Family Lore, a Variant of Uncertain Significance, and CADASIL.
CADASIL
cerebrovascular disorders
family history
genetic diseases
inborn
Journal
American journal of medical genetics. Part C, Seminars in medical genetics
ISSN: 1552-4876
Titre abrégé: Am J Med Genet C Semin Med Genet
Pays: United States
ID NLM: 101235745
Informations de publication
Date de publication:
20 Oct 2024
20 Oct 2024
Historique:
revised:
16
09
2024
received:
27
08
2024
accepted:
28
09
2024
medline:
21
10
2024
pubmed:
21
10
2024
entrez:
21
10
2024
Statut:
aheadofprint
Résumé
An infant presents in extremis. After the medical team stabilizes him, the race is on to figure out why he got so sick in the first place. The consulting genetics team thinks that it is unlikely his problems are due to a genetic cause, but his extreme, confounding presentation is enough to justify trio exome sequencing. When the results reveal an unexpected, paternally inherited variant of uncertain significance (VUS) in NOTCH3, fresh questions arise. The infant's presenting symptoms and descriptive diagnoses, including hematemesis, epistaxis, and gastric ulcers, certainly do not fit the mold of CADASIL. However, closer inspection of his family history yields tantalizing clues: a father and paternal grandfather with seizures, and a paternal grandfather with unexplained mood disturbances in middle age. Combining details gleaned from the family history and medical literature, the clinical genetics and laboratory genetics team collaborated, reclassified the VUS as likely pathogenic, and offered a new unifying diagnosis to explain much of the family's lore.
Identifiants
pubmed: 39428697
doi: 10.1002/ajmg.c.32117
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e32117Informations de copyright
© 2024 Wiley Periodicals LLC.
Références
Hack, R. J., J. Rutten, and S. A. Lesnik Oberstein. 2000. “CADASIL Synonym: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.”
Mizuta, I., A. Watanabe‐Hosomi, T. Koizumi, et al. 2017. “New Diagnostic Criteria for Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukocencephalopathy in Japan.” Journal of the Neurological Sciences 381: 62–67. https://doi.org/10.1016/j.jns.2017.08.009.
Ni, W., Y. Zhang, L. Zhang, J. J. Xie, H. F. Li, and Z. Y. Wu. 2022. “Genetic Spectrum of NOTCH3 and Clinical Phenotype of CADASIL Patients in Different Populations.” CNS Neuroscience and Therapeutics 28, no. 11: 1779–1789. https://doi.org/10.1111/cns.13917.
Wang, M. M. 2018. “CADASIL.” Handbook of Clinical Neurology 148: 733–743. https://doi.org/10.1016/B978‐0‐444‐64076‐5.00047‐8.