First report of inherited protein S deficiency caused by paternal &lt;I&gt;PROS1&lt;/I&gt; mosaicism

Nagaya, Satomi; Maruyama, Keiko; Watanabe, Atsushi; Meguro‐Horike, Makiko; Imai, Yasuhito; Hiroshima, Yukihiko; Horike, Shin‐ichi; Kokame, Koichi; Morishita, Eriko

doi:10.3324/haematol.2021.278527

Cited by 3 publications

(1 citation statement)

References 16 publications

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“…With recent advances in genetic analysis technology, some genetic variants originally thought to be de novo mutations have been shown to be caused by parental somatic or gonadal mosaic mutations (6)(7)(8). Recent studies revealing parental mosaicism emphasize the importance of using more sensitive analysis techniques, such as digital polymerase chain reaction (dPCR), pyrosequencing, high-resolution melting analysis, and nextgeneration sequencing (NGS), rather than conventional direct sequencing (i.e., Sanger sequencing).…”

Section: Introductionmentioning

confidence: 99%

Low-frequency maternal novel MYH7 mosaicism mutation in recurrent fetal-onset severe left ventricular noncompaction: a case report

et al. 2023

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BackgroundLeft ventricular noncompaction (LVNC) is a rare inherited cardiomyopathy with a broad phenotypic spectrum. The genotype-phenotype correlations in fetal-onset LVNC have not yet been fully elucidated. In this report, we present the first case of severe fetal-onset LVNC caused by maternal low-frequency somatic mosaicism of the novel myosin heavy chain 7 (MYH7) mutation.Case presentationA 35-year-old pregnant Japanese woman, gravida 4, para 2, with no significant medical or family history of genetic disorders, presented to our hospital. In her previous pregnancy at 33 years of age, she delivered a male neonate at 30 weeks of gestation with cardiogenic hydrops fetalis. Fetal echocardiography confirmed LVNC prenatally. The neonate died shortly after birth. In the current pregnancy, she again delivered a male neonate with cardiogenic hydrops fetalis caused by LVNC at 32 weeks of gestation. The neonate died shortly after birth. Genetic screening of cardiac disorder-related genes by next-generation sequencing (NGS) was performed which revealed a novel heterozygous missense MYH7 variant, NM_000257.3: c.2729A > T, p.Lys910Ile. After targeted and deep sequencing by NGS, the same MYH7 variant (NM_000257.3: c.2729A > T, p.Lys910Ile) was detected in 6% of the variant allele fraction in the maternal sequence but not in the paternal sequence. The MYH7 variant was not detected by conventional direct sequencing (Sanger sequencing) in either parent.ConclusionsThis case demonstrates that maternal low-frequency somatic mosaicism of an MYH7 mutation can cause fetal-onset severe LVNC in the offspring. To differentiate hereditary MYH7 mutations from de novo MYH7 mutations, parental targeted and deep sequencing by NGS should be considered in addition to Sanger sequencing.

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Section: Introductionmentioning

confidence: 99%

Low-frequency maternal novel MYH7 mosaicism mutation in recurrent fetal-onset severe left ventricular noncompaction: a case report

et al. 2023

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Identification of two de novo variants causing inherited antithrombin deficiency by quantitative analysis of variant alleles

Togashi,

Nagaya,

Meguro-Horike

et al. 2024

Thrombosis Research

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Pathophysiological analysis of hereditary thrombophilia—Bedside to Bench—

MORISHITA

2023

Nihon Kessen Shiketsu Gakkaishi

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Pathophysiological analysis of hereditary thrombophilia-Bedside to Bench-Eriko MORISHITA 要約：血液凝固・制御機構は血管内での血液流動性を維持するために，巧妙なバランスのもとに機能している．しかし，そのバランスに異常が生じて過凝固状態となると血栓性疾患を引き起こし，止血機構に異常が生じると出血性疾患を引き起こす．筆者は臨床現場において様々な血液凝固異常症の患者に遭遇し，その臨床症状ならびに生化学的，分子生物学的解析を詳細に行うことにより，血栓形成の分子機構の解明に極めて有用な情報を提供してきた．遺伝性プロトロンビン(PT)異常症発端者(PT Himi)は，PT 活性が 10％であったが，無症候であった．PT p.Met380Thr および PT p.Arg431His の 2 種類のバリアントを有し，活性化されると 2 種類の異常トロンビン(Himi I, II)が生成される．分子病態解析にて，Himi I は凝固活性が低下していたが軽度のアンチトロンビン抵抗性を示し，Himi II は軽度の凝固活性低下とトロンボモジュリンとの結合不全を示した．結果として，止血・凝固阻止のリバランスにより無症候性となる可能性が推測された．また，30 歳代より頻回に静脈血栓症を反復する兄弟を解析したところ，新たな活性化プロテイン C(APC)抵抗性を示す Factor V 異常症 (FV p.Tyr1989Cys)を発見した．分子病態解析にて FV p.Tyr1989Cys は FV Nara(FV p.Trp1920Arg)と類似しており，さらにリン脂質結合能の低下をもたらす可能性が推測された．筆者らが経験した世界初の先天性ヘムオキシゲナーゼ-1(HO-1)欠損症患児は，広範な生体防御機構の機能異常と著明な血栓形成による多臓器不全を認めた．そこで筆者らは，①患者末梢血単球より作成した Epstein-Barr ウイルス形質変換 B 細胞(LCL)に細胞傷害性ストレスを加え，組織因子(TF)ならびに PAI-1 が著増すること，さらに欠損患者由来 LCL に HO-1 遺伝子を導入するとその増加が抑制されること，②ヘムの分解産物である CO は細胞傷害性ストレス刺激に対して単球や血管内皮細胞上で TF や PAI-1 発現を抑制，TM 発現を増加させ，それは MAP キナーゼ系を介することなどを示し，HO-1 の新たな機能として抗血栓性作用を提唱した．さらに，日本骨髄バンクの協力を得て非血縁者造血幹細胞移植(stem cell transplantation: SCT)症例(血液悪性腫瘍移植患者とドナー約 600 組)を対象として，HO-1 の遺伝子一塩基多型(single nucleotide polymorphism: SNP)と SCT 後転帰の関連性を解析し，ドナー HO-1 SNP rs2071746 の genotyping はドナー選択と移植戦略のテーラーメイド化に有用である可能性を示した．以上のような特殊な凝固異常症に加えて，これまでに AT・PC・PS 欠乏症疑い約 500 例の遺伝子解析を行い，さらに遺伝子組換え変異蛋白質を作成して機能解析を行うことにより，表現型と遺伝子型の関連を明らかにしてきた．このような研究成果が，最終的には治療法の開発へとつながっていくことを期待したい．

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First report of inherited protein S deficiency caused by paternal <I>PROS1</I> mosaicism

Abstract: Not available.

Cited by 3 publications

References 16 publications

Low-frequency maternal novel MYH7 mosaicism mutation in recurrent fetal-onset severe left ventricular noncompaction: a case report

Low-frequency maternal novel MYH7 mosaicism mutation in recurrent fetal-onset severe left ventricular noncompaction: a case report

Identification of two de novo variants causing inherited antithrombin deficiency by quantitative analysis of variant alleles

Pathophysiological analysis of hereditary thrombophilia—Bedside to Bench—

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