Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.
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.
Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Dong-Hui
DH
Chen
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Jennifer E
JE
Below
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA; Division of Hematology, University of Washington School of Medicine, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Akiko
A
Shimamura
Division of Hematology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Sioban B
SB
Keel
Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA.
Mark
M
Matsushita
Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA.
John
J
Wolff
Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA.
Youngmee
Y
Sul
Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Emily
E
Bonkowski
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Maria
M
Castella
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Toshiyasu
T
Taniguchi
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Deborah
D
Nickerson
Division of Hematology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Thalia
T
Papayannopoulou
Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195, USA; Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA; Geriatric Research, Education, and Clinical Center, Veterans Administration Puget Sound Veterans Health Care Center, Seattle, WA 98108, USA. Electronic address: tomnroz@uw.edu.
Thomas D
TD
Bird
Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA; Geriatric Research, Education, and Clinical Center, Veterans Administration Puget Sound Veterans Health Care Center, Seattle, WA 98108, USA; Division of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA. Electronic address: wendyrun@uw.edu.
Wendy H
WH
Raskind
D000293:Adolescent; D000328:Adult; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology; D002648:Child; D002869:Chromosome Aberrations; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010198:Pancytopenia / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C514443:SAMD9 protein, human; D025521:Tumor Suppressor Proteins