Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing.
Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing.
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通过外显子组和全基因组测序鉴定儿科急性发作神经精神综合征（PANS）的超罕见遗传变异
DOI：
10.1038/s41598-022-15279-3
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发表时间：
2022-06-30
影响因子：
4.6
通讯作者：
van der Spek, Peter J.
中科院分区：
文献类型：
--
作者：
Trifiletti, Rosario;Lachman, Herbert M.;Manusama, Olivia;Zheng, Deyou;Spalice, Alberto;Chiurazzi, Pietro;Schornagel, Allan;Serban, Andreea M.;van Wijck, Rogier;Cunningham, Janet L.;Swagemakers, Sigrid;van der Spek, Peter J.
在儿童急性发作性神经精神综合征（PANS）中描述了突然发作的严重神经精神症状，包括强迫症、抽搐、焦虑、情绪波动、易怒和限制进食。症状发作通常与感染暂时相关，提示潜在的自身免疫/自身炎性病因，尽管通常缺乏直接证据。病理机制可能是异质性的，但我们假设一个或多个生物学途径的收敛。因此，我们对386例美国患者进行了全外显子组测序（WES），对10例来自欧盟的重度PANS患者进行了全基因组测序（WGS）。我们专注于识别从头或超罕见（MAF）< 0.001的潜在有害遗传变异。在21例病例中，在11个基因（PPM 1D、SGCE、PLCG 2、NLRC 4、CACNA 1B、SHANK 3、CHK 2、GRIN 2A、RAG 1、GABRG 2和SYNGAP 1）中发现了候选突变，其中包括两个或多个不相关的受试者，其中四个基因中存在超罕见变异。这些基因汇聚成两大功能类别。一种调节外周免疫应答和小胶质细胞（PPM 1D、CHK 2、NLRC 4、RAG 1、PLCG 2）。另一种主要在神经元突触中表达（SHANK 3、SYNGAP 1、GRIN 2A、GABRG 2、CACNA 1B、SGCE）。在自闭症谱系障碍和肌阵挛-肌张力障碍中也描述了这些神经元基因的突变。事实上，12/21例病例在既存神经发育障碍的基础上发生PANS。这两类基因在肠神经系统和脉络丛中也高度表达。因此，PANS候选基因的遗传变异可能通过破坏外周和中枢免疫功能、神经传递和/或感染等应激源后的血-CSF/脑屏障发挥作用。
Abrupt onset of severe neuropsychiatric symptoms including obsessive–compulsive disorder, tics, anxiety, mood swings, irritability, and restricted eating is described in children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Symptom onset is often temporally associated with infections, suggesting an underlying autoimmune/autoinflammatory etiology, although direct evidence is often lacking. The pathological mechanisms are likely heterogeneous, but we hypothesize convergence on one or more biological pathways. Consequently, we conducted whole exome sequencing (WES) on a U.S. cohort of 386 cases, and whole genome sequencing (WGS) on ten cases from the European Union who were selected because of severe PANS. We focused on identifying potentially deleterious genetic variants that were de novo or ultra-rare (MAF) < 0.001. Candidate mutations were found in 11 genes (PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1) in 21 cases, which included two or more unrelated subjects with ultra-rare variants in four genes. These genes converge into two broad functional categories. One regulates peripheral immune responses and microglia (PPM1D, CHK2, NLRC4, RAG1, PLCG2). The other is expressed primarily at neuronal synapses (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). Mutations in these neuronal genes are also described in autism spectrum disorder and myoclonus-dystonia. In fact, 12/21 cases developed PANS superimposed on a preexisting neurodevelopmental disorder. Genes in both categories are also highly expressed in the enteric nervous system and the choroid plexus. Thus, genetic variation in PANS candidate genes may function by disrupting peripheral and central immune functions, neurotransmission, and/or the blood-CSF/brain barriers following stressors such as infection.
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影响因子：
30.5
作者：
Alves de Lima K;Rustenhoven J;Da Mesquita S;Wall M;Salvador AF;Smirnov I;Martelossi Cebinelli G;Mamuladze T;Baker W;Papadopoulos Z;Lopes MB;Cao WS;Xie XS;Herz J;Kipnis J
通讯作者：
Kipnis J
影响因子：
3.8
作者：
Dixon, Grant A.;Perez, Carlos A.
通讯作者：
Perez, Carlos A.
影响因子：
4.3
作者：
Davari，Kathrin;Frankenberger，Samantha;Jungnickel，Berit
通讯作者：
Jungnickel，Berit
影响因子：
9.3
作者：
DePaula-Silva, Ana Beatriz;Gorbea, Carlos;Fujinami, Robert S.
通讯作者：
Fujinami, Robert S.
影响因子：
3.3
作者：
Delgado-Alvarado, Manuel;Matilla-Duenas, Antoni;Riancho, Javier
通讯作者：
Riancho, Javier