UBA2 variants underlie a recognizable syndrome with variable aplasia cutis congenita and ectrodactyly

Schnur, Rhonda E.; Yousaf, Sairah; Liu, James H.; Chung, Wendy K.; Rhodes, Lindsay; Marble, Michael; Zambrano, Regina; Sobreira, Nara; Jayakar, Parul; Schultz, Matthew; Pichurin, Pavel N.; Olson, Rory J.; Graham, Gail E.; Osmond, Matthew; Contreras-García, Gustavo Adolfo; Campo-Neira, Karina A.; Peñaloza-Mantilla, Camilo A.; Flage, Mark; Kuppa, Srikar; Rdz-Navarro, Karina; Sacoto, María J. Guillen; Wentzensen, Ingrid M.; Scarano, Maria I.; Juusola, Jane; Prada, Carlos E.; Hufnagel, Robert B.

doi:10.1038/s41436-021-01182-1

Cited by 8 publications

(12 citation statements)

References 33 publications

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“…Thus far, we have upgraded variants to likely diagnoses for 23 of the 60 genes (38%). Ten of these genes have been published, in collaboration with our group, as novel disease‐gene associations 14–24 . Another four families have benefited from recent cohort publications by external research programs 25–28 .…”

Section: Resultsmentioning

confidence: 99%

“…Ten of these genes have been published, in collaboration with our group, as novel disease-gene associations. [14][15][16][17][18][19][20][21][22][23][24] Another four families have benefited from recent cohort publications by external research programs. [25][26][27][28] The remaining nine genes are part of ongoing collaborations.…”

Section: Translational Research Reanalysis Resultsmentioning

confidence: 99%

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Bridging clinical care and research in Ontario, Canada: Maximizing diagnoses from reanalysis of clinical exome sequencing data

et al. 2022

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We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods,

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Section: Resultsmentioning

confidence: 99%

Section: Translational Research Reanalysis Resultsmentioning

confidence: 99%

Bridging clinical care and research in Ontario, Canada: Maximizing diagnoses from reanalysis of clinical exome sequencing data

et al. 2022

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“…SUMOylation, in turn, plays an essential role in a variety of biological processes including cell growth, migration, and cellular responses to stress (Yang et al, 2017). Heterozygous pathogenic variants in UBA2 are associated with a recently described genetic disorder characterized by highly variable neurologic, cardiac, renal, skeletal, dermatologic, and extremity phenotypes (Schnur et al, 2021). UBA2 is partially deleted in Subject 23 by an ~175 kb interstitial deletion of chromosome 19q13.11.…”

Section: Discussionmentioning

confidence: 99%

Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data

Hardcastle

Berry

Campbell

et al. 2022

American J of Med Genetics Pt A

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Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.

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“…Similarly, with respect to VEXAS syndrome, somatic variations at amino acid residue 41 has resulted in decreased in vitro expression levels of the different UBA1 isoforms, leading to the associated symptoms that vary among patients and various affected organs including the bone marrow, skin, lymph nodes, joints and cartilage 99,100 . Similarly, frameshift and missense variations in UBA2 were linked to ACCESS syndrome associated with significant symptom variability including developmental delay, scalp defects and ectrodactyly of the hands and feet 62,101 . Although data regarding UBA2 and ACCESS syndrome are limited, researchers have attributed the development of the disease to the impaired SUMOylation because of the variants 62 .…”

Section: Human Phenotypes and Animal And Cellular Disease Models Asso...mentioning

confidence: 99%

“…Additionally, E1 enzyme members, including UBA1, UBA2 and UBA4, have not been extensively explored in mammalian models. A zebrafish animal model where both UBA1 and UBA2 were ablated exhibited growth abnormalities in contrast to their wild‐type counterparts 62,100,102 . Furthermore, UBA5 has been systematically deleted in various species such as Caenorhabditis elegans , zebrafish and drosophila 66,103 .…”

Section: Human Phenotypes and Animal And Cellular Disease Models Asso...mentioning

confidence: 99%

Genetic disruption of mammalian endoplasmic reticulum‐associated protein degradation: Human phenotypes and animal and cellular disease models

Badawi

Mohamed

Varghese

et al. 2023

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Endoplasmic reticulum-associated protein degradation (ERAD) is a stringent quality control mechanism through which misfolded, unassembled and some native proteins are targeted for degradation to maintain appropriate cellular and organelle homeostasis. Several in vitro and in vivo ERAD-related studies have provided mechanistic insights into ERAD pathway activation and its consequent events; however, a majority of these have investigated the effect of ERAD substrates and their consequent diseases affecting the degradation process. In this review, we present all reported human single-gene disorders caused by genetic variation in genes that encode ERAD components rather than their substrates. Additionally, after extensive literature survey, we present various genetically manipulated higher cellular and mammalian animal models that lack specific components involved in various stages of the ERAD pathway.

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UBA2 variants underlie a recognizable syndrome with variable aplasia cutis congenita and ectrodactyly

Cited by 8 publications

References 33 publications

Bridging clinical care and research in Ontario, Canada: Maximizing diagnoses from reanalysis of clinical exome sequencing data

Bridging clinical care and research in Ontario, Canada: Maximizing diagnoses from reanalysis of clinical exome sequencing data

Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data

Genetic disruption of mammalian endoplasmic reticulum‐associated protein degradation: Human phenotypes and animal and cellular disease models

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