血液中可检测到的嵌合变异扩展了与下丘脑错构瘤相关的临床遗传学谱。
Mosaic variants detectable in blood extend the clinicogenetic spectrum of -related hypothalamic hamartoma.
作者信息
Green Timothy E, Bennett Mark F, Immisch Ilka, Freeman Jeremy L, Klein Karl Martin, Kerrigan John F, Vadlamudi Lata, Heinzen Erin L, Scheffer Ingrid E, Harvey A Simon, Rosenow Felix, Hildebrand Michael S, Berkovic Samuel F
机构信息
Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia.
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
出版信息
Genet Med Open. 2023 Apr 20;1(1):100810. doi: 10.1016/j.gimo.2023.100810. eCollection 2023.
PURPOSE
Hypothalamic hamartoma (HH) can be syndromic (eg, Pallister-Hall syndrome [PHS], HH, and mesoaxial polydactyly) or nonsyndromic. Most PHS cases have germline variants in , but a minority remain unresolved. Some nonsyndromic HH cases have mosaic variants in the brain. PHS and nonsyndromic HH are regarded as 2 separate -related disorders, clinically and genetically. Here, we searched for mosaic variants in unsolved cases.
METHODS
High-depth exome sequencing was performed on leukocyte-derived DNA in 1 unsolved PHS and 25 nonsyndromic HH cases. We searched for mosaic variants in and other HH-associated genes. Mosaic variants were confirmed by droplet-digital polymerase chain reaction.
RESULTS
The PHS case had a stop-gain variant c.2845G>T; p.(Glu949Ter) at 6.9% variant allele fraction (VAF). Two nonsyndromic cases had variants-a stop-gain (c.2639C>A; p.(Ser880Ter), VAF 3.7%) and a frameshift (c.3326_3330del; p.(Glu1109AlafsTer18), VAF 7.8%). The nonsyndromic patient with 3.7% VAF in blood had 35.8% VAF in HH tissue. He had a vestigial extra digit removed adjacent to his left fifth finger.
CONCLUSION
mosaicism is associated with a phenotypic spectrum from PHS to HH with subtle extra PHS features, to isolated nonsyndromic HH. High-depth sequencing permits detection of low-level mosaicism, which is an important cause of both syndromic and nonsyndromic HH.
目的
下丘脑错构瘤（HH）可伴有综合征（如帕利斯特-霍尔综合征[PHS]、HH和中轴多指畸形）或不伴有综合征。大多数PHS病例存在种系变异，但少数病例仍未得到解决。一些非综合征性HH病例在大脑中存在镶嵌变异。PHS和非综合征性HH在临床和遗传学上被视为两种独立的相关疾病。在此，我们在未解决的病例中寻找镶嵌变异。
方法
对1例未解决的PHS病例和25例非综合征性HH病例的白细胞衍生DNA进行了高深度外显子组测序。我们在[具体基因]和其他HH相关基因中寻找镶嵌变异。通过液滴数字聚合酶链反应确认镶嵌变异。
结果
PHS病例有一个c.2845G>T的终止密码子获得变异；p.(Glu949Ter)，变异等位基因分数（VAF）为6.9%。两例非综合征性病例有[具体基因]变异——一个终止密码子获得变异（c.2639C>A；p.(Ser880Ter)，VAF 3.7%）和一个移码变异（c.3326_3330del；p.(Glu1109AlafsTer18)，VAF 7.8%）。血液中VAF为3.7%的非综合征性患者在HH组织中的VAF为35.8%。他切除了左手第五指旁边残留的多余手指。
结论
[具体基因]镶嵌现象与从PHS到HH的一系列表型相关，伴有细微的额外PHS特征，再到孤立的非综合征性HH。高深度测序能够检测到低水平的镶嵌现象，这是综合征性和非综合征性HH的一个重要原因。
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