Hepacam的致病变异与皮质下囊肿2A的巨脑白质脑病相关(MLC2A,MIM#613,925,常染色体隐性),和皮质下囊肿2B的巨脑白质脑病,remitting,有或没有智力发育受损(MLC2B,MIM#613,926,常染色体显性)。这些疾病的特征是大头畸形,癫痫发作,电机延迟,认知障碍,共济失调,和痉挛。这些患者的脑磁共振成像(MRI)显示大脑半球白质肿胀和皮质下囊肿,主要在额叶和颞区。迄今为止,据报道,来自39个家庭的45个个体在HEPACAM中具有双等位基因和杂合变体,引起MLC2A和MLC2B,分别。一名9岁男性出现发育迟缓,步态异常,癫痫发作,大头畸形,构音障碍,痉挛,和反射亢进.MRI显示皮质下囊肿伴弥漫性脑白质受累。先证者中的全外显子组测序(WES)没有发现任何临床相关的单核苷酸变体。然而,来自先证者的WES数据的拷贝数变异分析显示,HEPACAM外显子3和4的拷贝数为4。通过定量PCR进行验证和分离,该定量PCR证实了这些外显子在父母双方的先证者和携带者状态中的纯合复制。据我们所知,这是HEPACAM基因内复制导致MLC2A的首次报道.
Disease-causing variants in HEPACAM are associated with megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A, MIM# 613,925, autosomal recessive), and megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development (MLC2B, MIM# 613,926, autosomal dominant). These disorders are characterised by macrocephaly, seizures, motor delay, cognitive impairment, ataxia, and spasticity. Brain magnetic resonance imaging (MRI) in these individuals shows swollen cerebral hemispheric white matter and subcortical cysts, mainly in the frontal and temporal regions. To date, 45 individuals from 39 families are reported with biallelic and heterozygous variants in HEPACAM, causing MLC2A and MLC2B, respectively. A 9-year-old male presented with developmental delay, gait abnormalities, seizures, macrocephaly, dysarthria, spasticity, and hyperreflexia. MRI revealed subcortical cysts with diffuse cerebral white matter involvement. Whole-exome sequencing (WES) in the proband did not reveal any clinically relevant single nucleotide variants. However, copy number variation analysis from the WES data of the proband revealed a copy number of 4 for exons 3 and 4 of HEPACAM. Validation and segregation were done by quantitative PCR which confirmed the homozygous duplication of these exons in the proband and carrier status in both parents. To the best of our knowledge, this is the first report of an intragenic duplication in HEPACAM causing MLC2A.