Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia

Jane E. Churpek, Khateriaa Pyrtel, Krishna-Latha Kanchi, Jin Shao, Daniel Koboldt, Christopher A. Miller, Dong Shen, Robert Fulton, Michelle O’Laughlin, Catrina Fronick, Iskra Pusic, Geoffrey L. Uy, Evan M. Braunstein, Mark Levis, Julie Ross, Kevin Elliott, Sharon Heath, Allan Jiang, Peter Westervelt, John F. DiPersio, Daniel C. Link, Matthew J. Walter, John Welch, Richard Wilson, Timothy J. Ley, Lucy A. Godley and Timothy A. Graubert

Data supplements

Article Figures & Data


  • Figure 1

    Familial MDS/AML pedigrees. (A) Partial pedigrees of families 1001 and 1002 with GATA2-associated MDS/AML; complete pedigrees are provided in supplemental Figure 1. Subjects who provided samples for sequencing are indicated by numerals. GATA2 genotypes are provided in Table 1. Two individuals with MDS acquired somatic ASXL1 mutations, as shown. (B) Partial pedigree of family 1015 with RUNX1-associated MDS/AML (left); complete pedigree is provided in supplemental Figure 1. The number of somatic variants (SNVs, indels) detected by exome sequencing in the 3 individuals (indicated by numerals in the pedigree) is shown in the circles (right). The size of the circles is proportional to the median VAFs of somatic SNVs in each case. NOS, not otherwise specified.

  • Figure 2

    Somatic variants in familial MDS/AML vs de novo AML. (A) Targeted sequencing of known RMGs demonstrated fewer mutations in familial cases compared to de novo cases (median, 2.0 vs 5.0; P = .0013 by 2-tailed Mann-Whitney). (B) Somatic mutation VAFs detected by exome sequencing in asymptomatic RUNX1 carriers and familial MDS and AML cases from GATA2 or RUNX1 families are shown. Age at sample collection is indicated by the x-axis labels (black, RUNX1 carrier; red, GATA2 carrier). Clonal hematopoiesis was detectable in 6 of 9 asymptomatic RUNX1 carriers.

  • Figure 3

    Clonal evolution in RUNX1 carriers. Asymptomatic carriers of pathogenic germ line RUNX1 variants develop early-onset clonal hematopoiesis (cumulative risk of 81% by age 50 years). As depicted in the model, this finding provides a rationale for testing the hypothesis that clonal hematopoiesis may provide a biomarker for early detection of disease progression in high-risk families.


  • Table 1

    Pathogenic germ line variants detected by targeted sequencing

    FamilySubjectGeneTranscriptCoding changeSubstitutionGenotypeProteindbSNP IDMAF
    1001001GATA2NM_001145661.1Intronicc.1017+572 (C>T)HeterozygousNoneNone0
    1002001GATA2NM_001145661.1Missensec.1192 (C>T)Heterozygousp.R398Wrs3879066290
    1003001GATA2NM_001145661.1Missensec.1061 (C>T)Heterozygousp.T354Mrs3879066310
    1011001SBDSNM_016038.2Missensec.506 (G>A)Heterozygousp.R169Hrs1139939960
    001SBDSNM_016038.2Splicec.258+2 (T>C)Heterozygouse2+2rs1139939930.002
    001FANCANM_000135.2Missensec.1340 (C>T)Heterozygousp.S447Lrs1495517590.0002
    001FANCANM_000135.2Splicec.3349-3 (C>T)Heterozygouse34-3rs3738614150.0001
    1015001RUNX1NM_001754.4Nonsensec.1163 (C>A)Heterozygousp.S388*None0
    • dbSNP ID, Database of Single Nucleotide Polymorphisms identification number; MAF, minor allele frequency.23,24

  • Table 2

    Characteristics of patient cohort selected for tumor/normal sequencing

    SubjectRelationshipAge, yRMG*ExomeGeneProteinWHO classificationKaryotype
    1001-005Sister21XXGATA2IntronicAML with MDS-related featuresNormal
    1002-001Proband48XXGATA2p.R398WRCMDadd(3)(q21),+8, del(12)(p11.2p13)
    1003-003Father68XXGATA2p.T354MAML with MDS-related featuresNormal
    1006-005Maternal first cousin61XUnknownNARAEB-INormal
    1010-009Niece44XUnknownNAMDS, unclassifiedt(12;17;13) (q24.1;q23;q14.1)
    1012-001Proband30XUnknownNAAML NOS (AML-M6a)Normal
    1014-001Proband65XUnknownNAAML NOS (AML-M6)Normal
    1015-001Proband37XXRUNX1p.R388XMDS with isolated del(5q)del(5q)
    1015-002Mother49XXRUNX1p.R388XAML with MDS-related featuresNormal
    1015-004Daughter18XRUNX1p.R388XUnaffected carrierNot done
    1016-001Proband54XUnknownNAAML NOS (AML-M6)Unknown
    1019-001Proband14XRUNX1p.W279XHypoplastic without overt dysplasiaNormal
    1019-003Father54XRUNX1p.W279XUnaffected carrierNot done
    1021-003Father40XRUNX1p.R204XUnaffected carrierNot done
    1021-004Uncle35XRUNX1p.R204XUnaffected carrierNot done
    1021-005Paternal grandmother61XXRUNX1p.R204XRAEB-INormal
    1022-001Proband41XRUNX1p.L472fsX123Unaffected carrierNot done
    1022-005Daughter8XRUNX1p.L472fsX123Unaffected carrierNot done
    1022-007Brother46XRUNX1p.L472fsX123Unaffected carrierNot done
    1024-001Proband50XRUNX1p.Y260XDysmegakaryopoiesisdel(11q23), -Y
    1024-005Daughter19XRUNX1p.Y260XUnaffected carrierUnknown
    • AML-M6, acute erythroid leukemia; AML-M6a, erthroleukemia, consisting of myeloblasts and erythroid precursors; NA, not applicable; RAEB-I, refractory anemia with excess blasts (5%-10% marrow blasts); RAEB-II, refractory anemia with excess blasts (11%-20% marrow blasts); RCMD, refractory cytopenia with multilineage dysplasia; WHO, World Health Organization.

    • * Targeted sequencing of 264 RMGs.