so interview participants ranged from extensive users of social media to those who chose to remain off all social media. All interviews were conducted by phone, recorded, and then transcribed. Interview transcripts were then coded using the 6 steps outlined by Braun and Clarke. Three researchers (TAD, SLV, and CMEH) performed initial coding. After this, the study team conducted a review of themes and all members of the team agreed upon a final analysis and presentation of data. Results: We conducted 31 interviews (mean age 40, SD 10.04 years; n=27, 87% were women; n=30, 97% were non-Hispanic White). Thematic analysis revealed that social media DRSG users identified the informational usefulness of these groups as being related to the gathering and sharing of specific information about an RD, clarification about the importance and meaning of certain symptoms, and obtaining insight into an RD's progression and prognosis. Participants also identified that DRSGs were useful sources of practical information, such as tips and tricks about managing RD-related issues and concerns. In addition, participants found DRSGs to be a useful space for sharing their disease-related stories but also highlighted a feeling of exhaustion from overexposure and overuse of DRSGs. Conclusions: This study identifies the usefulness of DRSGs for the RD community and provides a set of recommendations to improve future instances of DRSGs. These recommendations can be used to create DRSGs that are less prone to splintering into other DRSGs, thus minimizing the risk of having important RD-related information unhelpfully dispersed amongst a multitude of support groups.
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    Macrocephaly and developmental delay caused by missense variants in RAB5C
    (Oxford University Press, 2023) Koop, Klaas; Yuan, Weimin; Tessadori, Federico; Rodriguez-Polanco, Wilmer R.; Grubbs, Jeremy; Zhang, Bo; Osmond, Matt; Graham, Gail; Sawyer, Sarah; Conboy, Erin; Vetrini, Francesco; Treat, Kayla; Płoski, Rafal; Pienkowski, Victor Murcia; Kłosowska, Anna; Fieg, Elizabeth; Krier, Joel; Mallebranche, Coralie; Alban, Ziegler; Aldinger, Kimberly A.; Ritter, Deborah; Macnamara, Ellen; Sullivan, Bonnie; Herriges, John; Alaimo, Joseph T.; Helbig, Catherine; Ellis, Colin A.; van Eyk, Clare; Gecz, Jozef; Farrugia, Daniel; Osei-Owusu, Ikeoluwa; Adès, Lesley; van den Boogaard, Marie-Jose; Fuchs, Sabine; Bakker, Jeroen; Duran, Karen; Dawson, Zachary D.; Lindsey, Anika; Huang, Huiyan; Baldridge, Dustin; Silverman, Gary A.; Grant, Barth D.; Raizen, David; Undiagnosed Diseases Network; van Haaften, Gijs; Pak, Stephen C.; Rehmann, Holger; Schedl, Tim; van Hasselt, Peter; Medical and Molecular Genetics, School of Medicine
    Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors and heterogeneous effects on interactions with effector proteins. Studies in C. elegans confirmed that all four variants were damaging in vivo and showed defects in endocytic pathway function. The variant heterozygotes displayed phenotypes that were not observed in null heterozygotes, with two shown to be through a dominant negative mechanism. Expression of the human RAB5C variants in zebrafish embryos resulted in defective development, further underscoring the damaging effects of the RAB5C variants. Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild-to-moderate developmental delay through disruption of the endocytic pathway.
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    Performance of Dysmorphology‐Based Screening for Genetic Disorders in Pediatric Congenital Heart Disease Supports Wider Genetic Testing
    (Wiley, 2024) Helm, Benjamin M.; Helvaty, Lindsey R.; Conboy, Erin; Geddes, Gabrielle C.; Graham, Brett H.; Lah, Melissa; Wetherill, Leah; Landis, Benjamin J.; Ware, Stephanie M.; Medical and Molecular Genetics, School of Medicine
    Background: Dysmorphology evaluation is important for congenital heart disease (CHD) assessment, but there are no prior investigations quantifying the screening performance compared to standardized genetics evaluations. We investigated this through systematic dysmorphology assessment in CHD patients with standardized genetic testing in primarily pediatric patients with CHD. Methods: Dysmorphology evaluations preceding genetic testing results allowed us to test for associations between dysmorphic status and genetic diagnoses while adjusting for extracardiac anomalies (ECAs). We use a test-negative case-control design on a pediatric inpatient CHD cohort for our study. Results: Of 568 patients, nearly 96% of patients completed genetic testing, primarily chromosome microarray (CMA) ± exome sequencing-based genetic testing (493/568, 86.8%). Overall, 115 patients (20.2%) were found to have genetic diagnoses, and dysmorphic patients had doubled risk of genetic diagnoses, after ECA adjustment (OR = 2.10, p = 0.0030). We found that 7.9% (14/178) of ECA-/nondysmorphic patients had genetic diagnoses, which increased to 13.5% (26/192) in the ECA-/dysmorphic patients. Nearly 43% of ECA+/dysmorphic patients had genetic diagnoses (63/147). The positive predictive value of dysmorphic status was only 26.3%, and the negative predictive value of nondysmorphic status was 88.7%. Conclusions: Dysmorphology-based prediction of genetic disorders is limited because of diagnoses found in apparently isolated CHD. Our findings represent one of the only assessments of phenotype-based screening for genetic disorders in CHD and should inform clinical genetics evaluation practices for pediatric CHD.
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    Reanalysis and Reclassification of UBA2 Variants in Patient with Syndactyly, Polydactyly, Aplasia Cutis Congenita and Other Anomalies Reveals Diagnosis
    (2025-04-25) Liaqat, Khurram; Felipe, Kimberly; Treat, Kayla; McPheron, Molly; Conboy, Erin; Vetrini, Francesco
    Aplasia cutis congenita and ectrodactyly skeletal syndrome (ACCES) is known to cause by heterozygous mutation in the UBA2 gene. In this report we present the case of 7-year-old male with cutis aplasia, syndactyly, pre-axial polydactyly, and severe complex hypospadias. The exome sequencing identified a heterozygous frameshift variant [c.52_58dupGGCCGGG p.(Val20Gfs*31)] in UBA2 gene. This variant is absent in gnomAD and has been predicted to be pathogenic by various as insilico tools. Following enrollment of the patient at Undiagnosed Rare Disease Clinic (URDC) this frameshift variant [c.52_58dupGGCCGGG p.(Val20Gfs*31)] was reclassified as a pathogenic from Variant of unknown significance (VUS) according to ACMG guidelines. The variant classification affects the patient diagnosis, precision therapy and family screening. In this study, we highlighted the importance of reanalysis of genetic data for reclassification of variant from VUS to pathogenic in unsolved cases.
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    Reanalysis of a novel variant in the IGF1R gene in a family with variable prenatal and postnatal growth retardation and dysmorphic features: benefits and feasibility of IUSM-URDC (Undiagnosed Rare Disease Clinic) program
    (Cold Spring Harbor Laboratory Press, 2022-03-24) Jacobs, Annalise; Burns, Catherine; Patel, Purva; Treat, Kayla; Helm, Benjamin M.; Conboy, Erin; Vetrini, Francesco; Pediatrics, School of Medicine
    IGF1R-related disorders are associated with intrauterine growth restriction (IUGR), postnatal growth failure, short stature, microcephaly, developmental delay, and dysmorphic facial features. We report a patient who presented to medical genetics at 7 mo of age with a history of IUGR, poor feeding, mild developmental delays, microcephaly, and dysmorphic facial features. Whole-exome sequencing revealed a novel c.1464T > G p.(Cys488Trp) variant in the IGF1R gene, initially classified as a variation of uncertain significance (VUS). We enrolled the patient in the URDC (Undiagnosed Rare Disease Clinic) and performed additional studies including deep phenotyping and familial segregation analysis, which demonstrated that the patient's IGF1R VUS was present in phenotypically similar family members. Furthermore, biochemical testing revealed an elevated serum IGF-1 level consistent with abnormal IGF-1 receptor function. Workup resulted in the patient's variant being upgraded from a VUS to likely pathogenic. Our report expands the variant and phenotypic spectrum of IGF1R-related disorders and illustrates benefits and feasibility of reassessing a VUS beyond the initial molecular diagnosis by deep phenotyping, 3D modeling, additional biochemical testing, and familial segregation studies through the URDC, a multidisciplinary clinical program whose major goal is to end the diagnostic odyssey in patients with rare diseases.