ClinVar Genomic variation as it relates to human health

Ataxia-Pancytopenia Syndrome In affected members of a family (UW-AP) of Irish, German, and Native American ancestry with ataxia-pancytopenia syndrome (ATXPC; 159550), Chen et al. (2016) identified a heterozygous c.2640C-A transversion (c.2640C-A, NM_152703.3) in the SAMD9L gene, resulting in a his880-to-gln (H880Q) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 131), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variant were not performed. Patient lymphoblastoid cells were initially heterozygous for the mutation, but 2 cell lines showed loss of heterozygosity (LOH) for the mutant allele after 3 weeks to 6 months in culture, indicating that these patients were somatic mosaic for the mutation in their hematopoietic systems. The findings demonstrated a selective growth advantage in cultured cells without the mutant allele, suggesting a role for SAMD9L in the regulation of cell proliferation. Monosomy 7 Myelodysplasia and Leukemia Syndrome 1 In 2 sibs (family 1) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; 252270), Wong et al. (2018) identified a heterozygous germline H880Q mutation in the SAMD9L gene that was inherited from their asymptomatic father. HEK293T cells transfected with the H880Q mutation showed suppression of cell cycle progression compared to wildtype, suggesting a gain-of-function effect. The father was found to carry a Q569P variant in SAMD9L that was in cis with H880Q and was able to partially mitigate the cell cycle abnormalities. Both sibs developed AML. Bone marrow examination of both sibs showed deletion of the paternal copy of chromosome 7, yielding monosomy 7. Deep sequencing showed that the SAMD9L gene was present at a low frequency (less than 5%) in the bone marrow of both children, indicating selective loss of the chromosome harboring the SAMD9L mutation. Leukemic cells in both affected sibs showed acquisition of somatic mutations in other genes, including RUNX1, SETBP1, BRAF, and KRAS, which likely contributed to leukemogenesis. Both patients died. The family was previously reported as family 1 by Shannon et al. (1989). (less)

Ataxia-Pancytopenia Syndrome In affected members of a family (UW-AP) of Irish, German, and Native American ancestry with ataxia-pancytopenia syndrome (ATXPC; 159550), Chen et al. (2016) identified a heterozygous c.2640C-A transversion (c.2640C-A, NM_152703.3) in the SAMD9L gene, resulting in a his880-to-gln (H880Q) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 131), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variant were not performed. Patient lymphoblastoid cells were initially heterozygous for the mutation, but 2 cell lines showed loss of heterozygosity (LOH) for the mutant allele after 3 weeks to 6 months in culture, indicating that these patients were somatic mosaic for the mutation in their hematopoietic systems. The findings demonstrated a selective growth advantage in cultured cells without the mutant allele, suggesting a role for SAMD9L in the regulation of cell proliferation. Monosomy 7 Myelodysplasia and Leukemia Syndrome 1 In 2 sibs (family 1) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; 252270), Wong et al. (2018) identified a heterozygous germline H880Q mutation in the SAMD9L gene that was inherited from their asymptomatic father. HEK293T cells transfected with the H880Q mutation showed suppression of cell cycle progression compared to wildtype, suggesting a gain-of-function effect. The father was found to carry a Q569P variant in SAMD9L that was in cis with H880Q and was able to partially mitigate the cell cycle abnormalities. Both sibs developed AML. Bone marrow examination of both sibs showed deletion of the paternal copy of chromosome 7, yielding monosomy 7. Deep sequencing showed that the SAMD9L gene was present at a low frequency (less than 5%) in the bone marrow of both children, indicating selective loss of the chromosome harboring the SAMD9L mutation. Leukemic cells in both affected sibs showed acquisition of somatic mutations in other genes, including RUNX1, SETBP1, BRAF, and KRAS, which likely contributed to leukemogenesis. Both patients died. The family was previously reported as family 1 by Shannon et al. (1989). (less)