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Molecular diagnosis and clinical features of 117 Japanese FA patients
Figure 2. Frequency distribution of total (A) versus unique (B) Fanconi anemia (FA) gene mutations in the 117 Japanese FA patients. The frequency of the total FA gene mutation was based on subtyping of 117 FA cases, while frequency of unique FA gene mutations was derived from 84 genetic variants detected in the 117 FA patients.
AB
Table 3. Hematologic findings and outcome of 10 Japanese Fanconi anemia patients with VACTERL-H association.
Individual
Case 18-1
Case 30 Case 37 Case 60 Case 61 Case 64 Case 69
Case 73-1
Onset of BMF (months)
0
70 49 58 24 40 12
BM status at HSCT
RCMD
SAA RAEB1 SAA
Karyotype of BM
46,XY,add(2)(q33)
46,XX 46,XX, complex 46,XY
Age at HSCT (months)
13
153 192 72 51 61 62
88
45
13
Outcome after HSCT (months)
Alive (105)
Dead/Esophageal cancer (165)
Alive (66)
Alive (167)
Alive (160)
Alive (73)
Alive (144)/Tongue SCC
at 14 years old
Dead/Oral SCC (111)
Dead(2)
Alive (59)
RCMD 46,XY,add(5)(p15) SAA 46,XX RCMD 46,XY
48 SAA 46,XY
Case96 7 SAA 46,XY
Case 99-1 0 RCMD 46,XY,+del(3)(q12)
BM: bone marrow; BMF: bone marrow failure; FA: Fanconi anemia; HSCT: hematopoietic stem cell transplantation; RAEB: refractory anemia with excess of blasts; RCMD: refractory cytopenia with multilineage dysplasia; SAA: severe aplastic anemia; SCC: squamous cell carcinoma.
single nucleotide (guanine) insertion after exon 3 and skip- ping of exon 4, respectively (Figure 3). For Case 97, cells were not available and we could not verify the actual splicing defect caused by the c.3006+3A>G mutation. The patient’s mother had only the c.3346_3347 insT mutation, while the father’s genome was unavailable. The mutation at the +3 splice donor position was indicative of a poten- tial splice defect31 and we therefore considered that c.3006+3A>G would be a pathogenic mutation. This mutation was very rare and not reported as an SNV in the 3.5KJNv2 and ExAC database.
We also revisited available clinical data from 103 addi- tional FA patients, and identified seven more cases with VACTERL-H (Tables 2 and 3). These include three FA-A, one FA-C case, two FA-G cases, and one FA-P case. All these seven cases met with VACTERL-H criteria with only three features. Four of the seven cases showed the CRL
defect combination pattern. Compared with these cases, FA-B and FA-I cases with VACTERL-H association appeared to have higher number of malformations (from 5 to 7). We were unable to obtain detailed clinical infor- mation from the remaining nine patients. Thus, altogether there were ten VACTERL-H cases out of 108 cases with clinical data in our series, which seems slightly high com- pared to the previous report by Alter and Rosenberg (108 cases out of 2,245).28
Early-onset malignancies associated with the FANCD1 (BRCA2) or FANCN (PALB2) complementation group
We identified two FA-D1 patients and one FA-N patient in our series. To the best of our knowledge, no FA-N cases and only one FA-D1 case (AP37P in Table 4) have been previously reported from Japan.32,33 The two FA-D1 cases in our study had compound heterozygous mutations, of
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