Experience of chromosomal microarray applied in prenatal and postnatal settings in Hong Kong

Abstract

Chromosomal microarray (CMA) is recommended as a first tier investigation for patients with developmental delay (DD), intellectual disability (ID), autistic spectrum disorder (ASD), and multiple congenital anomalies (MCA). It is widely used in the prenatal and postnatal settings for detection of chromosomal aberrations. This is a retrospective review of all array comparative genomic hybridization (aCGH/ array CGH) findings ascertained in two major prenatal and postnatal genetic diagnostic centers in Hong Kong from June 2012 to December 2017. Medical records were reviewed for cases with pathogenic and variants of uncertain clinical significance (VUS). Classification of copy number variants (CNVs) was based on current knowledge and experience by August 2018. The aims of this review are to study the diagnostic yield of array CGH application in prenatal and postnatal settings in Hong Kong and to describe the spectrum of abnormalities found. Prenatal indications included abnormal ultrasound findings, positive Down syndrome screening, abnormal noninvasive prenatal test results, advanced maternal age and family history of chromosomal or genetic abnormalities. Postnatal indications included unexplained DD, ID, ASD, and MCA. A total of 1,261 prenatal subjects and 3,096 postnatal patients were reviewed. The prenatal diagnostic yield of pathogenic CNV and VUS (excluding those detectable by karyotype) was 3.5%. The postnatal diagnostic yield of pathogenic CNV was 15.2%. The detection rates for well-defined microdeletion and microduplication syndromes were 4.6% in prenatal and 6.1% (1 in 16 index patients) in postnatal cases, respectively. Chromosomes 15, 16, and 22 accounted for over 21 and 25% of pathogenic CNVs detected in prenatal and postnatal cohorts, respectively. This review provides the first large scale overview of genomic imbalance of mostly Chinese patients in prenatal and postnatal settings.

Chromosomal microarray analysis for pregnancies with or without ultrasound abnormalities in women of advanced maternal age

“…25,26 The penetration of the variants was estimated to be 10.4%, 27 and the prevalence in patients with mental retardation, ID, and/or multiple congenital anomalies was about two to fourfold of that in control population. [27][28][29] It is well known that being rich in low copy repeats 34 ; the penetration was estimated to be 10.6%. As shown in our study, fetuses with SL can be found in ultrasound normal or soft marker group, although they were live born with normal phenotype, long-time follow-up is crucial to assess the actual risks for neurodevelopmental disorders.…”

Systematic evidence-based review: outcomes from exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability

“…2,3 More recent studies on cohorts of patients with CA/ DD/ID have documented diagnostic yields ranging from 16% to 28%. [4][5][6] As a result, CMA is a well-established tool in clinical practice, yet this testing will not capture singlenucleotide variations (SNVs) or small insertion/deletions (indels), smaller structural variants, and other pathogenic variant types contributing to CA/DD/ID.…”

Submicroscopic aberrations of chromosome 16 in prenatal diagnosis

“…NDE1 (nudE nuclear distribution gene E homolog 1) and NTAN1 (N-terminal asparagine amidase) are the two genes that may be relevant to the neurocognitive phenotype. Loss or mutation of these genes has resulted in neurological manifestations in animal models, but the phenotypic consequences of gain are not that clear [10,11]. Microdeletions of 16p13.11 have been associated with multiple phenotypic manifestations, including neurodevelopmental phenotypes such as autism, epilepsy, and non-CNS phenotypes, such as physical dysmorphisms and other congenital anomalies [12][13][14][15].…”