Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.

TitleAtaxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.
Publication TypeJournal Article
Year of Publication2016
AuthorsChen, D-H, Below, JE, Shimamura, A, Keel, SB, Matsushita, M, Wolff, J, Sul, Y, Bonkowski, E, Castella, M, Taniguchi, T, Nickerson, D, Papayannopoulou, T, Bird, TD, Raskind, WH
JournalAm J Hum Genet
Volume98
Issue6
Pagination1146-58
Date Published2016 Jun 02
ISSN1537-6605
Abstract

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.

DOI10.1016/j.ajhg.2016.04.009
Alternate JournalAm. J. Hum. Genet.
PubMed ID27259050
PubMed Central IDPMC4908176
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
UC2 HL102926 / HL / NHLBI NIH HHS / United States
UC2 HL103010 / HL / NHLBI NIH HHS / United States
R24 DK099808 / DK / NIDDK NIH HHS / United States
RC2 HG005608 / HG / NHGRI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
R01 NS069719 / NS / NINDS NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
UC2 HL102924 / HL / NHLBI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
I01 CX001006 / CX / CSRD VA / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
UC2 HL102925 / HL / NHLBI NIH HHS / United States