Page 338 - 2022_01-Haematologica-web

Letters to the Editor
First report of inherited protein S deficiency caused by paternal PROS1 mosaicism
Inherited protein S (PS) deficiency is a thrombophilic disorder with an autosomal dominant mode of inheri- tance.1 In plasma, 60% of PS exists in a complex with C4b binding protein and the remaining 40% in free form; only free PS functions as a cofactor for the activated pro- tein C. Inherited PS deficiency is classified into types I, II, and III according to the level of PS activity or free and total PS antigen.2 Types I and III have different pheno- types but they are considered to be caused by the same genetic abnormality. According to the Human Gene Mutation Database Pro (https://my. qiagendigitalinsights. com/bbp/view/hgmd/pro/all/php), 453 variants localized in the protein S gene (PROS1 gene) have been reported worldwide as of January 2021. Among these, missense/nonsense variants account for 61% (277 vari- ants). However, genetic variants have been reported as undetectable in approximately half of the families with PS deficiency.3 Based on the Suita study, which examined the prevalence of PS deficiency in the Japanese general population, the prevalence is 1.12%;4 about 5-10 times higher than that in Europe and America (0.16–0.21%).5 PS deficiency is the most common inherited throm- bophilia in Japan.6,7 In this study, we identified a novel PROS1 variant and paternal mosaicism in a family with inherited PS deficiency in which both parents are asymp- tomatic. This is the first report of inherited thrombophilia due to parental mosaicism and highlights the importance
of including information about potential mosaicism in genetic counseling.
The proband was a 34-year-old Japanese woman who was hospitalized with histiocytic necrotizing lym- phadenitis. On admission to the hospital, total PS antigen (NSauto total protein S; NASCA Co., Ltd., Yokohama, Japan), free PS antigen (NSauto free protein S; NASCA Co., Ltd.), and PS activity levels (HemosIL PS-clot; I.L.Japan Co.,Ltd., Tokyo, Japan) were 55%, 25%, and <10%, respectively (Figure 1A). In the proband, acute inflammation caused by histiocytic necrotizing lym- phadenitis may have increased vascular permeability, resulting in a decrease in free PS and a significant decrease in PS activity. The D-dimer concentration was significantly increased to 25.3 mg/mL (reference range, <1 mg/mL), but contrast-enhanced computed tomogra- phy showed no obvious thrombosis. In addition, the proband’s sister had already been diagnosed with PS defi- ciency after developing deep vein thrombosis in her leg at 25 years old and is on warfarin therapy (Figure 1A). Based on the above, the proband was diagnosed with type I PS deficiency. Both parents have normal levels of PS activity and antigen (Figure 1A), and the father had suffered a stroke at 62 years old and was taking edoxaban but the mother had no history of thrombosis.
This study was approved by the Ethics Committee for Human Genome and Gene Analysis Research at Kanazawa University (approval no. 450-5) and by the National Cerebral and Cardiovascular Center (approval no. M14-026). After obtaining informed consent from the proband and her family members, genomic DNA was
A
B
Figure 1. Protein S antigen and activity levels of a protein S-deficient family and the results of Sanger sequencing. (A) Levels of total protein S (PS) antigen, free PS antigen, and PS activity in PS-deficient family members. The type of PS deficiency of the proband and sister were shown. (B) Pedigree and sequencing results. Arrow indicates the proband, and filled symbols indicate affected patients. The proband and her sister were heterozygous for c.246T>G (p.Tyr82*) whereas the parents seemed to have no causative variants. Data from the father showed a very small peak of G (black) with a normal peak of T (red). Abbreviations: RR: reference range; NA: not applicable; *, warfarin therapy.
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haematologica | 2022; 107(1)