Citations 2
The clinical utility of functional testing in fibroblasts to diagnose primary mitochondrial disease
Hove, Johan L.K. Van , Friederich, Marisa W. , Hove, Roxanne A. Van , Lee, Jessica C. , Knight, Kaz M. , Donovan, Tonia E, Silveira, Lori, Hirano, Michio, Abdenur, José E. , Cassiman, David, Cohen, Bruce H. , Elsea, Sarah H. , Enns, Gregory M., Gahl, William A, Gavrilova, Ralitza, Geddes, Gabriella C, Glamuzima, Emma E, Goldstein, Amy , Haas, Richard , Khan, Aneal , Kripps, Kimberly A. , Lehman, April, Lichter-Konecki, Uta, Morava, Eva, Rosenfeld, Jill A, Saneto, Russel P., Scaglia, Fernando , Shelkowitz, Emily , Smith, Wendy E, Soler-Alfonso, Claudia, Coster, Rudy N.A. Van, Vockley, Gerard, Wigby, Kristen, Wolfe, Lynne A. , Wortmann, Saskia B. , Van Hove, Johan L K , Ganetzky, Rebecca D , Cohen, Bruce H , Elsea, Sarah , Khan, Aneal , Larson, Austin A , Lehman, April N , Mayr, Johannes A , Scaglia, Fernando , Simon, Mariella , Smet, Joél E G , Tarnopolsky, Mark , Wolfe, Lynne A , Wortmann, Saskia , Yang, Jennifer H , Donovan, Tonia E., Ganetzky, Rebecca , Hirano, Michio , Butler, Merlin G. , Cassiman, David , Enns, Gregory M. , Gahl, William A. , Glamuzina, Emma E , Larson, Austin , Lichter‐Konecki, Uta , Morava, Éva , Peterson, James T. , Rosenfeld, Jill A. , Saneto, Russell P. , Smith, Wendy E. , Soler‐Alfonso, Claudia , Tarnopolsky, Mark A. , Vanlander, Arnaud Vincent , Vermeersch, Pieter , Wigby, Kristen M. , Yang, Jennifer H.
No container title available | June 16, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Genome sequencing of the heterogeneous primary mitochondrial disorders (PMD) frequently reveals variants of uncertain significance that require functional tests for diagnosis, and does not identify variants in all patients. We analyzed mitochondrial enzyme assays, blue native polyacrylamide gel electrophoresis (BN-PAGE) with in-gel activity staining, complex I assembly blot, and select protein abundances in fibroblasts of a case series of 204 PMD patients divided into functional classes, in comparison to 51 controls and 53 differential diagnostic conditions. Overall, sensitivity and specificity for respiratory chain enzyme assays were 46% and 93% respectively, for BN-PAGE 40% and 98%, for complex I assembly assay 49% and 99%. The overall sensitivity of all tests was 76%, specificity 93%, with positive predictive value 96% and negative predictive value 67%. Categories with high sensitivity were isolated complex deficiencies, nuclear DNA-encoded mitochondrial protein synthesis defects, co-factor defects, and mitochondrial amino-acyl-tRNA synthetase conditions when aided by protein abundance. Mitochondrial DNA mutations and maintenance disorders showed poor sensitivities. Secondary dysfunctions were rare. A complete battery of functional tests showed strong diagnostic clinical utility in fibroblasts. One sentence summary A combination of four mitochondrial functional tests to identify or confirm suspected primary mitochondrial disease in fibroblasts had good sensitivity and excellent specificity, well beyond what was perceived using enzyme assays only.
Recurrent duplications of 17q12 associated with variable phenotypes
Mitchell, Elyse, Douglas, Andrew G. L. , Kjaegaard, Susanne, Callewaert, Bert , Janssens, Sandra , Yuen, Amy Lawson, Skinner, Cindy , Failla, Pinella , Alberti, A , Avola, Emanuela , Fichera, Marco , Kibæk, Maria, Digilio, M. Cristina , Hannibal, Mark , Hollander, Nicolette S. den , Bizzarri, Veronica, Renieri, Alessandra , Mencarelli, Maria Antonietta , Fitzgerald, Tomas , Piazzolla, Serena, Oudenhove, Elke Van , Romano, Corrado , Schwartz, Charles E. , Rajan, Diana, Crolla, John A., Carter, Nigel, Hodge, Jennelle C. , Vanlander, Arnaud Vincent , Eichler, Evan E , Slavotinek, Anne , Escobar, Luis Fernando , Mefford, Heather C. , Callewaert, Bert , Renieri, Alessandra
American Journal of Medical Genetics Part A | September 30, 2015 | Volume: 167 | Issue: 12 | Pages: 3038-3045
The ability to identify the clinical nature of the recurrent duplication of chromosome 17q12 has been limited by its rarity and the diverse range of phenotypes associated with this genomic change. In order to further define the clinical features of affected patients, detailed clinical information was collected in the largest series to date (30 patients and 2 of their siblings) through a multi‐institutional collaborative effort. The majority of patients presented with developmental delays varying from mild to severe. Though dysmorphic features were commonly reported, patients do not have consistent and recognizable features. Cardiac, ophthalmologic, growth, behavioral, and other abnormalities were each present in a subset of patients. The newly associated features potentially resulting from 17q12 duplication include height and weight above the 95th percentile, cataracts, microphthalmia, coloboma, astigmatism, tracheomalacia, cutaneous mosaicism, pectus excavatum, scoliosis, hypermobility, hypospadias, diverticulum of Kommerell, pyloric stenosis, and pseudohypoparathryoidism. The majority of duplications were inherited with some carrier parents reporting learning disabilities or microcephaly. We identified additional, potentially contributory copy number changes in a subset of patients, including one patient each with 16p11.2 deletion and 15q13.3 deletion. Our data further define and expand the clinical spectrum associated with duplications of 17q12 and provide support for the role of genomic modifiers contributing to phenotypic variability. © 2015 Wiley Periodicals, Inc.