SMC1A基因变异相关疾病的表型及基因型特点

Clinical characteristics and gene analysis of SMC1A gene related disorders

目的:分析 SMC1A基因变异相关疾病的临床表现及遗传学特点。 方法:总结复旦大学附属儿科医院2018年2月至2022年1月收治的5例 SMC1A基因变异患儿的基本状况、特殊面容、畸形、癫痫、发育、脑电图、头颅影像、基因检测及随访结果,分析其表型及基因型。 结果:5例患儿中女性4例(2例为同胞姐妹),男性1例。1例男性患儿具有典型特殊面容(上睑下垂、连眉、鼻短、鼻孔前倾)及多发畸形(隐睾、房间隔缺损、卵圆孔未闭、小头)。4例女性患儿中2例合并小头畸形,2例合并卵圆孔未闭。4例患儿癫痫发病年龄为2月龄至4岁4月龄,其中3例为局灶性发作、2例为双侧强直阵挛。3例患儿为丛集性发作。1例为轻度发育迟缓,4例为中重度发育迟缓。4例合并癫痫患儿脑电图均异常,3例背景活动变慢,4例为痫样放电(3例为局灶性,1例为广泛性)。1例患儿头颅磁共振成像显示皮质略增厚。5例患儿存在4个 SMC1A基因变异(c.580_587del、c.2699delG、c.3362G>A、c.1486C>T),包括2个移码变异及2个错义变异;3例杂合,2例嵌合(嵌合率分别为17.5%和88.1%)。对5例患儿随访3个月到4年,结果发现2例的癫痫为难治性,5例均有精神运动发育缓慢或停滞、无发育倒退、均有体格生长迟缓。德朗热综合征临床评分为2~6分。1例表型兼具不典型德朗热综合征及发育性癫痫性脑病,1例表型为发育性癫痫性脑病,1例表型为不典型德朗热综合征,另2例(错义变异)患儿表型较轻,为非难治性癫痫及中重度发育迟缓。 结论:SMC1A基因变异患儿均伴有不同程度的发育障碍,多合并以丛集性发作为特点的癫痫、不同程度的特殊外貌及畸形。 SMC1A基因相关疾病的表型异质性大,除德朗热综合征及发育性癫痫性脑病,部分 SMC1A基因错义变异的表型较轻。

Objective To analyze the clinical characteristics and genetic features of SMC1A gene related disorders.Methods The data of 5 children with SMC1A gene variants were collected from Children′s Hospital of Fudan University from February 2018 to January 2022.The clinical features,electroencephalogram(EEG),brain imaging and gene testing results were summarized.Results Among the 5 patients,4 are females and 1 is male.Two female cases are siblings.One boy had dysmorphic features,consisting of bilateral ptosis,synophrys,a short nose and upturned nasal tip.He also had patent foramen ovale plus atrial septal defect,unilateral cryptorchidism and microcephaly.Three cases had microcephaly.Two girls had patent foramen ovale,and 2 girls had microcephaly.Four cases had epilepsy,and age at seizure onset ranged from 2 to 52 months.Multiple seizure types were observed,including bilateral tonic clonic seizures in 2 patients,and focal seizures in 3 patients.The seizures in 3 cases were in cluster.All patients had developmental delay,including 1 patient with mild and 4 patients with moderate to severe developmental delay.Three patients had slow background activity in EEG.Interictal EEG showed abnormal discharges in 4 patients,including focal discharges in 3 cases and generalized discharges in 1 case.Brain magnetic resonance imaging was normal in 3 patients and showed mild cortical thickening in 1 case.All cases harbored 4 SMC1A gene variants,including 2 missense variants and 2 frameshift variants(c.580_587del,c.2699delG,c.3362G>A,c.1486C>T).Three cases harbored heterozygous SMC1A variants and 2 cases carried somatic mosaic SMC1A variants with 17.5%and 88.1%mosaicism in peripheral blood.The follow-up lasted for 3 months to 4 years.The epilepsy was refractory in 2 cases.During the follow-up,all cases had very slow developmental progress or developmental retardation.All cases had different levels of growth retardation.The scores of Cornelia de Lange syndrome(CdLS)phenotypes in 5 cases were 2-6.One case had the combined phenotypes of atypical CdLS and developmental epileptic encephalopathy(DEE).The phenotype was atypical CdLS in 1 case and DEE in 1 case.The phenotypes of 2 cases with SMC1A missense variants were mild,manifesting as non-refractory epilepsy and moderate to severe developmental delay.Conclusions All of cases with SMC1A gene variants have developmental delay.Most of the patients have clusters of seizures and some dysmorphisms.The phenotypes of SMC1A gene related disorders are diverse.Except CdLS and DEE,there are some patients with mild phenotype due to missense variants of SMC1A gene.