Fjaer Roar, Brodtkorb Eylert, Øye Ane-Marte, Sheng Ying, Vigeland Magnus Dehli, Kvistad Kjell Arne, Backe Paul Hoff, Selmer Kaja Kristine
Department of Medical Genetics, Oslo University Hospital and University of Oslo, Kirkeveien 166, Bygg 25, Avdeling for Medisinsk Genetikk, Postboks 4956 Nydalen 0424 Oslo, Norway.
Department of Neurology and Clinical Neurophysiology, St. Olav's University Hospital, Trondheim, Norway; Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
Eur J Med Genet. 2015 Nov;58(11):624-8. doi: 10.1016/j.ejmg.2015.10.005. Epub 2015 Oct 19.
The genetic understanding of primary familial brain calcification (PFBC) has increased considerably in recent years due to the finding of causal genes like SLC20A2, PDGFRB and PDGFB. The phenotype of PFBC is complex and has as of yet been poorly delineated. The most common clinical presentations include movement disorders, cognitive symptoms and psychiatric conditions. We report a family including two sisters with brain calcifications due to a variant in SLC20A2 and generalized tonic-clonic seizures as the principal phenotypic trait.
The affected siblings underwent whole exome sequencing and candidate variants and cosegregation in the family were validated by Sanger sequencing.
Both siblings and their asymptomatic father were heterozygous for a variant in SLC20A2. The siblings also had a variant in CHRNB2, a known epilepsy gene associated with autosomal dominant frontal lobe epilepsy, which they had inherited from the mother.
To our knowledge, the reported siblings represent the third and fourth subjects with confirmed SLC20A2 variants exhibiting epilepsy as a phenotypic trait. Our findings support seizures as part of the phenotypic spectrum of SLC20A2-related PFBC. However, the present phenotype may also result from additional genetic influence, such as the identified missense variant in CHRNB2.
近年来，由于发现了SLC20A2、PDGFRB和PDGFB等致病基因，对原发性家族性脑钙化（PFBC）的遗传学认识有了显著提高。PFBC的表型复杂，目前尚未得到很好的描述。最常见的临床表现包括运动障碍、认知症状和精神疾病。我们报告了一个家族，其中两姐妹因SLC20A2基因变异而出现脑钙化，并以全身强直阵挛性癫痫作为主要表型特征。
对受影响的兄弟姐妹进行全外显子组测序，并通过桑格测序验证家族中的候选变异和共分离情况。
两兄弟姐妹及其无症状的父亲在SLC20A2基因上存在一个变异的杂合子。两兄弟姐妹在CHRNB2基因上也有一个变异，CHRNB2是一个已知的与常染色体显性额叶癫痫相关的癫痫基因，他们从母亲那里遗传了该基因。
据我们所知，所报告的兄弟姐妹是第三和第四例确诊的具有癫痫作为表型特征的SLC20A2基因变异患者。我们的研究结果支持癫痫是SLC20A2相关PFBC表型谱的一部分。然而，目前的表型也可能是由其他遗传影响导致的，比如在CHRNB2基因中发现的错义变异。
