@article {810, title = {Missed diagnoses: Clinically relevant lessons learned through medical mysteries solved by the Undiagnosed Diseases Network.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 10}, pages = {e1397}, abstract = {

BACKGROUND: Resources within the Undiagnosed Diseases Network (UDN), such as genome sequencing (GS) and model organisms aid in diagnosis and identification of new disease genes, but are currently difficult to access by clinical providers. While these resources do contribute to diagnoses in many cases, they are not always necessary to reach diagnostic resolution. The UDN experience has been that participants can also receive diagnoses through the thoughtful and customized application of approaches and resources that are readily available in clinical settings.

METHODS: The UDN Genetic Counseling and Testing Working Group collected case vignettes that illustrated how clinically available methods resulted in diagnoses. The case vignettes were classified into three themes; phenotypic considerations, selection of genetic testing, and evaluating exome/GS variants and data.

RESULTS: We present 12 participants that illustrate how clinical practices such as phenotype-driven genomic investigations, consideration of variable expressivity, selecting the relevant tissue of interest for testing, utilizing updated testing platforms, and recognition of alternate transcript nomenclature resulted in diagnoses.

CONCLUSION: These examples demonstrate that when a diagnosis is elusive, an iterative patient-specific approach utilizing assessment options available to clinical providers may solve a portion of cases. However, this does require increased provider time commitment, a particular challenge in the current practice of genomics.

}, keywords = {Adolescent, Child, Child, Preschool, Databases, Factual, Diagnosis, Computer-Assisted, Female, Genetic Diseases, Inborn, Genetic Testing, Humans, Information Dissemination, Male, Middle Aged, Missed Diagnosis, National Institutes of Health (U.S.), Phenotype, Precision Medicine, Undiagnosed Diseases, United States, Young Adult}, issn = {2324-9269}, doi = {10.1002/mgg3.1397}, author = {Cope, Heidi and Spillmann, Rebecca and Rosenfeld, Jill A and Brokamp, Elly and Signer, Rebecca and Schoch, Kelly and Kelley, Emily G and Sullivan, Jennifer A and Macnamara, Ellen and Lincoln, Sharyn and Golden-Grant, Katie and Orengo, James P and Clark, Gary and Burrage, Lindsay C and Posey, Jennifer E and Punetha, Jaya and Robertson, Amy and Cogan, Joy and Phillips, John A and Martinez-Agosto, Julian and Shashi, Vandana} } @article {562, title = {Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 11 01}, pages = {794-807}, abstract = {

Ca signaling is vital for various cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, gene transcription, and cellular proliferation. The endoplasmic reticulum (ER) is the largest intracellular Ca store, and dysregulation of ER Ca signaling and homeostasis contributes to the pathogenesis of various complex disorders and Mendelian disease traits. We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. Through whole-exome sequencing and family-based genomics, we identified bi-allelic variants in CCDC47 that encodes the Ca-binding ER transmembrane protein CCDC47. CCDC47, also known as calumin, has been shown to bind Ca with low affinity and high capacity. In mice, loss of Ccdc47 leads to embryonic lethality, suggesting that Ccdc47 is essential for early development. Characterization of cells from individuals with predicted likely damaging alleles showed decreased CCDC47 mRNA expression and protein levels. In~vitro cellular experiments showed decreased total ER Ca storage, impaired Ca signaling mediated by the IPR Ca release channel, and reduced ER Ca refilling via store-operated Ca entry. These results, together with the previously described role of CCDC47 in Ca signaling and development, suggest that bi-allelic loss-of-function variants in CCDC47 underlie the pathogenesis of this multisystem disorder.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.014}, author = {Morimoto, Marie and Waller-Evans, Helen and Ammous, Zineb and Song, Xiaofei and Strauss, Kevin A and Pehlivan, Davut and Gonzaga-Jauregui, Claudia and Puffenberger, Erik G and Holst, Charles R and Karaca, Ender and Brigatti, Karlla W and Maguire, Emily and Coban-Akdemir, Zeynep H and Amagata, Akiko and Lau, C Christopher and Chepa-Lotrea, Xenia and Macnamara, Ellen and Tos, Tulay and Isikay, Sedat and Nehrebecky, Michele and Overton, John D and Klein, Matthew and Markello, Thomas C and Posey, Jennifer E and Adams, David R and Lloyd-Evans, Emyr and Lupski, James R and Gahl, William A and Malicdan, May Christine V} }