Fauth Christine, Steindl Katharina, Toutain Annick, Farrell Sandra, Witsch-Baumgartner Martina, Karall Daniela, Joset Pascal, Böhm Sebastian, Baumer Alessandra, Maier Oliver, Zschocke Johannes, Weksberg Rosanna, Marshall Christian R, Rauch Anita
Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Institute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
Am J Med Genet A. 2016 Feb;170A(2):392-402. doi: 10.1002/ajmg.a.37452. Epub 2015 Nov 6.
Hypomorphic germline mutations in the PIGA (phosphatidylinositol glycan class A) gene recently were recognized as the cause of a clinically heterogeneous spectrum of X-linked disorders including (i) early onset epileptic encephalopathy with severe muscular hypotonia, dysmorphism, multiple congenital anomalies, and early death ("MCAHS2"), (ii) neurodegenerative encephalopathy with systemic iron overload (ferro-cerebro-cutaneous syndrome, "FCCS"), and (iii) intellectual disability and seizures without dysmorphism. Previous studies showed that the recurrent PIGA germline mutation c.1234C>T (p.Arg412*) leads to a clinical phenotype at the most severe end of the spectrum associated with early infantile lethality. We identified three additional individuals from two unrelated families with the same PIGA mutation. Major clinical findings include early onset intractable epileptic encephalopathy with a burst-suppression pattern on EEG, generalized muscular hypotonia, structural brain abnormalities, macrocephaly and increased birth weight, joint contractures, coarse facial features, widely spaced eyes, a short nose with anteverted nares, gingival overgrowth, a wide mouth, short limbs with short distal phalanges, and a small penis. Based on the phenotypic overlap with Simpson-Golabi-Behmel syndrome type 2 (SGBS2), we hypothesized that both disorders might have the same underlying cause. We were able to confirm the same c.1234C>T (p.Arg412*) mutation in the DNA sample from an affected fetus of the original family affected with SGBS2. We conclude that the recurrent PIGA germline mutation c.1234C>T leads to a recognizable clinical phenotype with a poor prognosis and is the cause of SGBS2.
PIGA（磷脂酰肌醇聚糖A类）基因的亚效等位基因种系突变最近被认为是导致一系列临床异质性X连锁疾病的原因，这些疾病包括：（i）早发性癫痫性脑病，伴有严重肌张力减退、畸形、多种先天性异常和早亡（“MCAHS2”）；（ii）伴有全身铁过载的神经退行性脑病（铁脑皮肤综合征，“FCCS”）；以及（iii）无畸形的智力残疾和癫痫发作。先前的研究表明，复发性PIGA种系突变c.1234C>T（p.Arg412*）导致的临床表型处于与早期婴儿致死率相关的最严重范围。我们从两个无关家庭中鉴定出另外三名携带相同PIGA突变的个体。主要临床发现包括早发性难治性癫痫性脑病，脑电图显示爆发抑制模式，全身性肌张力减退，脑结构异常，巨头畸形和出生体重增加，关节挛缩，面部特征粗糙，眼距宽，短鼻伴鼻孔前倾，牙龈增生，嘴巴宽大，四肢短小伴远端指骨短，以及小阴茎。基于与2型辛普森-戈拉比-贝梅尔综合征（SGBS2）的表型重叠，我们推测这两种疾病可能有相同的潜在病因。我们能够在受SGBS影响的原家庭中一名患病胎儿的DNA样本中确认相同的c.1234C>T（p.Arg412*）突变。我们得出结论，复发性PIGA种系突变c.1234C>T导致一种预后不良的可识别临床表型，是SGBS2的病因。
