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Letters to the Editor
carry the variant allele, but the semen could not be col- lected and analyzed due to lack of consent. For a defini- tive diagnosis of gonadal mosaicism, it is necessary to prove the presence of mosaicism in the father's semen, but in this case, since the two children are heterozygous for the same variant, it is probable that the father has somatogonadal mosaicism.13
In recent years, some cases of various diseases that were originally considered to be caused by de novo vari- ants have actually been attributed to parental somatic or gonadal mosaicism.13-15 Since the sensitivity of variation detection in Sanger sequencing, considered the standard for evaluating PROS1 variants, is limited to approximate- ly 15-20%,8,9 heterozygous variants can be detected but mosaicisms are likely to be undetectable. Thus, another more sensitive method, such as dPCR or pyrosequencing, is needed for the genetic evaluation of parental mosaicism. In this study, we detected a mosaic variant in the father of two heterozygous sisters with PS deficiency. This is the first case of parental mosaicism in an inherited PS-deficient family, suggesting that parental mosaicism may exist among some patients who have been thought to have de novo variants of inherited thrombophilia. It has been reported that approximately 20% of sporadic cases of hemophilia A, as determined by traditional Sanger sequencing methods, have an asymptomatic mosaic
*SN and KM contributed equally as co-first authors. Correspondence:
ERIKO MORISHITA - eriko86@staff.kanazawa-u.ac.jp doi:10.3324/haematol.2021.278527
Received: June 23, 2021.
Accepted: October 1, 2021.
Pre-published: October 14, 2021. Disclosures: no conflicts of interest to disclose.
Contributions: SN: investigation, visualization and writing, original draft; KM: investigation, visualization and writing, original draft;
SN and KM are co-first authors. AW: methodology and supervision; MH: investigation; YI: investigation; YH: resources; SH: methodology, investigation, formal analysis; KK: investigation, formal analysis, funding acquisition, supervision; EM: conceptualization, funding acquisition, supervision, writing-review and editing.
Funding: this work was partially supported by Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan to EM (grant number 20FC0201) and KK (grant number 20FC1024).
References
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mother.15 The percentage of parental mosaicism present 766.
in sporadic cases of inherited PS deficiency needs to be determined by accumulating more cases in the future.
In conclusion, in cases of autosomal-dominant inherit- ed thrombophilia, when the causative variant is detected only in the proband and a de novo variant is suspected, it is necessary to investigate the presence of parental mosaicism. For this purpose, it is very informative to quantify the variant allele ratio using multiple readily accessible specimens, such as blood, saliva, hair follicles, and urine to confirm the parental mosaicism. Furthermore, semen analysis should be performed as genetic screening for germline mosaicism in fathers of patients with de novo variants, and this analysis could be useful for prenatal counseling. In sporadic cases of inher- ited diseases, even if neither parent has the same variant using traditional sequencing methods, confirming the mosaicism of the parents is very important regarding the recurrence risk for the patient’s siblings and is essential information for genetic counseling.
Satomi Nagaya,1,* Keiko Maruyama,2,* Atsushi Watanabe,3 Makiko Meguro-Horike,4 Yuta Imai,1 Yuki Hiroshima,5 Shin-Ichi Horike,4 Koichi Kokame2 and Eriko Morishita1,6
1Department of Clinical Laboratory Science, Division of Health
Sciences, Graduate School of Medical Science, Kanazawa University,
Kanazawa, Ishikawa; 2Department of Molecular Pathogenesis,
National Cerebral and Cardiovascular Center, Suita, Osaka;
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11. Carvalho TM, Dourado RM, Nakatani SM, et al. Digital PCR detec- tion of EGFR somatic mutations in non-small-cell lung cancer forma- lin fixed paraffin embedded samples. Mol Cell Probes. 2021;58:101745.
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13. Yamamoto K, Kubota T, Takeyari S, et al. Parental somatogonadal COL2A1 mosaicism contributes to intrafamilial recurrence in a fam- ily with type 2 collagenopathy. Am J Med Genet A. 2020;182(3):454-
3Division of Clinical Genetics, Kanazawa University Hospital,
4 460.
Kanazawa, Ishikawa; Advanced Science Research Center, Kanazawa University, Kanazawa, Ishikawa; 5Department of Hematology, Nagano Red Cross Hospital, Nagano, Nagano
and 6Department of Hematology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
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