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Table 2 Genotypic data and relationship with leukaemia

From: Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders

Pedigrees and patients Number of affected patients/number of leukaemia cases and type of leukaemia (age at diagnosis) Type of germline RUNX1 mutation and predicted change at protein level(a) Localisation Sequence change(b) Predicted effect Acquired RUNX1
Mutation at AML stage (Ref [11, 33])
     c.DNA protein   
Pedigree
A
4/2
AML-M0 and UC-AML
(33–39 y)
  exon 4 c.320G > A p.Arg107His   
Pedigree
B
8/5.
UC-AML, AML-M0, AML-M4, 2 AML-M5
(6–42 y)
  exon 5 c.467C > A p.Ala156Glu   p.Arg129Ser
Duplication of mutated
allele
Pedigree
C
4/4
secondary AML to MDS, 2 AML-M1, T-ALL
(15–56 y)
- substitution
- missense within the RHD
exon 6 c.602G > A p.Arg201Gln Dominant
Negative
RUNX1
protein
 
Pedigree
D
5/3
UC-AML, AML-M4, T-ALL
(28–60 y)
  exon 6 c.611G > A p.Arg204Gln p.Ala160Thr
Pedigree
E
7/2
AML, MDS
(47–53 y)
  exon 6 c.587C > G P.Thr196Arg   
Pedigree
F
4/4
CLL, AML-M5, T-ALL and AML-M0
(18–55 y)
- insertion (frameshift)
- normal RHD, severely truncated TAD
exon 9 c. 999_1003dup p.Gln335Argfs261   p.Gly138ProfsX12
Pedigree
G
2/0 - deletion (frameshift)
- normal RHD,severely truncated TAD
exon 9 c. 1092del p.Ile364Metfs230   
Pedigree
H
2/1
AML-M2
(6 y)
- deletion (frameshift)
- truncated RHD, no TAD and a small
abnormal C terminal peptide
exon 5 c. 442_449del p.Thr148Hisfs9   p.Thr121HisfsX9
Pedigree
I
5/1
AML-M1
(45 y)
- substitution (nonsense)
- premature termination: severely truncated
protein, shorter RHD, no TAD
exon 5 c. 496C > T p.Arg166X Loss of function p.Arg166X+ (LOH)
Patient
J
1/0   3.4 Mb deletion in
21q22.12
NA p.0  
Patient
K
1/1
secondary AML to MDS
(14 y)
- complete deletion of RUNX1
- p.0 (haploinsufficiency)
2.16 Mb deletion in
21q22.12
NA p.0  
  1. Sequence variants were numbered starting from the first base of the ATG codon, numbering based on reference sequence NM_1754.4 containing 9 exons with 8 coding exons
  2. a: The effect of the mutation at the protein level was not tested in vitro as we did not perform any functional analyses. This classification is based on the type and/or position of the mutations affecting the RUNX1 coding region
  3. RHD: runt homology domain; TAD: trans-activation domain; LOH: loss of heterozygosity
  4. b: Theoretical effect at the protein level (the effects of the RUNX1 mutation on pre-mRNA splicing and mRNA translation were not studied). Mutant premature stop codons often trigger nonsense-mediated mRNA decay. Nonsense and out-of-frame variations might correspond to null alleles