Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada

Abstract

BackgroundThe aim of this guideline is to provide updated recommendations for Canadian genetic counsellors, medical geneticists, maternal fetal medicine specialists, clinical laboratory geneticists and other practitioners regarding the use of chromosomal microarray analysis (CMA) for prenatal diagnosis. This guideline replaces the 2011 Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) Joint Technical Update.MethodsA multidisciplinary group consisting of medical geneticists, genetic counsellors, maternal fetal medicine specialists and clinical laboratory geneticists was assembled to review existing literature and guidelines for use of CMA in prenatal care and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the CCMG membership-at-large for feedback and, following incorporation of feedback, was approved by the CCMG Board of Directors on 5 June 2017 and the SOGC Board of Directors on 19 June 2017.Results and conclusionsRecommendations include but are not limited to: (1) CMA should be offered following a normal rapid aneuploidy screen when multiple fetal malformations are detected (II-1A) or for nuchal translucency (NT) ≥3.5 mm (II-2B) (recommendation 1); (2) a professional with expertise in prenatal chromosomal microarray analysis should provide genetic counselling to obtain informed consent, discuss the limitations of the methodology, obtain the parental decisions for return of incidental findings (II-2A) (recommendation 4) and provide post-test counselling for reporting of test results (III-A) (recommendation 9); (3) the resolution of chromosomal microarray analysis should be similar to postnatal microarray platforms to ensure small pathogenic variants are detected. To minimise the reporting of uncertain findings, it is recommended that variants of unknown significance (VOUS) smaller than 500 Kb deletion or 1 Mb duplication not be routinely reported in the prenatal context. Additionally, VOUS above these cut-offs should only be reported if there is significant supporting evidence that deletion or duplication of the region may be pathogenic (III-B) (recommendation 5); (4) secondary findings associated with a medically actionable disorder with childhood onset should be reported, whereas variants associated with adult-onset conditions should not be reported unless requested by the parents or disclosure can prevent serious harm to family members (III-A) (recommendation 8).The working group recognises that there is variability across Canada in delivery of prenatal testing, and these recommendations were developed to promote consistency and provide a minimum standard for all provinces and territories across the country (recommendation 9).

Chromosomal microarray analysis in fetuses with congenital anomalies of the kidney and urinary tract: A prospective cohort study and meta‐analysis

“…The yield of CMA over karyotyping in fetuses with isolated CAKUT was lower than that in fetuses with other isolated malformation, such as congenital heart defects (~7.0%), musculoskeletal malformations (~8.0%), and central nervous system abnormalities (~6.0%) . The incremental yield of CMA over karyotyping in the nonisolated CAKUT group was also lower than that in previous reported studies . One possible reason for the low detection rate of CMA in CAKUT is that many CAKUT cases were caused by a single gene defect.…”

“…The variants classified into the pathogenic or likely pathogenic categories were reported regardless of size, while variants classified into likely benign or benign categories were not reported. To minimize the reporting of uncertain findings in the prenatal context, variants of VOUS that were smaller than 500 kb deletion or 1 Mb duplication were not reported, which was consistent with the CCMG‐SOGC recommendation . All clinically significant CNVs identified by CMA were further confirmed by real‐time qPCR according to the standard procedures.…”

“…However, reports of CMA analysis in prenatal cases with CAKUT are limited, and the sample size in the published studies has been small. To date, the usefulness and diagnostic yield of CMA in prenatal cases of CAKUT remain unclear …”

Prenatal diagnosis of chromosomal aberrations by chromosomal microarray analysis in fetuses with ultrasound anomalies in the urinary system

“…Although CMA is recommended when a single or multiple fetal anomalies are identified by ultrasound, there remains a paucity of studies that focus on the relationships between CNVs and ultrasonic anomalies in the urinary system . Our study specifically focused on CMA findings in fetuses with ultrasonographic anomalies of the urinary system and performed follow‐up assessment in an attempt to elucidate the genetic and clinical value of CNVs in anomalies of the urinary system.…”

“…The detected CNVs were each evaluated for size and type (deletion or duplication), the morbidity of the impacted gene(s) (eg, loss or gain of function), and inheritance pattern and compared with values in the following publicly available databases and in the scientific literature: (a) Database of Genomic Variants (DGV; http://projects.tcag.ca/variation/), (b) Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER; http://decipher.sanger.ac.uk/), (c) GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1116/), (d) Clinical Genome Resource (ClinGene; https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/), (e) Online Mendelian Inheritance in Man (OMIM; http://www.ncbi.nlm.nih.gov/omim), and PubMed (https://www.ncbi.nlm.nih.gov/pubmed). The clinical significance of each CNV was defined and classified into three categories: pathogenic, uncertain clinical significance (VUS) (subclassified as likely pathogenic, variant of uncertain significance or likely benign) and benign according to the guidelines . The CNVs defined as benign or likely benign were not reported.…”