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M. Mori et al.
cases were referred to us in order to carry out HSCT, our data could be biased toward a proportion of patients with more severe malformations and may not reflect all indi- viduals carrying FA gene variants. The relatively high inci- dence of VACTERL-H anomalies in our series could reflect this46 and/or this may be due to the impact of the ALDH2 genotype.
An important issue is how prevalent the FA-causing vari- ants in the Japanese population are. We estimate that at least approximately 2.6% of the Japanese population might carry pathogenic variants in FA genes, using the 3.5KJPNv2 database. In Japan, approximately ten individuals with FA are born per one million births each year according to the report from the Japanese Society of Pediatric Hematology/Oncology.49 FA-G accounted for 25% of Japanese FA patients according to our study and approxi- mately two FA-G patients are estimated to be born each year in Japan. Our estimated allele frequency for FANCG (0.16%) from the 3.5KJPNv2 database is a reasonable one given the birth rate of the FA-G patients. Rogers et al. report- ed that at least one FA disease-causing variant among 16 FA genes (nonsense, splice altering, frame shifts, and a subset of missense variants that are judged to be highly deleteri- ous) was identified in 4.3% of individuals from the ESP and
1KGP studies.50 This estimate was substantially higher than ours, but our numbers may increase if we include deleteri- ous missense mutation data in the future.
In conclusion, the molecular diagnostic strategy and data described in this study provide a basis for future molecular work-ups and clinical management for Japanese FA patients. In four cases, we failed to achieve a definitive subtyping; this could be due to technical problems or due to novel FA genes awaiting discovery. These remain as “unclassified”, and could be of particular interest in further attempts to elucidate FA etiology.
Acknowledgments
The authors would like to thank patients and families for par- ticipating in the study, Dr. James Hejna (Kyoto University) for critical reading of the manuscript, and Akiko Watanabe and Fan Peng for technical and secretarial help.
Funding
This work was supported by JSPS KAKENHI Grant Number JP15H01738 [to MT], grants from the Ministry of Health, Labor, and Welfare [to SK and to EI], and grants from Uehara Memorial Foundation [to MT], and Astellas Foundation for Research on Metabolic Disorders [to MT].
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