De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome.
De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome.
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DOI：
10.1016/j.ymgmr.2018.06.001
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发表时间：
2018-09
影响因子：
1.9
通讯作者：
Gonzalez-Heydrich J
中科院分区：
文献类型：
--
作者：
Torres A;Brownstein CA;Tembulkar SK;Graber K;Genetti C;Kleiman RJ;Sweadner KJ;Mavros C;Liu KX;Smedemark-Margulies N;Maski K;Yang E;Agrawal PB;Shi J;Beggs AH;D'Angelo E;Lincoln SH;Carroll D;Dedeoglu F;Gahl WA;Biggs CM;Swoboda KJ;Berry GT;Gonzalez-Heydrich J
复杂的表型可能代表新的综合征，是几个遗传和环境因素的复合相互作用。我们描述了一个9岁的男性与高功能自闭症谱系障碍和Muckle-Wells综合征谁在5岁时表现出顽固，干扰他在家里和学校的功能。6岁后，他出现间歇性疲劳和嗜睡发作，持续数小时至数周，并在数月内演变为更慢性的嗜睡症。全外显子组测序显示可能与其临床表型相关的基因中有三个突变。该患者在ATP 1A 3基因中存在预测的致病性新发杂合p.Ala681Thr突变（chr 19：42480621 C>T，GRCh 37/hg 19）。已知该基因的突变会导致儿童交替性偏瘫、快速发作的肌张力障碍性帕金森综合征和CAPOS综合征，有时伴有自闭症特征。患者还具有NLRP 3基因中p.Arg490Lys/p.Val200Met突变的复合杂合性（分别为chr 1：247588214 G>A和chr 1：247587343 G>A）。NLRP 3突变以常染色体显性方式与临床重叠的自身炎性疾病（包括Muckle-Wells综合征）相关。p.Arg490Lys是一种已知的致病突变，遗传自患者的父亲。p.Val200Met突变，从他的母亲遗传，是一个未知意义的变体（VUS）。新的ATP 1A 3突变是否导致或在患者的疲劳和嗜睡发作中起作用仍有待确定。两个NLRP 3突变的前所未有的组合可能是他复杂表型的其他方面的原因。
Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5 years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient's father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient's episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype.
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影响因子：
4.8
作者：
Rodacker, Vivien;Toustrup-Jensen, Mads;Vilsen, Bente
通讯作者：
Vilsen, Bente
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影响因子：
3.9
作者：
Gotham, Katherine;Risi, Susan;Lord, Catherine
通讯作者：
Lord, Catherine
影响因子：
3.9
作者：
Hus, Vanessa;Lord, Catherine
通讯作者：
Lord, Catherine
影响因子：
--
作者：
Aróstegui, JI;Aldea, A;Yagüe, J
通讯作者：
Yagüe, J
影响因子：
30.8
作者：
Heinzen, Erin L.;Swoboda, Kathryn J.;Hitomi, Yuki;Gurrieri, Fiorella;Nicole, Sophie;de Vries, Boukje;Tiziano, F. Danilo;Fontaine, Bertrand;Walley, Nicole M.;Heavin, Sinead;Panagiotakaki, Eleni;Fiori, Stefania;Abiusi, Emanuela;Di Pietro, Lorena;Sweney, Matthew T.;Newcomb, Tara M.;Viollet, Louis;Huff, Chad;Jorde, Lynn B.;Reyna, Sandra P.;Murphy, Kelley J.;Shianna, Kevin V.;Gumbs, Curtis E.;Little, Latasha;Silver, Kenneth;Ptacek, Louis J.;Haan, Joost;Ferrari, Michel D.;Bye, Ann M.;Herkes, Geoffrey K.;Whitelaw, Charlotte M.;Webb, David;Lynch, Bryan J.;Uldall, Peter;King, Mary D.;Scheffer, Ingrid E.;Neri, Giovanni;Arzimanoglou, Alexis;van den Maagdenberg, Arn M. J. M.;Sisodiya, Sanjay M.;Mikati, Mohamad A.;Goldstein, David B.
通讯作者：
Goldstein, David B.