Tan Ee-Shien, Yong Min-Hwee, Lim Eileen Cp, Li Zhi-Hui, Brett Maggie Sy, Tan Ene-Choo
Genetics Service, KK Women's & Children's Hospital, 100 Bukit Timah Road 229899 Singapore, Singapore.
Cytogenetics Laboratory, KK Women's & Children's Hospital, 100 Bukit Timah Road 229899 Singapore, Singapore.
Mol Cytogenet. 2014 May 16;7:32. doi: 10.1186/1755-8166-7-32. eCollection 2014.
The 15q11-q13 region contains many low copy repeats and is well known for its genomic instability. Several syndromes are associated with genomic imbalance or copy-number-neutral uniparental disomy. We report on two patients: Patient 1 is a boy with developmental delay and autism; and Patient 2 is a girl with developmental delay, hypotonia and dysmorphism. We performed analyses to delineate their dosage in the 15q region, determine whether the patients' dosage correlates with phenotypic severity, and whether genes in the amplified regions are significantly associated with identified functional networks.
For the proximal region of 15q, molecular cytogenetic analysis with Agilent oligonucleotide array showed a copy number of 3 for Patient 1 and a copy number of 4 for Patient 2. Fluorescent in situ hybridization analysis of Patient 2 showed two different populations of cells with different marker chromosomes. Methylation analysis of the amplified region showed that the extra copies of small nuclear ribonucleoprotein polypeptide N gene were of maternal origin. Phenotypic severity did not correlate with the size and dosage of 15q, or whether the amplification is interstitial or in the form of a supernumerary marker. Pathway analysis showed that in Patient 2, the main functional networks that are affected by the genes from the duplicated/triplicated regions are developmental disorder, neurological disease and hereditary disease.
The 15q11-q13 gains that were found in both patients could explain their phenotypic presentations. This report expands the cohort of patients for which 15q11-q13 duplications are molecularly characterized.
15q11 - q13区域包含许多低拷贝重复序列，以其基因组不稳定性而闻名。几种综合征与基因组失衡或拷贝数中性单亲二体相关。我们报告了两名患者：患者1是一名患有发育迟缓与自闭症的男孩；患者2是一名患有发育迟缓、肌张力减退和畸形的女孩。我们进行了分析，以确定他们在15q区域的剂量，确定患者的剂量是否与表型严重程度相关，以及扩增区域中的基因是否与已确定的功能网络显著相关。
对于15q的近端区域，使用安捷伦寡核苷酸阵列进行的分子细胞遗传学分析显示，患者1的拷贝数为3，患者2的拷贝数为4。对患者2进行的荧光原位杂交分析显示有两种不同群体的细胞带有不同的标记染色体。对扩增区域的甲基化分析表明，小核核糖核蛋白多肽N基因的额外拷贝来自母系。表型严重程度与15q的大小和剂量无关，也与扩增是间质型还是额外标记染色体的形式无关。通路分析表明，在患者2中，受重复/三倍化区域基因影响的主要功能网络是发育障碍、神经疾病和遗传性疾病。
在两名患者中发现的15q11 - q13增益可以解释他们的表型表现。本报告扩大了对15q11 - q13重复进行分子特征分析的患者队列。
