Impact of integrated translational research on clinical exome sequencing

Klee, Eric W.; Cousin, Margot A.; Vairo, Filippo Pinto e; Morales‐Rosado, Joel A.; Macke, Erica L.; Jenkinson, W. Garrett; Ferrer, Alejandro Tiana; Schultz‐Rogers, Laura; Olson, Rory J.; Oliver, Gavin R.; Sigafoos, Ashley N.; Schwab, Tanya L.; Zimmermann, Michael T.; Urrutia, Raúl; Kaiwar, Charu; Gupta, Aditi; Blackburn, Patrick R.; Boczek, Nicole J.; Prochnow, Carri A.; Lowy, Rebecca J.; Mulvihill, Lindsay A.; McAllister, Tammy M.; Aoudia, Stacy L.; Kruisselbrink, Teresa M.; Gunderson, Lauren; Kemppainen, Jennifer L.; Fisher, Laura J.; Tarnowski, Jessica M.; Hager, Megan M.; Kroc, Sarah A.; Bertsch, Nicole L.; Agre, Katherine; Jackson, Jessica L.; Macklin-Mantia, Sarah; Murphree, Marine I.; Rust, Laura; Bolster, Jolene M. Summer; Beck, Scott A.; Atwal, Paldeep S.; Ellingson, Marissa S.; Barnett, Sarah S.; Rasmussen, Kristen; Lahner, Carrie A.; Niu, Zhiyv; Hasadsri, Linda; Ferber, Matthew J.; Marcou, Cherisse A.; Clark, Karl J.; Pichurin, Pavel N.; Deyle, David R.; Morava‐Kozicz, Eva; Gavrilova, Ralitza H.; Dhamija, Radhika; Wierenga, Klaas J.; Lanpher, Brendan C.; Babovic‐Vuksanovic, Dusica; Farrugia, Gianrico; Schimmenti, Lisa A.; Stewart, A. Keith; Lazaridis, Konstantinos N.

doi:10.1016/j.gim.2022.12.006

Cited by 1 publication

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“…In a second case, a pathogenic variant in SETD5 was identified (ENST00000402198.5: c.2347-1G > A, ACMG criteria PVS1, PM2, PP3, PP5). The variant has been previously reported as likely pathogenic in Clinvar (RCV000578558) and in two separate publications, but no clinical information was provided in these instances [59][60][61]. The variant is absent from GnomAD v4.0 and predicted to affect splicing (spliceAI acceptor loss prediction score = 0.99) (Fig.…”

Section: Identification Of Dmdd Candidate Gene Variants In Children W...mentioning

confidence: 99%

Knockout mice with pituitary malformations help identify human cases of hypopituitarism

Martinez-Mayer,

Brinkmeier,

O’Connell

et al. 2024

Genome Med

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Background Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia (SOD) and holoprosencephaly (HPE), are midline defects that cause significant morbidity for affected people. Variants in 67 genes are associated with CH, but a vast majority of CH cases lack a genetic diagnosis. Whole exome and whole genome sequencing of CH patients identifies sequence variants in genes known to cause CH, and in new candidate genes, but many of these are variants of uncertain significance (VUS). Methods The International Mouse Phenotyping Consortium (IMPC) is an effort to establish gene function by knocking-out all genes in the mouse genome and generating corresponding phenotype data. We used mouse embryonic imaging data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to screen 209 embryonic lethal and sub-viable knockout mouse lines for pituitary malformations. Results Of the 209 knockout mouse lines, we identified 51 that have embryonic pituitary malformations. These genes not only represent new candidates for CH, but also reveal new molecular pathways not previously associated with pituitary organogenesis. We used this list of candidate genes to mine whole exome sequencing data of a cohort of patients with CH, and we identified variants in two unrelated cases for two genes, MORC2 and SETD5, with CH and other syndromic features. Conclusions The screening and analysis of IMPC phenotyping data provide proof-of-principle that recessive lethal mouse mutants generated by the knockout mouse project are an excellent source of candidate genes for congenital hypopituitarism in children.

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Section: Identification Of Dmdd Candidate Gene Variants In Children W...mentioning

confidence: 99%