背景:已经在患有神经发育障碍的个体中描述了17p13.3微缺失或微重复(统称为拷贝数变体或CNV)。然而,在胎儿中很少报道17p13.3CNVs。这项研究旨在研究在产前和产后样本中具有不同大小和基因含量的17p13.3CNV的临床意义。
方法:对8806份样本中进行单核苷酸多态性分析的8例17p13.3CNV进行回顾性分析,随着核型分析,临床特征,和后续行动。
结果:8例17p13.3CNVs由5个胎儿组成,一个流产胚胎和两个先证者表现出严重的先天性缺陷。五个胎儿的产前检查适应症差异很大,包括超声异常(n=3),非侵入性产前检测显示的节段性缺失(n=1),和一个胎儿的母亲的智力残疾(n=1)。其中,两个和六个分别包含17p13.3的拷贝数损益。检测到的17p13.3CNV的大小范围为576kb至5.7Mb。病例1诊断为17p13.3重复综合征,以及第4、6和7例Miller-Dieker综合征(MDS)。在涉及YWHAE和CRK的两个病例(病例5和8)中,17p13.3区域的微缺失,保留PAFAH1B1,被归类为致病性。案例2有576kb的微复制,包括YWHAE和CRK,但不包括PAFAH1B1,后者是母体来源的,被认为是不确定意义的变体。案例3在染色体17p13.2q25.3上携带了一个约3.5的74.2Mb马赛克重复,在17p13.3p13.2和17q25.3上有两个缺失。病例3的核型为46,XY,r(17)(p13q25)。五个胎儿,只有病例2继续妊娠,在15个月大时表现出正常发育;其他病例则终止妊娠.
结论:17p13.3微缺失或微重复的临床发现因受试者而异,和17p13.3CNV通常在大小和基因含量上不同。含有典型MDS区域的微缺失或微重复,以及涉及YWHAE和CRK的微缺失,可能被归类为致病性。包括YWHAE和CRK而不是PAFAH1B1的小重复的临床意义仍然不确定。在遗传咨询中应考虑父母检测和临床异质性。
17p13.3 microdeletions or microduplications (collectively known as copy number variants or CNVs) have been described in individuals with neurodevelopmental disorders. However, 17p13.3 CNVs were rarely reported in fetuses. This study aims to investigate the clinical significance of 17p13.3 CNVs with varied sizes and gene content in prenatal and postnatal samples.
Eight cases with 17p13.3 CNVs out of 8806 samples that had been subjected to single nucleotide polymorphism array analysis were retrospectively analyzed, along with karyotyping, clinical features, and follow-up.
Eight cases with 17p13.3 CNVs consisted of five fetuses, one aborted embryo and two probands manifested severe congenital defects. The indications of prenatal testing varied considerably for the five fetuses, including ultrasound abnormalities (n = 3), segmental deletions indicated by non-invasive prenatal testing (n = 1), and intellectual disability in the mother of one fetus (n = 1). Of them, two and six harbored copy number gains and losses involving 17p13.3, respectively. The size of the detected 17p13.3 CNVs ranged from 576 kb to 5.7 Mb. Case 1 was diagnosed with 17p13.3 duplication syndrome, and cases 4, 6, and 7 with Miller-Dieker syndrome (MDS). Microdeletions of the 17p13.3 region in two cases (cases 5 and 8) involving YWHAE and CRK, sparing PAFAH1B1, were classified as pathogenic. Case 2 harbored a 576 kb microduplication, encompassing YWHAE and CRK but not PAFAH1B1, which was of maternal origin and considered a variant of uncertain significance. Case 3 carried one 74.2 Mb mosaic duplication of approximately 3.5 on chromosome 17p13.2q25.3, and two deletions at 17p13.3p13.2 and 17q25.3. The karyotype of case 3 was 46,XY,r(17)(p13q25). For five fetuses, only case 2 continued gestation and showed normal development at the age of 15 months; the others were subjected to termination of pregnancy.
The clinical findings of 17p13.3 microdeletions or microduplications varied among subjects, and 17p13.3 CNVs often differ in size and gene content. Microdeletions or microduplications containing the typical MDS region, as well as the microdeletions involving YWHAE and CRK, could be classified as pathogenic. The clinical significance of small duplications including YWHAE and CRK but not PAFAH1B1 remains uncertain, for which parental testing and clinical heterogeneity should be considered in genetic counseling.