Cytogenetics Department, VCGS Pathology, MCRI, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
J Med Genet. 2010 May;47(5):299-311. doi: 10.1136/jmg.2009.069906.
Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly sequence or Miller-Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller-Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes.
Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3.
Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3epsilon). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms.
The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations.
染色体 17p13.3 包含广泛的重复序列，是基因组不稳定的公认区域。PAFAH1B1（编码 LIS1）的单倍不足会导致孤立的无脑回序列或 Miller-Dieker 综合征，具体取决于缺失的大小。最近，米勒-迪克克综合征端粒关键区域的微缺失和微重复均已被鉴定出来，并与独特但重叠的表型相关。
对 7678 名因不明学习困难和/或自闭症而转诊的患者进行了全基因组微阵列筛查，无论是否存在其他先天性异常。分别在 17p13.3 中发现了 8 名和 5 名无关个体的微缺失和微重复。
与 6 例先前报道的微缺失病例进行比较，确定了一个 258 kb 的关键区域，包含 6 个基因，包括 CRK（编码 Crk）和 YWHAE（编码 14-3-3epsilon）。临床特征包括生长迟缓、面部畸形和发育迟缓。值得注意的是，只有轻微面部特征的个体和仅涉及 CRK 而不涉及 YWHAE 的染色体间缺失表明，跨越包含两个基因（TUSC5 和 YWHAE）的 109 kb 基因组区域负责主要的面部畸形表型。只有微重复表型包括自闭症。新病例和先前报道病例的微重复最小重叠区域跨越 72 kb，包含一个基因 YWHAE。这些基因组重排与低拷贝重复无关，可能是由于不同的分子机制造成的。
作者进一步描述了 17p13.3 微缺失和微重复的表型谱，并描述了一个较小的关键基因组区域，该区域允许确定具有独特面部畸形（微缺失）和自闭症（微重复）表现的候选基因。
