Implementation of high‐resolution SNP arrays in the investigation of fetuses with ultrasound malformations: 5 years of clinical experience

Chromosome microarray analysis (CMA) has proven to be a powerful tool in postnatal patients with intellectual disabilities, and it is increasingly used in prenatal diagnosis. However, its diagnostic capabilities in prenatal diagnosis vary, and clinical experiences have failed to establish a consensus regarding CMA indications, the design and resolution of microarrays, and the notification and interpretation of copy number variations (CNVs). We present our 5 years of clinical experience using whole‐genome high‐resolution single nucleotide polymorphism (SNP) arrays to investigate 446 fetuses that had structural malformations detected with ultrasound but for which standard karyotyping analysis showed normal karyotypes. CMA revealed genomic CNVs in 323 (72.4%) cases and clinically significant CNVs in 11.4% of the fetuses (51/446), including 2 cases of uniparental disomy (UPD) as well as 1 case of cryptic mosaic monosomy of chromosome X. Variants of unknown significance (VOUS) existed in 2.0% of the tested fetuses (9/446). Our results demonstrate the value of whole‐genome high‐resolution SNP arrays in fetuses with congenital malformations and give a higher detection rate of clinically significant genomic imbalance, especially for detecting UPD. Sufficient communication between technicians and genetic counselors, along with parental testing and comparison with data from in‐house or international sources, can significantly reduce VOUS.     

Benefits and Burdens of Using a SNP Array in Pregnancies at Increased Risk for the Common Aneuploidies

We present the nature of pathogenic SNP array findings in pregnancies without ultrasound (US) abnormalities and show the additional diagnostic value of SNP array as compared with rapid aneuploidy detection and karyotyping. 1,330 prenatal samples were investigated with a 0.5‐Mb SNP array after the exclusion of the most common aneuploidies. In 2.7% (36/1,330) of the cases, pathogenic chromosome aberrations were found; a microscopically detectable abnormality in 0.7% and a submicroscopic aberration in 2%. Our results show that in addition to the age‐ or screening‐related aneuploidy risk, in pregnancies without US abnormalities, there is a risk of 1:148 (9/1,330) for a (sub)microscopic abnormality associated with an early‐onset often severe disease, 1:222 (6/1,330) for a submicroscopic aberration causing an early‐onset disease, 1:74 (18/1,330) for carrying a susceptibility locus for a neurodevelopmental disorder, and 1:443 (3/1,330) for a late‐onset disorder (hereditary neuropathy with liability to pressure palsies in all three cases). These risk figures are important for adequate pretest counseling so that prospective parents can make informed individualized choices between targeted prenatal testing and broad testing with SNP array. Based on our results, we believe if invasive testing is performed, SNP array should be the preferred cytogenetic technique irrespective of the indication.     

The influence of SNP‐based chromosomal microarray and NIPT on the diagnostic yield in 10,000 fetuses with and without fetal ultrasound anomalies

Prenatal diagnostics has been impacted by technological changes in the past decade, which have affected the diagnostic yield. The aim of this study was to evaluate the impact of SNP array and noninvasive prenatal testing (NIPT) on the diagnostic yield and the number of invasive tests in our center. The frequency of pathogenic fetal unbalanced chromosome aberrations was studied in 10,005 cases referred for prenatal testing in 2009–2015. Chromosomal SNP microarray analysis replaced karyotyping in all invasively tested pregnancies and since 2014 a choice between NIPT and diagnostic testing with microarray was offered to women with an increased risk for common aneuploidy. The introduction of microarray led to an additional yield of submicroscopic pathogenic chromosome aberrations: 3.6% in fetuses with ultrasound anomalies and 1.9% in fetuses without ultrasound anomalies. The introduction of NIPT led to a decrease of invasive tests and of diagnostic yield. Moreover, a diagnostic delay in about 1:350 cases was observed. Since 20%–33% of pathogenic fetal chromosome aberrations are different from the common aneuploidies and triploidy, whole‐genome analysis should be offered after invasive sampling. Because NIPT (as a second screening) has led to a decreased diagnostic yield, it should be accompanied by an appropriate pretest counseling.     

单核苷酸多态性芯片与染色体核型分析在唐氏筛查高风险孕妇产前诊断中的比较研究

目的:探讨单核苷酸多态性芯片(SNP array)在唐氏筛查高风险孕妇胎儿染色体分析中的应用价值。方法:选取312例因唐氏筛查高风险的孕妇,行羊膜腔穿刺术后获得羊水,对羊水进行G显带核型分析和SNP array检测,比较核型分析与SNP array检测结果,并按年龄分组比较拷贝数变异(CNVs)的发生率差别。结果:核型分析和SNP array均准确发现2例21三体(0.64%),6例核型分析提示染色体平衡重组(1.92%)的样本经SNP array分析证实不存在重排片段重复或缺失。在303例核型正常的胎儿羊水细胞中,SNP array检测发现176例CNVs,其中良性CNVs 106例,临床意义不明确的CNVs(VOUS)61例,新发CNVs(de novo CNVs)9例,未发现已知的致病性CNVs。唐氏筛查高风险组与唐氏筛查高风险合并高龄组CNVs的分布差别无统计学意义(P0.05)。此外,本研究中首次报道14种CNVs。结论:SNP array可进一步确定核型分析的平衡易位是否存在染色体微缺失/重复。在核型正常的胎儿中,SNP array可检测出大量拷贝数异常,发现14种新的CNVs但现有数据库无法判断其临床意义,需进一步研究确认。此外,孕妇年龄对胎儿基因组中新发CNVs的发生率无明显影响。     

Chromosome microarray analysis should be offered to all invasive prenatal diagnostic testing following a normal rapid aneuploidy test result

Chromosomal microarray analysis (CMA) has now replaced karyotyping in the analysis of prenatal cases with a fetal structural anomaly, whereas in those pregnancies undergoing invasive prenatal diagnosis with a normal fetal ultrasound, conventional karyotyping is still performed. The aims of this study were to establish the diagnostic yield of CMA in prenatal diagnosis, and to provide new data that might contribute to reconsider current practices. We reviewed 2905 prenatal samples with a normal rapid aneuploidy detection test referred for evaluation by CMA testing. Our study revealed pathogenic and reported susceptibility copy number variants associated with syndromic disorders in 4.8% (n = 138/2905) of cases, being 2.8% (n = 81/2905) the estimated added diagnostic value of CMA over karyotyping. Clinically significant CMA abnormality was detected in 5.4% (107/1975) of the fetuses with ultrasound anomalies and in 1.4% (5/345) of those considered as low-risk pregnancies. Our series shows that in prenatal samples, CMA increases 2-fold the diagnostic yield achieved by conventional karyotyping.     

Genomic array as compared to karyotyping in myelodysplastic syndromes in a prospective clinical trial

Karyotyping is considered as the gold standard in the genetic subclassification of myelodysplastic syndrome (MDS). Oligo/SNP‐based genomic array profiling is a high‐resolution tool that also enables genome wide analysis. We compared karyotyping with oligo/SNP‐based array profiling in 104 MDS patients from the HOVON‐89 study. Oligo/SNP‐array identified all cytogenetically defined genomic lesions, except for subclones in two cases and balanced translocations in three cases. Conversely, oligo/SNP‐based genomic array profiling had a higher success rate, showing 55 abnormal cases, while an abnormal karyotype was found in only 35 patients. In nine patients whose karyotyping was unsuccessful because of insufficient metaphases or failure, oligo/SNP‐based array analysis was successful. Based on cytogenetic visible abnormalities as identified by oligo/SNP‐based genomic array prognostic scores based on IPSS/‐R were assigned. These prognostic scores were identical to the IPSS/‐R scores as obtained with karyotyping in 95%‐96% of the patients. In addition to the detection of cytogenetically defined lesions, oligo/SNP‐based genomic profiling identified focal copy number abnormalities or regions of copy neutral loss of heterozygosity that were out of the scope of karyotyping and fluorescence in situ hybridization. Of interest, in 26 patients we demonstrated such cytogenetic invisible abnormalities. These abnormalities often involved regions that are recurrently affected in hematological malignancies, and may therefore be of clinical relevance. Our findings indicate that oligo/SNP‐based genomic array can be used to identify the vast majority of recurrent cytogenetic abnormalities in MDS. Furthermore, oligo/SNP‐based array profiling yields additional genetic abnormalities that may be of clinical importance.     

Pregnant couples at increased risk for common aneuploidies choose maximal information from invasive genetic testing

Genomic array detects more pathogenic chromosome aberrations than conventional karyotyping (CK), including genetic variants associated with a susceptibility for neurodevelopmental disorders; susceptibility loci (SL). Consensus regarding the scope of invasive prenatal diagnosis (PND) pregnant couples should be offered is lacking. This study examined pregnant couples' preferences, doubts and satisfaction regarding the scope of invasive PND. Eighty‐two couples choosing prenatal screening (PNS) and 59 couples choosing invasive PND were offered a choice between 5 (comparable to CK) and 0.5 Mb resolution array analysis outcomes, the latter with or without reporting SL. A pre‐test self‐report questionnaire and post‐test telephone interview assessed their choices in‐depth. Actual (PND) and hypothetical (PNS) choices differed significantly (p < 0.001). Ninety‐five percent of the couples in the PND group chose 0.5 Mb array, vs 69% in the PNS group. Seven percent of the PND group wished not to be informed of SL. Ninety percent was satisfied with their choice and wished to decide about the scope themselves. Pregnant couples wish to make their own choices regarding the scope of invasive PND. It therefore seems justified to offer them a choice in both the resolution of array and disclosure of SL.     

Detection of submicroscopic constitutional chromosome aberrations in clinical diagnostics: a validation of the practical performance of different array platforms

For several decades etiological diagnosis of patients with idiopathic mental retardation (MR) and multiple congenital anomalies (MCA) has relied on chromosome analysis by karyotyping. Conventional karyotyping allows a genome-wide detection of chromosomal abnormalities but has a limited resolution. Recently, array-based comparative genomic hybridization (array CGH) technologies have been developed to evaluate DNA copy-number alterations across the whole-genome at a much higher resolution. It has proven to be an effective tool for detection of submicroscopic chromosome abnormalities causing congenital disorders and has recently been adopted for clinical applications. Here, we investigated four high-density array platforms with a theoretical resolution < or =100 kb: 33K tiling path BAC array, 500K Affymetrix SNP array, 385K NimbleGen oligonucleotide array and 244K Agilent oligonucleotide array for their robustness and implementation in our diagnostic setting. We evaluated the practical performance based on the detection of 10 previously characterized abnormalities whose size ranged from 100 kb to 3 Mb. Furthermore, array data analysis was performed using four computer programs developed for each corresponding platform to test their effective ability of reliable copy-number detection and their user-friendliness. All tested platforms provided sensitive performances, but our experience showed that accurate and user-friendly computer programs are of crucial importance for reliable copy-number detection.     

三例22号染色体异常胎儿的产前遗传学分析

目的应用超声以及多种遗传学检测技术对3例产前筛查提示染色体可能异常的胎儿进行分析,为遗传咨询提供依据。方法对3例孕妇进行胎儿超声检查、核型分析、单核苷酸多态性微阵列芯片(single nucleotide polymorphism-based microarray,SNP-Array)检测,并通过荧光原位杂交(fluorescence in situ hybridization,FISH)对结果进行验证。结果三例胎儿均发现22号染色体存在异常。例1在22q13.2q13.33区存在7.1 Mb的杂合缺失,涉及SHANK3、FBLN1等54个OMIM基因;例2为嵌合体核型,约12%的细胞22q13.31q13.33区存在6.6 Mb的杂合缺失,覆盖SHANK3、PPARA等48个OMIM基因,另有5%的细胞22q11.1q13.2区存在26.1 Mb的拷贝重复,覆盖285个OMIM基因;例3在22q11.1q11.21区存在1.7 Mb的二次重复,涉及CECR1、CECR2、ATP6V1E1等10个OMIM基因。三例胎儿父母的核型及SNP-Array检测结果均未见异常,提示胎儿为新发变异。结论22号染色体微缺失/微重复所致疾病的严重性不仅与其范围有关,还与染色体结构、基因剂量及环境等密切相关。在产前诊断中综合运用超声和多种遗传学检测技术可以显著提高表型变异较大的遗传学异常的检出率。     

Intrauterine phenotype features of fetuses with Williams–Beuren syndrome and literature review

Williams–Beuren syndrome (WBS) is a well-defined multisystem chromosomal disorder that is caused by a chromosome 7q11.23 region heterozygous deletion. We explored prenatal diagnosis of WBS by ultrasound as well as multiple genetic methods to characterize the structural variants of WBS prenatally. Expanded noninvasive prenatal testing (NIPT-plus) was elected as a regular prenatal advanced screen for risk assessments of fetal chromosomal aneuploidy and genome-wide microdeletion/microduplication syndromes at the first trimester. At the second and three trimester, seven prenatal cases of WBS were evaluated for the indication of the invasive testing, the ultrasound features, cytogenetic, single-nucleotide polymorphism array (SNP array), and fluorescent quantitative PCR (QF-PCR) results. The NIPT-plus results for seven fetuses were low risk. All cryptic aberrations were detected by the SNP array as karyotyping analyses were negative. Subsequently, QF-PCR further confirmed the seven deletions. Combining our cases with 10 prenatal cases from the literature, the most common sonographic features were intrauterine growth retardation (82.35%, 14/17) and congenital cardiovascular abnormalities (58.82%, 10/17). The manifestations of cardiovascular defects mainly involve supravalvar aortic stenosis (40%, 4/10), ventricular septal defect (30%, 3/10), aortic coarctation (20%, 2/10), and peripheral pulmonary artery stenosis (20%, 2/10). To the best of our knowledge, this is the first largest prenatal study of WBS cases with detailed molecular analysis. Aortic coarctation combined with persistent left superior vena cava and right aortic arch cardiovascular defects were first reported in prenatal WBS cases by our study.     

孕妇产前诊断指征与胎儿染色体异常的关系

目的探讨产前诊断指征和产前诊断胎儿染色体异常间的关系。方法选择2018年6月至2018年12月于贵港市人民医院就诊的孕妇100例,收集所有孕妇产前诊断指征的资料,同时收集羊膜腔穿刺术检测胎儿染色体核型分析的结果。结果胎儿染色体异常共9例,总异常率占9.00%,其中无创基因检测异常组的胎儿染色体异常检出率为60.00%,明显高于高龄组的3.03%、唐氏筛查高危组的5.26%及胎儿超声异常组的7.69%,差异均有统计学意义(P<0.05);夫妇染色体异常组的胎儿染色体异常检出率为50.00%,明显高于高龄组,差异均有统计学意义(P<0.05);高龄组、唐氏筛查高危组、胎儿超声异常组间异常检出率无明显差异(P>0.05)。结论产前诊断指征与胎儿染色体异常密切相关,羊膜腔穿刺行染色体核型分析,能够有效检出胎儿染色体异常,对于有产前诊断指征的孕妇应尽早接受产前诊断,以降低新生儿出生缺陷的发生率。     

Update on the use of exome sequencing in the diagnosis of fetal abnormalities

Unexpected fetal abnormalities detected through ultrasound scanning in pregnancy may have a monogenic aetiology but are difficult to diagnose. Next generation sequencing now enables us to sequence fetal exomes, providing increased resolution and broader diagnostic capability compared to traditional cytogenetic prenatal tests, improving the yield and accuracy of diagnoses and allowing better counselling for expectant parents.Here we review published studies of exome sequencing (ES) for prenatal diagnosis over the last 5 years and address important questions for its clinical implementation, including clinical utility, which groups benefit most, and practical and ethical challenges for interpreting and reporting results.We observe that fetal ES substantially improves diagnostic yield relative to cytogenetic techniques. However, diagnostic rates vary widely between studies, largely attributable to differences in case selection. Recently several large studies report variations in diagnostic yield between phenotypic groups, with fetuses with multisystem abnormalities most likely to receive a diagnosis from fetal ES. Challenges for prenatal ES include the limitations of ultrasound-based fetal phenotyping, the need for rapid return of results in pregnancy, and technical limitations compared to whole genome sequencing. We also consider ethical issues around potential secondary findings and variants of uncertain significance and the complex counselling needs these present.Prenatal ES is a valuable tool to diagnose fetal abnormalities and, as it is implemented in the clinic, more large-scale research will serve to further delineate its clinical utility, as well as generating new knowledge about fetal phenotypes and informing guidelines for case selection, reporting results and genetic counselling.     

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。     

Full karyotyping, rapid aneuploidy diagnosis or both when invasive prenatal testing is performed for diagnosis of thalassaemia?

A retrospective study was performed to compare the detection rate of chromosomal abnormalities by different approaches of full karyotyping, rapid aneuploidy diagnosis (RAD) or both when invasive prenatal testing is performed for diagnosis of thalassaemia. The karyotype results of 1120 prenatal samples obtained from thalassaemia couples from January 1985 to December 2002 in a referral centre for prenatal diagnosis were studied. The detection rate of chromosomal abnormalities by four different approaches were compared: (i) karyotyping for all samples; (ii) RAD (21,18,13,X,Y) for all samples; (iii) RAD for all samples + karyotyping for cases with ultrasound abnormalities; and (iv) RAD (21,18,13) for all + RAD (X,Y) for cases with ultrasound abnormalities consistent with Turner syndrome + karyotyping for cases with ultrasound abnormalities. Normal karyotypes were found in 1103 samples (98.5%). There were 17 cases (1.5%) of chromosomal abnormalities: four cases (0.36%) were clinically significant, eight cases (0.7%) were of borderline clinical significance and five cases (0.44%) were not confirmed by subsequent prenatal or postnatal tests. The incidences of autosomal (7/1120 = 0.63%) and sex chromosomal (5/1120 = 0.45%) abnormalities were not higher than those (0.41 and 0.22%, respectively) from newborn surveys (Hook and Hamerton, 1977) (P = 0.398 and 0.216, respectively). Approach 1 would detect all 17 chromosomal abnormalities. Approach 2 would detect three of four clinically significant chromosomal abnormalities but not detect six of eight chromosomal abnormalities of borderline clinical significance and three of five chromosomal abnormalities not confirmed by subsequent prenatal or postnatal tests. Approach 3, in addition, would be able to detect all four clinically significant chromosomal abnormalities. Approach 4 would detect all four clinically significant chromosomal abnormalities but would not detect seven of eight chromosomal abnormalities of borderline clinical significance and four of five chromosomal abnormalities not confirmed by subsequent prenatal or postnatal tests. RAD (21,18,13) for all + RAD (X,Y) for cases with ultrasound abnormalities consistent with Turner syndrome + karyotyping for cases with ultrasound abnormalities seemed to be the best approach for the detection of chromosomal abnormalities when invasive prenatal testing is performed for diagnosis of thalassaemia.     

细菌人工染色体标记-微球鉴别/分离法对1239份羊水的快速产前诊断

目的探讨细菌人工染色体标记-微球鉴别/分离法(bacterial artificial chromosomes-on-beads,BoBs)联合染色体核型分析在产前诊断中的应用价值。方法1239例有产前诊断指征的孕妇羊水细胞行染色体核型分析和BoBs检测,检测结果进行比较分析。结果1239例羊水中共发现胎儿染色体异常30例,检出率为2.42%,其中染色体核型分析检出25例,BoBs检出25例。30例异常核型中,染色体非整倍体17例,BoBs检测结果与染色体核型分析结果吻合;染色体微缺失/微重复综合征8例,染色体核型分析检出3例;染色体结构异常5例,BoBs检测未见异常。结论BoBs技术联合染色体核型分析可快速检测胎儿染色体异常及常见微缺失/微重复综合征,大大提高了产前诊断的效率及准确性。     

The introduction of arrays in prenatal diagnosis: a special challenge

Genome-wide arrays are rapidly replacing conventional karyotyping in postnatal cytogenetic diagnostics and there is a growing request for arrays in the prenatal setting. Several studies have documented 1-3% additional abnormal findings in prenatal diagnosis with arrays compared to conventional karyotyping. A recent meta-analysis demonstrated that 5.2% extra diagnoses can be expected in fetuses with ultrasound abnormalities. However, no consensus exists as to whether the use of genome-wide arrays should be restricted to pregnancies with ultrasound abnormalities, performed in all women undergoing invasive prenatal testing or offered to all pregnant women. Moreover, the interpretation of array results in the prenatal situation is challenging due to the large numbers of copy number variants with no major phenotypic effect. This also raises the question of what, or what not to report, for example, how to deal with unsolicited findings. These issues were discussed at a working group meeting that preceded the European Society of Human Genetics 2011 Conference in Amsterdam. This article is the result of this meeting and explores the introduction of genome-wide arrays into routine prenatal diagnosis. We aim to give some general recommendations on how to develop practical guidelines that can be implemented in the local setting and that are consistent with the emerging international consensus.     

联合运用多种技术鉴别四例胎儿新发标记染色体

目的探讨传统细胞遗传学技术联合SNP - array （ single nucleotide polymorphisms array, SNP - array）在识别胎儿微小额外标记染色体（ supernumerary marker chromosome, sSMC）致病性中的临床应用价值。方法通过常规G显带技术分析胎儿染色体核型,针对发现的sSMC,应用C显带技术分析ssMC,如果sSMC非异染色质,进一步进行SNP—array辨别其来源并分析相应的表型。结果通过对8575例产前诊断标本G显带核型分析发现4例新发标记染色体,其中C显带示2例为异染色质结构,2例为非异染色质结构。这2例非异染色质结构病例进一步行SNP—array检测,结果示一例未见致病性改变,另一例为4号染色体部分重复。结论SNP—array能够在基因组水平上识别胎儿sSMC的成分,结合传统的细胞遗传学技术应用于产前诊断中,为确定sSMC的致病性提供了可靠的产前诊断技术平台。     

High‐resolution molecular karyotyping in patients with developmental delay and/or multiple congenital anomalies in a clinical setting

Wincent J, Anderlid B‐M, Lagerberg M, Nordenskjöld M, Schoumans J. High‐resolution molecular karyotyping in patients with developmental delay and/or multiple congenital anomalies in a clinical setting. Microarray‐based comparative genomic hybridization (array‐CGH) enables genomewide investigation of copy‐number changes at high resolution and has recently been implemented as a clinical diagnostic tool. In this study we evaluate the usefulness of high‐resolution arrays as a diagnostic tool in our laboratory and investigate the diagnostic yield in the first 160 patients who were clinically referred for investigation of developmental delay (DD)/multiple congenital anomalies (MCA). During this period both 38K BAC‐arrays and 244K oligonucleotide‐arrays were used. Copy‐number variations (CNVs) not previously reported as normal variants were detected in 22.5% of cases. In 13.1% the aberrations were considered causal to the phenotype and in 9.4% the clinical significance was uncertain. There was no difference in diagnostic yield between patients with mild, moderate or severe DD. Although the effective resolution of the 244K oligonucleotide‐arrays was higher than the 38K BAC‐array, the diagnostic yield of both platforms was approximately equal and no causal aberrations <300 kb were detected in this patient cohort. We experienced that increasing the resolution of a whole genome screen in the diagnostic setting has its drawback of detecting an increased number of CNVs with uncertain contribution to a phenotype. Based on our experiences, array‐CGH is recommended as the first‐step analysis in the genetic evaluation of patients with DD and/or MCA.     

Prenatal diagnosis of micrognathia in 41 fetuses: Retrospective analysis of outcome and genetic etiologies

Fetal micrognathia can be detected early in pregnancy. Prognosis of micrognathia depends on the risk of respiratory distress at birth and on the long‐term risk of intellectual disability. The purpose of this study was to evaluate the long‐term prognosis of fetuses with prenatal diagnosis of micrognathia by estimating the prevalence and the severity of confirmed genetic diagnosis in our cohort. Our retrospective study included 41 fetuses with prenatal diagnosis of micrognathia referred to the multidisciplinary centers for prenatal diagnosis in Nice and Marseille, France, between 2006 and 2016. Fetal micrognathia was associated with cleft palate in 27 cases. A genetic cause was confirmed in 21 cases (67%). A chromosomal abnormality was present in 12 cases, including three copy‐number variations diagnosed by array CGH. Monogenic disorders were identified in nine cases, most often after birth. Fetuses with family history of micrognathia or Pierre Robin sequence had a favorable outcome. Prognosis was good for the fetuses without associated findings and normal chromosomal analysis, with the exception of one case with a postnatal diagnosis of mandibulofacial dysostosis with microcephaly. Prognostic was poor for the fetuses with additional ultrasound anomalies, as only 5 out of 28 children had a good outcome. Prenatal diagnosis of micrognathia is an indicator of a possible fetal pathology justifying multidisciplinary management. Our study confirms the necessity of performing prenatal array CGH. Use of high‐throughput gene sequencing in prenatal period could improve diagnostic performance, prenatal counseling, and adequate postnatal care.     

Prenatal genetic analysis of two fetuses with Miller-Dieker syndrome北大核心CSCD

Objective To perform molecular cytogenetic study on two fetuses with abnormal ultrasound findings andanalyze their genotype-phenotype correlation. Methods G-banded karyotyping, single nucleotide polymorphismarray (SNP array) and fluorescence in situ hybridization (FISH) were performed on amniotic fluid cells fromboth fetuses and peripheral blood samples from their parents. Results of SNP array were analyzed withbioinformatics software. Results G-banded karyotyping failed to detect any abnormalities in both fetuses andtheir parents. SNP array detected a 2. 484 Mb terminal deletion at 17pl3. 3[arr[hgl9] 17pl3. 3(83 035-2 567405) X 1] in fetus 1 and a 3. 295 Mb terminal deletion at 17pl3. 3pl3. 2[arr[hgl9] 17pl3. 3pl3. 2 (83 035- 3377 560) X 1] in fetus 2. Both deletions have overlapped with the critical region of Miller-Diekersyndrome(MDS) and involved candidate genes such as PAFAH1B1, YWHAE and CRK. In addition, SNP array and FISHanalyses on the parental peripheral blood samples demonstrated that both 17pl3. 3 and 17pl3. 3pl3. 2 deletionswere of de novo origin. Metaphase FISH performed on amniotic fluid cells confirmed the presence of 17pl3. 3 and 17pl3. 3pl3. 2 deletions detected by the SNP array, while metaphase FISH performed on the parents excluded anypotential chromosome rearrangements. Conclusion Abnormal ultrasound features for fetuses with MDS mainlyinclude central nervous system anomalies. SNP array can efficiently detect 17pl3. 3 microdeletions underlyingMDS, and accurately map the breakpoints and involved genes, which may facilitate understanding of the genotypeand phenotype correlations for MDS.