Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L

Am J Hum Genet. 2016 Jun 2;98(6):1146-1158. doi: 10.1016/j.ajhg.2016.04.009.


Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy 7. Here, in the four-generation family UW-AP, linkage analysis revealed four regions that provided the maximal LOD scores possible, one of which was in a commonly microdeleted chromosome 7q region. Exome sequencing identified a missense mutation (c.2640C>A, p.His880Gln) in the sterile alpha motif domain containing 9-like gene (SAMD9L) that completely cosegregated with disease. By targeted sequencing of SAMD9L, we subsequently identified a different missense mutation (c.3587G>C, p.Cys1196Ser) in affected members of the first described family with AP syndrome, Li-AP. Neither variant is reported in the public databases, both affect highly conserved amino acid residues, and both are predicted to be damaging. With time in culture, lymphoblastic cell lines (LCLs) from two affected individuals in family UW-AP exhibited copy-neutral loss of heterozygosity for large portions of the long arm of chromosome 7, resulting in retention of only the wild-type SAMD9L allele. Newly established LCLs from both individuals demonstrated the same phenomenon. In addition, targeted capture and sequencing of SAMD9L in uncultured blood DNA from both individuals showed bias toward the wild-type allele. These observations indicate in vivo hematopoietic mosaicism. The hematopoietic cytopenias that characterize AP syndrome and the selective advantage for clones that have lost the mutant allele support the postulated role of SAMD9L in the regulation of cell proliferation. Furthermore, we show that AP syndrome is distinct from the dyskeratoses congenita telomeropathies, with which it shares some clinical characteristics.

MeSH terms

  • Adolescent
  • Adult
  • Cerebellar Ataxia / genetics*
  • Cerebellar Ataxia / pathology
  • Child
  • Chromosome Aberrations*
  • Chromosomes, Human, Pair 7 / genetics
  • Exome / genetics
  • Female
  • Genetic Linkage
  • Genotype
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Loss of Heterozygosity
  • Male
  • Middle Aged
  • Mutation, Missense / genetics*
  • Pancytopenia / genetics*
  • Pancytopenia / pathology
  • Pedigree
  • Proteins / genetics*
  • Tumor Suppressor Proteins / genetics
  • Young Adult


  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • SAMD9 protein, human
  • Tumor Suppressor Proteins

Supplementary concepts

  • Myelocerebellar Disorder