1例重度DEE-SWAS女性患者CNKSR2致病变异鉴定及强XCI检测及男性患者表型扩增

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Yu Katata, Yukimune Okubo, Haruhiko Nakamura, Naoya Saijo, Masakiyo Hayasaka, Jun Takayama, Shigeo Kure, Atsuo Kikuchi
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引用次数: 0

摘要

连接增强子激酶抑制因子Ras2 (CNKSR2)在神经元树突生长中起关键作用。CNKSR2的半合子致病性变异位于Xp22.12位点,与智力残疾、癫痫、发展性脑病和癫痫性脑病相关,并伴有睡眠时的尖峰波激活。作为一种x连锁隐性遗传疾病,神经系统症状通常表现在男性身上,而女性携带者通常无症状。在这里,我们报告了一名女孩(患者1)和一名男孩(患者2)患有致病性CNKSR2的截断变体。患者1有顽固性癫痫和严重的发育倒退;她的脑电图显示睡眠时持续的峰波活动。全基因组测序(WGS)显示了一个杂合的CNKSR2 c.2134C b> T, p.(Arg712Ter)变异(de novo,先前报道),x染色体失活分析显示她的白细胞DNA明显歪斜(85:15)。她的临床症状比先前报道的女性患者更严重,但经乙氧亚胺和磺胺治疗后症状有所改善。患者2有癫痫和Angelman综合征样症状。WGS发现临床遗传学半合子c.492C> a, p (Cys164Ter) CNKSR2变异(母系或新发)。x染色体失活偏斜的强度可能与严重程度有关。这些新的致病性CNKSR2变异扩大了这种疾病的表型谱。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of CNKSR2 Pathogenic Variant and Detection of Strong XCI in a Female Patient With Severe DEE-SWAS and Phenotype Expansion in Male Patients.

Connector enhancer of kinase suppressor of Ras2 (CNKSR2) is critical in neuronal dendrite growth. Hemizygous pathogenic variants of CNKSR2, which is located at Xp22.12, are associated with intellectual disability, epilepsy, and developmental and epileptic encephalopathy with spike wave activation during sleep. As an X-linked recessive genetic disorder, neurological symptoms usually manifest in males, while female carriers are typically asymptomatic. Here, we report a girl (Patient 1) and boy (Patient 2) with a pathogenic truncated variant of CNKSR2. Patient 1 had intractable epilepsy and severe developmental regression; her electroencephalogram showed continuous spike-and-wave activity during sleep. Whole-genome sequencing (WGS) revealed a heterozygous CNKSR2 c.2134C>T, p.(Arg712Ter) variant (de novo, previously reported), and X-chromosome inactivation analysis of her white blood cell DNA showed marked skewing (85:15). Her clinical symptoms were more severe than those of previously reported female patients, but they improved with ethosuximide and sulthiame treatment. Patient 2 had epilepsy and Angelman syndrome-like symptoms. WGS revealed a Clinical Genetics hemizygous c.492C>A, p (Cys164Ter) CNKSR2 variant (maternal or novel). The strength of the X-chromosome inactivation skewing may be related to severity. These novel pathogenic CNKSR2 variants have expanded the phenotypic spectrum of this disease.

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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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