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Clonal Elimination of the Pathogenic Allele as Diagnostic Pitfall in SAMD9L-Associated Neuropathy
Background: Heterozygous gain-of-function variants in SAMD9L are associated with ataxia-pancytopenia syndrome (ATXPC) and monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1). Association with peripheral neuropathy has rarely been described. Methods: Whole-exome sequencing (WES) from DNA extra...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9778166/ https://www.ncbi.nlm.nih.gov/pubmed/36553623 http://dx.doi.org/10.3390/genes13122356 |
Sumario: | Background: Heterozygous gain-of-function variants in SAMD9L are associated with ataxia-pancytopenia syndrome (ATXPC) and monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1). Association with peripheral neuropathy has rarely been described. Methods: Whole-exome sequencing (WES) from DNA extracted from peripheral blood was performed in a 10-year-old female presenting with demyelinating neuropathy, her similarly affected mother and the unaffected maternal grandparents. In addition to evaluation of single nucleotide variants, thorough work-up of copy number and exome-wide variant allele frequency data was performed. Results: Combined analysis of the mother’s and daughter’s duo-exome data and analysis of the mother’s and her parents’ trio-exome data initially failed to detect a disease-associated variant. More detailed analysis revealed a copy number neutral loss of heterozygosity of 7q in the mother and led to reanalysis of the exome data for respective sequence variants. Here, a previously reported likely pathogenic variant in the SAMD9L gene on chromosome 7q (NM_152703.5:c.2956C>T; p.(Arg986Cys)) was identified that was not detected with standard filter settings because of a low percentage in blood cells (13%). The variant also showed up in the daughter at 32%, a proportion well below the expected 50%, which in each case can be explained by clonal selection processes in the blood due to this SAMD9L variant. Conclusion: The report highlights the specific pitfalls of molecular genetic analysis of SAMD9L and, furthermore, shows that gain-of-function variants in this gene can lead to a clinical picture associated with the leading symptom of peripheral neuropathy. Due to clonal hematopoietic selection, displacement of the mutant allele occurred, making diagnosis difficult. |
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