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M. Mori et al.
continued from previous page
- -3.9 0.52 GA
+ -2.3 0.91 AA
Case 96
FANCI
c.158-2A>G:p.S54FfsX5
c.288G>A:p.C56FfsX8
c.343delA:
p.S115AfsX11
c.343delA:
p.S115AfsX11
A: Anal atresia
C: VSD/PDA
R: Right renal agenesis/ Left renal hypoplasia L: Bilateral absent thumb/ Bilateral absent radius H: Hydrocephalus
C: ASD/VSD/PS
R: horseshoe kidney
L: Bilateral floating thumbs/ bilateral radial hypoplasia
Skin pigmentation Microphthalmus Hypogenitalia Short stature (-8SD)
Intestinal malrotation
Duodenal stenosis Short stature (-5.8SD)
Case 99-1 FANCP
*Case 18-1, 73-1, and 99-1 had a sibling with Fanconi anemia (FA). ** Duodenal atresia is considered to be a part of the VACTERL association by some reports.27 ***ALDH2 wild type and the inactivating mutation (p.Glu504Lys) allele is referred to as G and A, respectively. ALDH2: aldehyde dehydrogenase-2; ASD: atrial septal defect; BM: bone marrow; DEB: diepoxybutane; PDA: patent ductus arteriosus; PS: pulmonary stenosis; SD: Standard Deviation;VACTERL-H: vertebral anomalies, anal atresia, cardiac anomalies, tracheal- esophageal fistula, esophageal atresia, renal structural abnormalities, limb anomalies, and hypocephalus;VSD: ventricular septal defect.
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Characteristics of Japanese FANCG pathogenic variants
In 29 FA-G patients (from 27 unrelated families), 57 mutant alleles were identified, and seven different FANCG variants were detected (Online Supplementary Table S4 and Online Supplementary Figure S3B). There were fewer unique mutation variants in FA-G compared with FA-A (Figure 2B). Three of the seven FANCG variants were novel. Of the three novel variants, two (c.907_908del and c.1386delC) were clearly pathogenic, whereas one muta- tion in intron 12 (c.1637-15G>A) was of uncertain signifi- cance. As previously reported, c.307+1G>C and 1066C>T accounted for most of the FANCG mutant alleles (49 of 57; 86%) in the Japanese FA-G patients.25,26 Thirteen of the 29 FA-G patients were homozygous for c.307+1G>C, and eight were compound heterozygous with one c.307+G>C allele. Five of the eight remaining FA-G patients had homozygous c.1066C>T mutations. Four cases were com- pound heterozygous for the c.307+G>C and c.1066C>T mutations. In the 3.5KJPNv2 data, FANCG c.307+1G>C and c.1066C>T mutation variants were present with fre- quencies of 0.1% and 0.04%, respectively (Table 1). These mutations were similarly detected in Korean FA-G patients24 but hardly ever observed in the other ethnic populations according to the ExAC database.
VACTERL-H phenotype caused by FANCB, FANCI, and other Fanconi anemia gene variants
We identified FANCB mutations in four affected males. The FANCB gene maps to the X-chromosome. Two of the four FA-B patients had a complete loss of the FANCB gene, as detected by aCGH (Figure 1B). In the remaining two patients, one harbored a nonsense mutation (c.516G>A/p.W172X) and one had a synonymous muta- tion (c.1497G>T/p.L499L) resulting in exon 7 skipping (Figure 1D and Online Supplementary Figure S4A). All four mutations were unique. The two FA-B cases with com- plete loss of FANCB displayed severe somatic abnormali- ties, consistent with VACTERL-H association (Table 2).
The VACTERL-H association is defined as having three or more of the following defects: vertebral anomalies, anal atresia, cardiac anomalies, tracheal-esophageal fistula, esophageal atresia, renal structural abnormalities, limb anomalies, and hydrocephalus.27 This set of anomalies has been reported in rare cases of FA, and is particularly asso- ciated with FA-B, I, J, N, or O cases.28 The most frequent combination patterns in these patients with VACTERL-H association were cardiac-renal-limb anomalies (CRL), anal-renal-limb anomalies (ARL), and vertebral-renal-limb anomalies (VRL), which accounted for more than half of the patients. Cases 60 and 61 had five and seven features of the VACTERL-H anomalies, respectively.
Compared with these two FA-B cases, Case 62 with C- terminally truncated FANCB protein showed a less severe phenotype and experienced later onset of bone marrow failure (Online Supplementary Figure S4A). A recent bio- chemical study revealed that FANCB together with FAAP100 and FANCL are the central subcomplex compo- nents of the FA core complex, which is essential for ID2 complex monoubiquitination, a key activation event in the FA pathway. The FANCB:FAAP100 subunits form a scaffold that drives dimer formation of FANCL,29 which is the E3 ligase component in the FA core complex. The trun- cated FANCB protein in Case 62 might, to some extent, maintain the ability to interact with FAAP100 or FANCL protein.30 We were unable to obtain clinical information from another FA-B patient (Case 63).
Two FA-I cases were identified, and both had com- pound heterozygous mutations (Online Supplementary Figure S4B). Case 96, with N-terminal premature termina- tion codons, had the five features of the VACTERL-H anomalies and died within two months after hematopoi- etic stem cell transplantation (HSCT) (Tables 2 and 3). On the other hand, Case 97, with C-terminal mutations, had only two features of the VACTERL-H and survived for more than 17 years after HSCT. In Case 96, a c.158-2A>G mutation in intron 3 and a c.288G>A mutation in the last codon of exon 4 caused splicing defects that resulted in a
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haematologica | 2019; 104(10)