Genotypic and phenotypic variability of 22q11.2 microduplications: An institutional experience

Duplications in the 22q11.2 region can cause 22q11.2 duplication syndrome and encompass a variety of phenotypes including developmental delays, facial abnormalities, cardiovascular defects, central nervous system delays, and other congenital abnormalities. However, the contribution of these contiguous duplicated regions to the clinical phenotypes has not been fully elucidated. In this study, we identified nine patients carrying different 22q11.2 microduplications detected by chromosomal microarray. Of these patients, seven pediatric patients presented with various clinical features including two neonate cases died shortly after birth, and two healthy adults. We examined region specific genotype–phenotype associations and found unpredictability associated with 22q11.2 duplications in these nine patients.     

De novo microduplication of the FMR1 gene in a patient with developmental delay,epilepsy and hyperactivity

Loss-of-function due to expansion of a CGG repeat located in the 5''UTR of the FMR1 gene is the most frequent cause of fragile X syndrome. Less than 1% of individuals with fragile X syndrome have been reported to have a partial or full deletion or point mutation of the FMR1 gene. However, whether a copy number gain of the FMR1 gene could result in certain clinical phenotypes has not been fully investigated. Here, we report the case of a child who presented with developmental delay starting at 9 months of age, fine motor and speech delay, progressive seizures since 18 months of age and hyperactivity. Molecular workup identified a de novo microduplication in the Xq27.3 region, including the FMR1 gene and the ASFMR1 gene. The expression level of the FMR1 gene in peripheral blood did not differ from that of the controls. In addition, an inherited 363-kb duplication on the chromosome 1q44 region and an inherited deletion of 168 kb on the chromosome 4p15.31 region were detected. It is not clear whether these inherited copy number variations (CNVs) also have a modifying role in the clinical phenotype of this patient.     

Detection of a familial 21q22.3 microduplication in a fetus associated with congenital heart defects

ObjectiveWe present a familial 21q22.3 microduplication in a fetus associated with prenatally detected congenital heart defects (CHD).Case reportA 38-year-old woman underwent amniocentesis at 22 weeks of gestation because of sonographic findings of double outlet of right ventricle, ventricular septal defect and transposition of great artery in the fetus. Her husband was 42 years old, and there was no CHD and congenital malformation in the family. Cytogenetic analysis revealed a karyotype of 46,XY in the fetus. Simultaneous array comparative genomic hybridization (aCGH) analysis using uncultured amniocytes revealed a 0.56-Mb microduplication of 21q22.3 or arr 21q22.3 (47,482,210-48,043,704)×3.0 [GRCh37 (hg19)] encompassing nine Online Mendelian Inheritance in Man (OMIM) genes of FTCD, SPATC1L, LSS, MCM3AP, YBEY, PCNT, DIP2A, S100B and PRMT2. aCGH analysis of the parental bloods revealed that the phenotypically normal father carried the same microduplication. The parents decided to continue the pregnancy, and a 3168-g male baby was delivered at term without Down syndrome phenotype except CHD. Mutational analysis of the CRELD1 gene on the DNA extracted from the cord blood showed no mutation in CRELD1. Postnatal molecular cytogenetic analysis of the cord blood confirmed the prenatal diagnosis. The infant underwent a successful heart surgery to correct the CHD and was doing well without psychomotor or developmental delay at six months of age.ConclusionPrenatal diagnosis of 21q22.3 microduplication associated with CHD should include a differential diagnosis of Down syndrome.     

染色体微阵列芯片分析技术应用于产前诊断为关键问题探讨

染色体微阵列芯片分析（CMA）包括比较基因组杂交微阵列（array CGH）和单核苷酸多态微阵列（SNP array）,可以在全基因组范围内高分辨检测染色体的微缺失和微重复,与传统染色体核型分析和荧光原位杂交（FISH）检测相比,具有高通量、高分辨率和高自动化检测的优势,同时可以一次性同步检测许多与出生缺陷和先天性疾病相关的基因组异常,近年来已经开始应用于侵入性产前诊断。回顾近年来多个大样本和多中心的临床试验对CMA技术用于产前诊断的研究结果,借鉴美国妇产科医师协会（ACOG）和母婴医学协会（SMFM）发布的CMA在产前诊断应用中的建议,对CMA在应用过程中如何选择微阵列芯片类型、检测的适用对象和检测的时期、检测结果的解释以及相关的遗传咨询等关键问题进行了详细讨论,并指出CMA在产前诊断应用中面临的机遇和挑战,以及检测前和检测后遗传咨询在实际应用中的重要性和必要性。     

一例15q11.2微重复患儿的临床及遗传学分析

目的明确1例发育迟缓、智力低下患儿遗传学病因及其来源,并对该家系下一胎行产前诊断。方法采集患儿及其父母外周血进行常规G显带核型分析及单核苷酸多态性微阵列芯片(single nucleotide polymorphism array,SNP array)检测;并对该孕妇行产前诊断,进行羊水细胞染色体核型分析及SNP array检测。结果患儿及其父母染色体核型未见异常。SNP array检测结果显示患儿15号染色体15q11.2区段存在855.3 kb重复,该重复遗传至表型正常的母亲,父亲检测结果未见异常。孕妇羊水细胞染色体核型及SNP array检测结果均未见异常。结论15q11.2微重复可能与体格/智力发育障碍相关,CYFIP1可能是其候选基因,但该重复仅可增加其发病风险,外显率较低,在临床咨询中应引起重视。