■SLC6A1相关神经发育障碍(SLC6A1-NDD)的表型谱包括智力障碍(ID),自闭症谱系障碍(ASD),癫痫,发育迟缓,从婴儿期早期或癫痫发作后开始,和其他神经系统特征,如张力减退和运动障碍。关于家族表型异质性的数据很少报道,因此,在我们的研究中,我们旨在调查具有SLC6A1变异体的家族内表型变异.
■我们收集了临床,39个人的实验室和遗传数据,包括17名先证者,属于13个具有SLC6A1遗传变体的家族。通过国际癫痫和遗传中心网络收集数据。
■整个39名受试者的主要临床发现是:(a)癫痫,主要表现为全身性癫痫发作,在71%的先证者和36%的兄弟姐妹或一级/二级亲属中报告。在一个家庭中,观察到相同类型的癫痫(全身性或局灶性);(b)ID在100%和13%的先证者和兄弟姐妹或一级/二级亲属中报告,分别;(C)在28%的SLC6A1携带者中检测到学习障碍,他们都是先证者的亲属;(d)整个队列中约有51%出现精神症状或行为障碍,包括82%的先证者。在有精神症状的19名患者中,其中40%被诊断为ASD;(e)观察到整个队列的38.5%的神经系统发现(主要是震颤和言语困难),包括10名先证者.我们的家族拥有12种不同的SLC6A1变体,一个是临时搭建的,两个停止增益,而剩下的是错觉。未鉴定基因型-表型关联。
■我们的研究表明,一级或二级亲属表现出不那么严重的表型,主要表现为轻度智力和/或学习障碍,与患有中度至重度身份证的先证者不同,广义的,有时很棘手,癫痫发作,行为和精神疾病。这些发现可能表明,部分患有轻度SLC6A1-NDD的个体可能会被遗漏,特别是那些年龄较大的不进行基因检测的人。需要进一步研究家族内表型变异以证实我们的结果,并可能扩大这些疾病的表型谱并有益于遗传咨询。
UNASSIGNED: Phenotypic spectrum of
SLC6A1-related neurodevelopmental disorders (
SLC6A1-NDD) includes intellectual disability (ID), autistic spectrum disorders (ASD), epilepsy, developmental delay, beginning from early infancy or after seizure onset, and other neurological features such as hypotonia and movement disorders. Data on familial phenotypic heterogeneity have been rarely reported, thus in our study we aimed to investigate intrafamilial phenotypic variability in families with
SLC6A1 variants.
UNASSIGNED: We collected clinical, laboratory and genetic data on 39 individuals, including 17 probands, belonging to 13 families harboring inherited variants of
SLC6A1. Data were collected through an international network of Epilepsy and Genetic Centers.
UNASSIGNED: Main clinical findings in the whole cohort of 39 subjects were: (a) epilepsy, mainly presenting with generalized seizures, reported in 71% of probands and 36% of siblings or first/second-degree relatives. Within a family, the same epilepsy type (generalized or focal) was observed; (b) ID reported in 100% and in 13% of probands and siblings or first/second-degree relatives, respectively; (c) learning disabilities detected in 28% of the SLC6A1 carriers, all of them were relatives of a proband; (d) around 51% of the whole cohort presented with psychiatric symptoms or behavioral disorders, including 82% of the probands. Out of the 19 patients with psychiatric symptoms, ASD were diagnosed in 40% of them; (e) neurological findings (primarily tremor and speech difficulties) were observed 38.5% of the whole cohort, including 10 probands. Our families harbored 12 different
SLC6A1 variants, one was a frameshift, two stop-gain, while the remaining were missense. No genotype-phenotype associations were identified.
UNASSIGNED: Our study showed that first-or second-degree relatives presented with a less severe phenotype, featuring mainly mild intellectual and/or learning disabilities, at variance with the probands who suffered from moderate to severe ID, generalized, sometimes intractable, epileptic seizures, behavioral and psychiatric disorders. These findings may suggest that a proportion of individuals with mild
SLC6A1-NDD might be missed, in particular those with an older age where genetic testing is not performed. Further studies on intrafamilial phenotypic variability are needed to confirm our results and possibly to expand the phenotypic spectrum of these disorders and benefit genetic counseling.