Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.
Clinic for Child Neurology and Psychiatry, University of Belgrade, Belgrade, Serbia.
Am J Med Genet A. 2021 May;185(5):1575-1581. doi: 10.1002/ajmg.a.62144. Epub 2021 Feb 27.
Mutations in the OPHN1 gene cause a rare X-linked recessive neurodevelopmental disorder characterized by intellectual disability, variably associated with cerebellar hypoplasia and distinctive facial appearance. In most of cases so far reported, the identified genomic variants involve the region encoding the central RhoGAP domain of the oligophrenin-1 protein, and are predicted to result in a complete loss of function. By using a NGS-based diagnostic approach, we identified three male and a female patients from two unrelated families carrying novel non-disruptive OPHN1 variants (the in-frame c.116_127 deletion and the missense c.2129C>T change, respectively), affecting either the BAR domain or the C-terminus proline-rich domain of the protein. Clinical and neuroimaging findings in the patients recapitulated the main features of OPHN1-related syndrome, including developmental delay, intellectual disability, behavioral disorder, dysmorphic features, seizures, cerebellar hypoplasia, and ventriculomegaly. Yet, we observed a wide variability even among affected siblings, confirming the lack of clear genotype-phenotype correlation. Our results expand the allelic spectrum of OPHN1 and illustrate the challenges for clinical interpretation of non-disruptive variants affecting X-linked genes.
OPHN1 基因突变导致一种罕见的 X 连锁隐性神经发育障碍，其特征为智力障碍，与小脑发育不良和独特的面部特征相关。迄今为止报道的大多数病例中，鉴定出的基因组变异涉及寡脑啡肽-1 蛋白中央 RhoGAP 结构域的编码区，预计会导致完全丧失功能。通过使用基于 NGS 的诊断方法，我们从两个无关的家庭中鉴定出了三名男性和一名女性患者，他们携带新的非破坏性 OPHN1 变异（分别为框内 c.116_127 缺失和错义 c.2129C>T 改变），影响蛋白的 BAR 结构域或 C 末端脯氨酸丰富结构域。患者的临床和神经影像学表现重现了 OPHN1 相关综合征的主要特征，包括发育迟缓、智力障碍、行为障碍、畸形特征、癫痫发作、小脑发育不良和脑室扩大。然而，我们观察到即使在受影响的兄弟姐妹之间也存在广泛的变异性，证实了明确的基因型-表型相关性的缺乏。我们的结果扩展了 OPHN1 的等位基因谱，并说明了影响 X 连锁基因的非破坏性变异的临床解释的挑战。
