Sc Hillman

Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta‐analysis

Array comparative genomic hybridization (CGH) is transforming clinical cytogenetics with its ability to interrogate the human genome at increasingly high resolution. The aim of this study was to determine whether array CGH testing in the prenatal population provides diagnostic information over conventional karyotyping.

Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta‐analysis

Chromosomal microarray analysis (CMA) is utilized in prenatal diagnosis to detect chromosomal abnormalities not visible by conventional karyotyping. A prospective cohort of women undergoing fetal CMA and karyotyping following abnormal prenatal ultrasound findings is presented in the context of a systematic review and meta‐analysis of the literature describing detection rates by CMA and karyotyping.

Co-twin prognosis after single fetal death: a systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis of the effects on the surviving twin of single fetal death comparing monochorionic to dichorionic twins to report the rates of co-twin death, preterm delivery, and neurologic morbidity in the surviving fetus. DATA SOURCES: MEDLINE (inception–December 2010), EMBASE (inception–December 2010), The Cochrane library (inception–December 2010), Web of Science (inception–December 2010), and British Nursing Index (inception–December 2010) were searched electronically. METHODS OF STUDY SELECTION: Selected studies had more than five cases of single fetal death with reports of co-twin death, neurologic morbidity, or both co-twin death and neurologic morbidity. They also must have defined the gestational age of single fetal death and chorionicity. TABULATION, INTEGRATION, AND RESULTS: The search yielded 1,386 citations. Full manuscripts were retrieved for 204 and 22 were included in the review and meta-analysis. Twenty manuscripts were used to calculate overall summary statistics for monochorionic and dichorionic twins showing rates of co-twin death after single fetal death (15% compared with 3%), rates of preterm delivery after single fetal death (68% compared with 54%), the rate of abnormal postnatal cranial imaging after single fetal death (34% compared with 16%), and the rate of neurodevelopmental impairment after single fetal death (26% compared with 2%). Odds ratios (ORs) were calculated from 16 manuscripts. There was no significant difference reported between preterm delivery of monochorionic or dichorionic twins (OR 1.1, 95% confidence interval [CI] 0.34–3.51, P=.9). After single fetal death, monochorionic twins had higher odds of an abnormal cranial imaging after delivery, this was not significant (OR 3.25, 95% CI 0.66–16.1, P=.12). After single fetal death, monochorionic twins were 4.81-times more likely to have neurodevelopmental morbidity (95% CI 1.39–16.6, P<.05). CONCLUSION: Monochorionic twins are at significantly increased odds of co-twin demise and neurodevelopmental morbidity after single fetal death.

Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound

The genetic etiology of non-aneuploid fetal structural abnormalities is typically investigated by karyotyping and array-based detection of microscopically detectable rearrangements, and submicroscopic copy-number variants (CNVs), which collectively yield a pathogenic finding in up to 10% of cases. We propose that exome sequencing may substantially increase the identification of underlying etiologies. We performed exome sequencing on a cohort of 30 non-aneuploid fetuses and neonates (along with their parents) with diverse structural abnormalities first identified by prenatal ultrasound. We identified candidate pathogenic variants with a range of inheritance models, and evaluated these in the context of detailed phenotypic information. We identified 35 de novo single-nucleotide variants (SNVs), small indels, deletions or duplications, of which three (accounting for 10% of the cohort) are highly likely to be causative. These are de novo missense variants in FGFR3 and COL2A1, and a de novo 16.8 kb deletion that includes most of OFD1. In five further cases (17%) we identified de novo or inherited recessive or X-linked variants in plausible candidate genes, which require additional validation to determine pathogenicity. Our diagnostic yield of 10% is comparable to, and supplementary to, the diagnostic yield of existing microarray testing for large chromosomal rearrangements and targeted CNV detection. The de novo nature of these events could enable couples to be counseled as to their low recurrence risk. This study outlines the way for a substantial improvement in the diagnostic yield of prenatal genetic abnormalities through the application of next-generation sequencing.

Additional information from chromosomal microarray analysis (CMA) over conventional karyotyping when diagnosing chromosomal abnormalities in miscarriage: a systematic review and meta-analysis

Approximately 50% of spontaneous miscarriages are associated with chromosome abnormalities. Identification of these karyotypic abnormalities helps to estimate recurrence risks in future pregnancies. Chromosomal microarray analysis (CMA) is transforming clinical cytogenetic practice with its ability to examine the human genome at increasingly high resolution.

Prenatal exome sequencing for fetuses with structural abnormalities: the next step

†College of Women’s and Children’s Health & School of Clinical and Experimental Medicine, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham, UK; Fetal Medicine Centre, Birmingham Women’s Foundation Trust, Edgbaston, Birmingham, UK; ‡Department of Clinical Genetics, Birmingham Women’s Foundation Trust, Edgbaston, Birmingham, UK; §Genome Mutation and Genetic Disease Group, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; ¶West Midlands Genetics Laboratory, Birmingham Women’s Foundation Trust, Edgbaston, Birmingham, UK *Correspondence. (e-mail: sarahchillman@hotmail.com)

“If it helps …” the use of microarray technology in prenatal testing: Patient and partners reflections

The objective was to gain insight into the experiences of women and their partners diagnosed with a fetal abnormality on prenatal ultrasound examination and receiving genetic testing including microarray. Twenty‐five semi‐structured interviews were performed with women +/− their partners after receiving the results of prenatal genetic testing. Framework analysis was performed to elicit themes and subthemes. Five main themes were recognized; diagnosis, genetic testing, family and support, reflections of the treatment received and emotions. Our results showed that women recall being told about QFPCR for trisomy 13, 18, and 21 but often no further testing. Women expected the conventional karyotype and microarray result would be normal following a normal QFPCR result. There were frequent misconceptions by couples regarding aspects of counseling/testing. Communication of variants of unknown (clinical) significance (VOUS) presents a particularly difficult challenge. Good clear communication by health care professionals is paramount. When counseling women and their partners for fetal chromosomal testing it should be reinforced that although the most common, trisomy 13, 18, and 21 only account for some of the chromosomal changes resulting in abnormal scan findings. Couples should have literature to take home summarizing scan anomalies and reinforcing information about genetic testing.

Microarray comparative genomic hybridization in prenatal diagnosis: a review

G‐band chromosomal karyotyping of fetal cells obtained by invasive prenatal testing has been used since the 1960s to identify structural chromosomal anomalies. Prenatal testing is usually performed in response to parental request, increased risk of fetal chromosomal abnormality associated with advanced maternal age, a high‐risk screening test and/or the presence of a congenital malformation identified by ultrasonography. The results of karyotyping may inform the long‐term prognosis (e.g. aneuploidy being associated with a poor outcome or microscopic chromosomal anomalies predicting global neurodevelopmental morbidity). Relatively recent advances in microarray technology are now enabling high‐resolution genome‐wide evaluation for DNA copy number abnormalities (e.g. deletions or duplications). While such technological advances promise increased sensitivity and specificity they can also pose difficult challenges of interpretation and clinical management. This review aims to give interested clinicians without an extensive prior knowledge of microarray technology, an overview of its use in prenatal diagnosis, the literature to date, advantages, potential pitfalls and experience from our own tertiary center. Copyright

How does altering the resolution of chromosomal microarray analysis in the prenatal setting affect the rates of pathological and uncertain findings

Abstract Objective: Chromosomal Microarray Analysis (CMA) has a higher detection rate of pathogenic chromosome abnormalities over conventional (G-band) karyotyping. The optimum resolution of CMA in the prenatal setting remains debatable. Our objective was to determine if an increased detection rate was obtained by performing differing resolution of CMA on the same fetal samples and whether this resulted in an increase in variants of uncertain clinical significance (VOUS). Methods: Sixty-two fetal cases initially underwent a 1 Mb targeted BAC microarray within a clinical diagnostic setting in addition to conventional karyotyping. At the conclusion of pregnancy, a higher resolution 60 K oligonucleotide microarray was performed. Results: The 1 Mb BAC analysis demonstrated a detection rate of pathogenic copy number variations (CNVs) in 4.1% (95% CI 2.1–7.6) of cases and a variation of unknown significance (VOUS) rate of 0.4% (95% CI 0.07–2.2) over conventional G-band karyotyping. The 60 K array had an additional pathogenic detection rate of 4.8% (95% CI 1.6–13.3) over the BAC array but also detected an additional 8% (95% CI 1.3–14.8) VOUS. Conclusion: As the CMA platform resolution increases detection rates increase but are associated with an increase in VOUS rates. Our findings support the need for further large scale studies to inform the national consensus on the resolution required and on reporting of VOUS in the antenatal setting.

A systematic review and thematic synthesis of qualitative studies on maternal emergency transport in low- and middle-income countries

Most maternal deaths are preventable with emergency obstetric care; therefore, ensuring access is essential. There is little focused information on emergency transport of pregnant women.