In trans early mosaic mutational escape and novel phenotypic features of germline SAMD9 mutation.
In trans early mosaic mutational escape and novel phenotypic features of germline SAMD9 mutation.
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反式早期嵌合突变逃逸和种系 SAMD9 突变的新表型特征。
DOI：
10.1111/bjh.16322
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发表时间：
2020
影响因子：
6.5
通讯作者：
Hockings C
中科院分区：
文献类型：
--
作者：
Hockings C
SAMD 9或SAMD 9 L的突变分别见于具有骨髓增生异常综合征（MDS）和急性髓性白血病（AML）家族易感性的患者中，这些患者分别与骨髓增生异常综合征（骨髓增生异常、感染、生长受限、肾上腺发育不全、生殖器表型和肠病）和ATXPC（共济失调-全血细胞减少综合征）相关（1-3）。SAMD 9和SAMD 9 L在造血细胞系中的野生型（WT）功能是抗增殖的。生殖系突变被认为是加重WT基因抗增殖作用的功能获得性（GOF）突变（4-6）。在受影响的个体中，已经描述了通过杂合性（-7或7 q-）或单亲二体性（UPD）的丢失或通过获得功能丢失（LOF）突变的功能性体细胞回复。到目前为止，LOF突变已经被描述为SAMD 9的顺式，但很少被描述为SAMD 9 L的反式（7，8）。在这里，我们提出了一个四代受AML和MDS与新的疾病特点和一个反式逆转突变符合生殖系嵌合体。先证者（III-1）在1986年提出的10岁的历史，过度瘀伤。她是四个兄弟姐妹中的一个，其中两个是死胎。还注意到她具有广泛的MDS和AML家族史，具体而言，她的母亲（II-1）患有MDS，阿姨（II-4）在MDS后11岁死于AML，堂兄（III-5）在8岁死于AML，母亲的堂兄（II-8）死于白血病（图1A）。她就诊时的血液学参数正常，但血小板功能检查异常。1998年（22岁），她发展为三系血细胞减少症。此时骨髓穿刺（BMA）显示MDS，5/30个中期分裂相中有7个q-（46，XX，del（7）（q22 q33）[5]/46，XX [25]）。在她20年的随访中发现了其他多系统异常; 2002年（26岁）对尿路感染、子宫腺肌病和髂股DVT进行的成像显示了重复左肾和输尿管、中间部位，包括右侧胃和脾、多个小脾、胰腺倒置、中线肝、横结肠错位和静脉引流解剖结构异常。
Mutations in SAMD9 or SAMD9L are found in patients with familial predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) associated with MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, and Enteropathy) and ATXPC (ataxia-pancytopenia syndrome)(1-3) respectively. The wild-type (WT) function of SAMD9 and SAMD9L in haematopoietic cell lines is antiproliferative. Germline mutations are thought to be gain-of-function (GOF) mutations exacerbating the antiproliferative effects of the WT gene (4-6). Functional somatic reversion has been described in affected individuals through loss of heterozygosity (-7 or 7q-) or uniparental disomy (UPD), or through acquisition of loss of function (LOF) mutations. Thus far LOF mutations have been described in cis for SAMD9, but rarely in trans for SAMD9L (7, 8). Here we present a four-generation pedigree affected by AML and MDS with novel disease features and a reversion mutation in trans consistent with germline mosaicism.The proband (III-1) presented in 1986 aged 10 with a history of excessive bruising. She was one of 4 siblings, 2 of which were stillborn. She was also noted to have an extensive family history of MDS and AML, specifically, her mother (II-1) had MDS, aunt (II-4) died of AML age 11 following MDS, cousin (III-5) died of AML age 8 and mother’s cousin (II-8) died of leukaemia (Figure 1A). Her haematological parameters at presentation were normal, however she had abnormal platelet function tests. In 1998 (age 22) she developed tri-lineage cytopenias. Bone marrow aspirate (BMA) at this time showed MDS with 7q-in 5/30 metaphases (46, XX, del (7)(q22q33)[5]/46, XX [25]). Additional multisystem abnormalities were identified over her 20 year follow-up; imaging undertaken for urinary tract infections, adenomyosis and an iliofemoral DVT in 2002 (age 26) revealed duplex left kidney and ureters, intermediate situs, including right sided stomach and spleen, multiple small splenenculi, reversed pancreas, midline liver, mispositioned transverse colon and abnormal anatomy of venous drainage.