UOG Journal Club: Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature

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Health & Medicine

Published on February 5, 2014

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Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature

M.C. de Wit, M.I. Srebniak, L.C.P. Govaerts, D. Van Opstal, R.J.H. Galjaard and A.T.J.I. Go

Link to free access article: http://onlinelibrary.wiley.com/doi/10.1002/uog.12575/abstract

UOG Journal Club: February 2014 Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature M.C. de Wit, M.I. Srebniak, L.C.P. Govaerts, D. Van Opstal, R.J.H. Galjaard and A.T.J.I. Go Volume 43, Issue 2, Date: February 2014, pages 139-147 Journal Club slides prepared by Dr Leona Poon (UOG Editor for Trainees)

• • • • • • Fetuses with multiple congenital abnormalities have a >18% chance of carrying a microscopic chromosomal abnormality (Nicolaides et al, 1992). Genomic microarray has been introduced in some prenatal centers as a diagnostic tool, instead of or in addition to cytogenetic karyotyping. Genomic microarray achieves a much higher resolution than cytogenetic karyotyping and reveals copy number variants (CNVs). Some CNVs can be of etiologic importance in congenital malformations and syndromes (Cooper et al, 2011). Clinically significant submicroscopic CNVs are found in 5-10% of fetuses with multiple ultrasound anomalies and a normal karyotype. Knowledge about the chances of finding a causative submicroscopic CNV in a fetus with an isolated ultrasound anomaly is scarce. Nicolaides KH et al. Lancet 1992;340:704-7. Cooper GM et al. Nat Genet 2011;43:838-46.

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Objectives 1. To establish the prevalence of genetic CNVs in fetuses with a structural ultrasound anomaly (restricted to one anatomical system) and a normal karyotype. 2. To determine the diagnostic and prognostic value of genomic array testing in these pregnancies.

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Search strategy: 8 May 2013 (Micro)array AND prenatal AND ultrasound anomalies EX animal, review, case report LIM English PubMed (n=775) Embase (n=496) Exclusion of duplicates (n=169) Exclusion criteria (title and abstract): n=1102 Inclusion criteria (full text): • Selection on normal karyotype or size array abberation stated • Description of cohorts composition regarding ultrasound findings (unsuitable n=18) • Clear judgment of pathogenicity of CNVs stated • Known number of pathogenic CNVs per group of fetuses with an anomaly in a specific anatomical system (unsuitable n=2) Criteria for critical appraisal:  Sample size  Moment of case recruitment  Description quality of ultrasound anomalies  Description quality of array platform and CNVs found n=38 • Use of technique other than genomic array • Array performed only for indications other than ultrasound anomalies • Non-prenatal setting • Cohort with only non-structural abnormalities Web of knowledge: no additional inclusions Exclusion because of overlapping cohorts (n=1) and exclusion of validation studies (n=1) Included studies (n=18)

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Methodology Study selection • Studies reporting on the prevalence of pathogenic submicroscopic CNVs in fetuses with an ultrasound anomaly were selected. They: • Described fetuses with a known normal karyotype and described their cohort in such a manner that fetuses with large genomic aberrations of >10 Mb and/or chromosome aberrations identified by rapid aneuploidy detection. • Described the composition of their cohort regarding the number of fetuses with a structural ultrasound anomaly in a specific anatomical system. • Reported a clear judgment of the CNVs regarding their presumed nature, for example, pathogenic or benign. • Showed the pathogenic CNVs in detail or gave the number of pathogenic CNVs per group of fetuses with an anomaly in a specific anatomical system.

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Methodology Data extraction • Four reviewers independently extracted data. • The appraisal included features of validated quality-assessment tools and used sample size, cohort selection, study perspective, the description quality of ultrasound findings and CNV classification as the parameters for assessment. • An array result was assumed to be causative and pathogenic if the reporting author classified it as such. • For every group of fetuses with an ultrasound anomaly restricted to one particular anatomical system, the prevalence of pathogenic CNVs and its 95% CI was calculated.

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Results Pooled prevalence of pathogenic submicroscopic CNVs in a specific anatomical system Isolated anomalies Resp CNS Facial 5/81 35/563 6/113 6.2% 6.2% 5.3% (0.9-11.4) (4.2-8.2) (1.2-9.4) Pooled prevalence (95% CI) Cardiac 22/476 4.6% (2.7-6.5) Pooled prevalence (95% CI) Isolated anomalies NT Cystic GIT Urogenital >3.5 mm hygroma 7/105 9/153 5/162 12/262 6.7% 5.9% 3.1% 4.6% (1.9-11.4) (2.2-9.6) (0.4-5.7) (2.0-7.1) MSK 24/305 7.9% (4.8-10.9) Total 125/2220 5.6% (4.7-6.6)

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Results Multiple All anomalies anomalies Tyreman (2009) 6/24 9/82 (11.1) Vialard (2009) 3/36 3/36 (8.3) Coppinger WG (2009) 1/62 5/122 (4.1) Coppinger TA (2009) 7 0/15 Kleeman (2009) 1 0/43 Evangelidou (2010) 0/8 Leung (2011) 2/10 4/48 (8.5) D’ Amours (2012) 2/24 4/47 (8.5) Lee (2012) 3/36 15/136 (11.0) Shaffer (2012) 77/808 159/2184 (7.3) Faas (2012) 1/40 2/90 (2.2) Ganesamoorthy (2013) 3/25 4/70 (5.7) Mademont-Soler (2013) 1/23 1/51 (2.0) Rooryck (2013) 2/56 (3.6) Schmid (2013) 4/10 5/45 (11.1) Hillman (2013) 11 6/187 (3.2) Scott (2013) 2/62 (3.2) Vestergaard (2013) 1/22 8/77 (10.3) Reference Prevalence of pathogenic submicroscopic CNVs in multiple / all anomalies Pooled prevalence (95% CI) Multiple All anomalies anomalies 104/1139 229/3359 9.1% 6.8% (7.5-10.8) (6.0-7.7)

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Limitations The prevalence of pathogenic submicroscopic CNVs between the reviewed studies varied between 0 to 11.1%. The most prevalent discrepancies can be: • Most probably explained by the predominantly small sample sizes: only four studies described cohorts of > 100 fetuses. • Partially explained by • Differences in cohort selection: ranging from ‘major ultrasound anomalies’ to ‘any abnormality detected by ultrasound’. • Some cases of non-structural anomalies or unspecified ultrasound findings were difficult for exclusion. • Enormous variety and resolution in the array platforms used (e.g. single nucleotide polymorphisms [SNPs] and bacterial artificial chromosomes [BACs]).

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Discussion • 5.6% (95% CI 4.7-6.6) chance of finding a causal submicroscopic CNV in fetuses with a structural ultrasound anomaly restricted to one anatomical system and a normal karyotype • The group with NT>3.5 mm has the lowest prevalence of pathogenic submicroscopic CNVs (3.1%, 95% CI 0.4-5.7) • Pathogenic genomic micro-imbalances are most frequently found in polymalformed fetuses (9.1%, 95% CI 7.5-10.8). • Clinically relevant submicroscopic CNVs are spread through the whole genome, therefore, screening for sub-telomeric abnormalities before array testing is not advised.

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Discussion • Screening with FISH for the 22q11 microdeletion before array testing appears to be of limited value. • The application of an internationally recognized fetal phenotype coding system would be of great value because such a system: • Would allow better comparison of cases • More reliable calculation of the prevalence of pathogenic submicroscopic CNVs in specific structural fetal defects • Discovery of new / novel pathogenic CNVs • The International Standards for Cystogenomic Arrays phenotype form ( https://www.iscaconsortium.org) is a good instrument that uses Human Phenotype Ontology terms.

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Discussion • To allow the discovery of new pathogenic CNVs, whole-genome array platforms should be recommended in prenatal setting. • If local policy does not allow genome-wide analysis, 2-step analysis could be performed: targeted analysis with a lower backbone resolution • Both pathogenic CNVs and variants of unknown clinical significance (VOUS) should be published and human genome build should be stated. • A clear definition for the term ‘incidental finding’ should be established. • Postnatal follow-up in cases with specific malformations on ultrasound is essential in drawing conclusions on microarray tests in prenatal diagnosis.

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Conclusions • Genomic microarray should be performed in fetuses with both isolated and multiple ultrasound anomalies. • Causative submicroscopic CNVs are found in 5.6% of fetuses with isolated anomalies and in 9.1% of fetuses with multiple anomalies. • Implementation of an international uniform classification system for ultrasound abnormalities is necessary to contribute to the comparability of cohorts.

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature De Wit et al., UOG 2014 Discussion points • Should genomic array replace traditional cytogenetic karyotyping in the prenatal diagnosis of fetuses with both isolated and multiple ultrasound anomalies? • Do we have enough evidence to support the use of genomic array in clinical settings? • If yes, • How should fetal medicine subspecialists and geneticists counsel women prior to invasive testing? • How will it impact on the current system of cytogenetic services? • If no, • How can we rapidly collate as much information on CNVs and VOUS?

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