Institute for Maternal and Child Health "Burlo Garofolo", 34137 Trieste, TS, Italy.
Department of Neuroradiology, San Raffaele Scientific Institute, 20132 Milan, MI, Italy.
Genes (Basel). 2024 Sep 10;15(9):1190. doi: 10.3390/genes15091190.
BACKGROUND/OBJECTIVES: Identifying novel variants in very rare disease genes can be challenging when patients exhibit a complex phenotype that expands the one described, and we provide such an example here. A few terminal truncating variants in cause spastic paraplegia (SP), intellectual disability (ID), nystagmus, and obesity (SINO, MIM #617296). Prompted by the result of next-generation sequencing on a patient referred for SP associated with complex brain dysmorphisms, we reviewed the phenotype of SINO patients focusing on their brain malformations, mainly described in prenatal age and first years of life, and tried to understand if the predicted effect of the mutant kidins220 may have caused them.
We performed whole exome sequencing (WES) and a literature and mutation databases review.
We report a young adult with SP, severe ID, strabismus, and macrocephaly exhibiting brain malformations at follow-up, partially overlapping with those described in tubulinopathy. WES analysis of the proband and parents identified the heterozygous de novo variant (NM_020738.4: c. 4144G > T) p. Glu 1382* in that was predicted to be causative of SINO.
The progression of myelination and the development of brain structures turned out to be crucial for identifying, at follow-up, the whole -related brain malformations. The truncated proteins associated with SINO lack a portion fundamental for the interaction of kidins220 with tubulins and microtubule-associated proteins. The complexity of the brain malformations displayed by our patient, and possibly by other reported SINO patients, could result from an impaired dynamic modulation of the microtubule cytoskeleton during embryogenesis. Brain malformations must be considered as part of the SINO spectrum phenotype.
背景/目的：当患者表现出超出已描述范围的复杂表型时，识别非常罕见疾病基因中的新型变异可能具有挑战性，我们在此提供了这样一个例子。几个 中的末端截断变异可导致痉挛性截瘫（SP）、智力障碍（ID）、眼球震颤和肥胖（SINO，MIM#617296）。在对一名因与复杂脑畸形相关的 SP 而转介的患者进行下一代测序的结果提示下，我们重点关注 SINO 患者的脑畸形表型，这些脑畸形主要在产前和生命的最初几年描述，并试图了解突变的 kidins220 预测效应是否导致了这些畸形。
我们进行了全外显子组测序（WES）和文献及突变数据库的回顾。
我们报告了一名年轻的成年患者，其 SP、严重 ID、斜视和随访时的大头畸形，其部分脑畸形与 微管病重叠。对先证者及其父母进行 WES 分析，发现了杂合的新生变异（NM_020738.4：c.4144G > T）p. Glu 1382*，该变异被预测为 SINO 的致病原因。
髓鞘形成和脑结构的发育对于在随访时识别与 SINO 相关的全脑畸形至关重要。与 SINO 相关的截断蛋白缺乏与 kidins220 与微管和微管相关蛋白相互作用的重要部分。我们患者表现出的脑畸形的复杂性，可能还有其他报道的 SINO 患者，可能是由于胚胎发育过程中微管细胞骨架的动态调节受损所致。脑畸形必须被视为 SINO 表型谱的一部分。
