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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
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Orphanet Journal of Rare Diseases

ISSN: 1750-1172