背景:Temple综合征(TS14)是一种罕见的印记障碍,由母体UPD14,印记缺陷或父系微缺失引起,导致母体表达基因增加和14q32印记域中父系表达基因沉默。经典的TS14表型特征包括出生前和出生后身材矮小,小手和小脚,肌张力减退,电机延迟,喂养困难,体重增加,沿着性早熟和性早熟。
方法:对患有精神运动和语言延迟的患者进行外显子阵列比较基因组杂交,肌张力减退,相对大头畸形,两岁时的手和脚都很小。6岁时,先证者因早熟而出现。通过MS-MLPA分析14q32区域内的基因剂量和甲基化。亚硫酸氢盐PCR和焦磷酸测序用于定量14q32结构域内四个已知印迹差异甲基化区域(DMR)的甲基化:DLK1DMR,IG-DMR,MEG3DMR和MEG8DMR。
结果:患者遗传了69Kb的缺失,包含整个DLK1基因,父系等位基因。两个母体甲基化间隔的相对超甲基化,DLK1和MEG8DMRs,在IG-DMR和MEG3DMR上观察到正常的甲基化水平,导致与TS14一致的表型。具有缺失的其他家族成员在DLK1和MEG8DMRs上显示出适度的甲基化变化,与亲本传递一致。
结论:我们描述了一个女孩,其临床表现提示Temple综合征是由于一个小的父系14q32缺失导致DLK1全基因缺失,以及母体甲基化的DLK1-DMR的超甲基化。
BACKGROUND: Temple syndrome (TS14) is a rare imprinting disorder caused by maternal UPD14, imprinting defects or paternal microdeletions which lead to an increase in the maternal expressed genes and a silencing the paternally expressed genes in the 14q32 imprinted domain. Classical TS14 phenotypic features include pre- and postnatal short stature, small hands and feet, muscular hypotonia, motor delay, feeding difficulties, weight gain, premature puberty along and precocious puberty.
METHODS: An exon array comparative genomic hybridization was performed on a patient affected by psychomotor and language delay, muscular hypotonia, relative macrocephaly, and small hand and feet at two years old. At 6 years of age, the proband presented with precocious thelarche. Genes dosage and methylation within the 14q32 region were analyzed by MS-MLPA. Bisulfite PCR and pyrosequencing were employed to quantification methylation at the four known imprinted differentially methylated regions (DMR) within the 14q32 domain: DLK1 DMR, IG-DMR, MEG3 DMR and MEG8 DMR.
RESULTS: The patient had inherited a 69 Kb deletion, encompassing the entire DLK1 gene, on the paternal allele. Relative hypermethylation of the two maternally methylated intervals, DLK1 and MEG8 DMRs, was observed along with normal methylation level at IG-DMR and MEG3 DMR, resulting in a phenotype consistent with TS14. Additional family members with the deletion showed modest methylation changes at both the DLK1 and MEG8 DMRs consistent with parental transmission.
CONCLUSIONS: We describe a girl with clinical presentation suggestive of Temple syndrome resulting from a small paternal 14q32 deletion that led to DLK1 whole-gene deletion, as well as hypermethylation of the maternally methylated DLK1-DMR.