Office of Bioinformatics and Epidemiology, Greenwood Genetic Center, Greenwood, South Carolina 29646, USA.
J Med Genet. 2011 Nov;48(11):761-6. doi: 10.1136/jmedgenet-2011-100225. Epub 2011 Oct 7.
The clinical features of Phelan-McDermid syndrome (also known as 22q13 deletion syndrome) are highly variable and include hypotonia, speech and other developmental delays, autistic traits and mildly dysmorphic features. Patient deletion sizes are also highly variable, prompting this genotype-phenotype association study.
Terminal deletion breakpoints were identified for 71 individuals in a patient cohort using a custom-designed high-resolution oligonucleotide array comparative genomic hybridisation platform with a resolution of 100 bp.
Patient deletion sizes were highly variable, ranging from 0.22 to 9.22 Mb, and no common breakpoint was observed. SHANK3, the major candidate gene for the neurologic features of the syndrome, was deleted in all cases. Sixteen features (neonatal hypotonia, neonatal hyporeflexia, neonatal feeding problems, speech/language delay, delayed age at crawling, delayed age at walking, severity of developmental delay, male genital anomalies, dysplastic toenails, large or fleshy hands, macrocephaly, tall stature, facial asymmetry, full brow, atypical reflexes and dolichocephaly) were found to be significantly associated with larger deletion sizes, suggesting the role of additional genes or regulatory regions proximal to SHANK3. Individuals with autism spectrum disorders (ASDs) were found to have smaller deletion sizes (median deletion size of 3.39 Mb) than those without ASDs (median deletion size 6.03 Mb, p=0.0144). This may reflect the difficulty in diagnosing ASDs in individuals with severe developmental delay.
This genotype-phenotype analysis explains some of the phenotypic variability in the syndrome and identifies new genomic regions with a high likelihood for causing important developmental phenotypes such as speech delay.
Phelan-McDermid 综合征（也称为 22q13 缺失综合征）的临床特征高度可变，包括张力减退、言语和其他发育迟缓、自闭症特征和轻度发育不良特征。患者缺失大小也高度可变，这促使了这种基因型-表型关联研究。
使用定制设计的高分辨率寡核苷酸阵列比较基因组杂交平台，分辨率为 100bp，对患者队列中的 71 名个体的末端缺失断点进行了鉴定。
患者缺失大小高度可变，范围从 0.22 到 9.22Mb，没有观察到常见的断点。SHANK3 是该综合征神经特征的主要候选基因，在所有病例中均缺失。16 个特征（新生儿张力减退、新生儿低反射、新生儿喂养问题、言语/语言延迟、爬行年龄延迟、行走年龄延迟、发育延迟严重程度、男性生殖器异常、发育不良的脚趾甲、大而多肉的手、大头畸形、身材高大、面部不对称、饱满的眉毛、非典型反射和长头畸形）与较大的缺失大小显著相关，表明 SHANK3 近端存在其他基因或调节区域的作用。患有自闭症谱系障碍（ASD）的个体发现缺失较小（中位数缺失大小为 3.39Mb），而没有 ASD 的个体缺失较大（中位数缺失大小为 6.03Mb，p=0.0144）。这可能反映了在严重发育迟缓的个体中诊断 ASD 的困难。
这种基因型-表型分析解释了该综合征的一些表型变异性，并确定了新的基因组区域，这些区域极有可能导致重要的发育表型，如言语延迟。
