Kasper Burkhard S, Kurzbuch Katrin, Chang Bernard S, Pauli Elisabeth, Hamer Hajo M, Winkler Jürgen, Hehr Ute
Department of Neurology, Epilepsy Center, Erlangen University, Erlangen, Germany.
Am J Med Genet A. 2013 Jun;161A(6):1323-8. doi: 10.1002/ajmg.a.35917. Epub 2013 May 1.
Periventricular nodular heterotopia (PNH) is a developmental disorder of the central nervous system, characterized by heterotopic nodules of gray matter resulting from disturbed neuronal migration. The most common form of bilateral PNH is X-linked dominant inherited, caused by mutations in the Filamin A gene (FLNA) and associated with a wide variety of other clinical findings including congenital heart disease. The typical patient with FLNA-associated PNH is female and presents with difficult to treat seizures. In contrast, hemizygous FLNA loss of function mutations in males are reported to be perinatally lethal. In X-linked dominant traits like FLNA-associated PNH the causal mutation is commonly inherited from the mother. Here, we present an exceptional family with paternal transmission of classic bilateral FLNA-associated PNH from a mildly affected father with somatic and germline mosaicism for a c.5686G>A FLNA splice mutation to both daughters with strikingly variable clinical manifestation and PNH extent in cerebral MR imaging. Our observations emphasize the importance to consider in genetic counseling and risk assessment the rare genetic constellation of paternal transmission for families with X-linked dominant inherited FLNA-associated PNH.
室周结节性异位（PNH）是一种中枢神经系统发育障碍，其特征是神经元迁移紊乱导致灰质异位结节。双侧PNH最常见的形式是X连锁显性遗传，由细丝蛋白A基因（FLNA）突变引起，并与包括先天性心脏病在内的多种其他临床发现相关。典型的与FLNA相关的PNH患者为女性，表现为难治性癫痫发作。相比之下，据报道男性中FLNA功能丧失的半合子突变在围产期是致死性的。在像与FLNA相关的PNH这样的X连锁显性性状中，致病突变通常从母亲遗传而来。在此，我们报告一个特殊的家系，患有经典双侧FLNA相关PNH的父亲存在体细胞和生殖细胞嵌合，其c.5686G>A的FLNA剪接突变传递给了两个女儿，她们在脑磁共振成像中的临床表现和PNH程度有显著差异。我们的观察结果强调，在遗传咨询和风险评估中，对于X连锁显性遗传的FLNA相关PNH家庭，要考虑罕见的父系遗传基因组合情况十分重要。
