Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder.
Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder.
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DOI：
10.1007/s00439-023-02552-2
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发表时间：
2023-07
期刊：
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
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作者：
接触素相关蛋白样2（CNTNAP 2）基因编码CASPR 2，CASPR 2是一种突触前1型跨膜蛋白，参与细胞间粘附和突触相互作用。双等位基因CNTNAP 2缺失与“Pitt-Hopkins样综合征-1”（MIM#610042）相关，而杂合变体的致病作用仍有争议。我们报告了22例携带单等位基因（n = 2）和双等位基因（n = 20）CNTNAP 2变体的新患者，并进行了文献综述，以表征基因型-表型相关性。患者（男：女14：8）年龄在3 - 19岁之间，患有全面发育迟缓（GDD）（n = 21）、中度至重度智力残疾（n = 17）和癫痫（n = 21）。癫痫发作主要开始于生命的头两年（中位数为22.5个月）。抗癫痫药物成功地控制了大约三分之二的患者的癫痫发作。9例患者（40.9%）存在自闭症谱系障碍（ASD）和/或其他神经精神共病。在大多数患者中观察到非特异性中线脑异常，而在3例受试者中观察到颞叶局灶性信号异常。基因型-表型相关性还包括50例先前发表的患者（15个单等位基因和35个双等位基因变异）。总体而言，GDD（p < 0.0001）、癫痫（p < 0.0001）、反射减退（p = 0.012）、ASD（p = 0.009）、语言障碍（p = 0.020）和严重认知障碍（p = 0.031）与双等位基因变异体的存在显著相关。我们已经定义了与双等位基因CNTNAP 2变体相关的主要特征，如严重的认知障碍、癫痫和行为异常。我们提出CASPR 2缺陷性神经发育障碍是一种完全隐性遗传疾病，而杂合子变异的贡献不太可能遵循常染色体显性遗传模式。在线版本包含补充材料，可通过10.1007/s 00439 -023-02552-2获得。
Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p < 0.0001), epilepsy (p < 0.0001), hyporeflexia (p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern. The online version contains supplementary material available at 10.1007/s00439-023-02552-2.
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影响因子：
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作者：
Al-Murrani A;Ashton F;Aftimos S;George AM;Love DR
通讯作者：
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影响因子：
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