Family Lore, a Variant of Uncertain Significance, and CADASIL
Rhys Duarte1, Liesbeth Vossaert1,2, Sandra A Darilek1,3
1Department of Molecular and Human Genetics, Baylor College of Medicine, Texas, USA.
Insights
A rare NOTCH3 gene variant, initially of uncertain significance, was identified in an infant with severe symptoms. This variant was reclassified as likely pathogenic, explaining the infant's condition and other family health issues.
Area of Science:
- Genetics
- Pediatrics
- Neurology
Background:
- Infants can present with severe, confounding symptoms requiring extensive diagnostic workups.
- Genetic factors are often considered, but initial assessments may not always point towards a clear genetic etiology.
- Trio exome sequencing is a powerful tool for diagnosing rare and complex pediatric conditions.
Purpose of the Study:
- To investigate the underlying cause of an infant's severe illness.
- To evaluate the role of genetic variants, specifically in the NOTCH3 gene, in the infant's presentation.
- To re-evaluate a variant of uncertain significance (VUS) based on clinical and family history data.
Main Methods:
- Clinical stabilization of the infant.
- Trio exome sequencing (parents and infant).
- Analysis of the NOTCH3 gene for paternally inherited variants.
- Correlation of genetic findings with infant's symptoms and family history.
- Literature review and expert collaboration for variant reclassification.
Main Results:
- Identification of a paternally inherited NOTCH3 variant of uncertain significance (VUS) in the infant.
- Infant's symptoms (hematemesis, epistaxis, gastric ulcers) did not align with typical CADASIL presentations.
- Family history revealed paternal relatives with seizures and mood disturbances.
- Reclassification of the NOTCH3 VUS to likely pathogenic based on integrated data.
- A unifying diagnosis was proposed for the family's constellation of symptoms.
Conclusions:
- The NOTCH3 gene can present with atypical phenotypes beyond classic CADASIL.
- Trio exome sequencing combined with thorough family history analysis is crucial for diagnosing complex genetic disorders.
- Reclassification of VUS is essential for accurate diagnosis and genetic counseling.
Abstract:
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.
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