Application of Array Comparative Genomic Hybridization in Newborns with Multiple Congenital Anomalies

Abstract

Major congenital anomalies are detectable in 2-3 % of the newborn population. Some of their genetic causes are attributable to copy number variations identified by array comparative genomic hybridization (aCGH). The value of aCGH screening as a first-tier test in children with multiple congenital anomalies has been studied and consensus adopted. However, array resolution has not been agreed upon, specifically in the newborn or infant population. Moreover, most array studies have been focused on mixed populations of intellectual disability/developmental delay with or without multiple congenital anomalies, making it difficult to assess the value of microarrays in newborns. The aim of the study was to determine the optimal quality and clinical sensitivity of high-resolution array comparative genomic hybridization in neonates with multiple congenital anomalies. We investigated a group of 54 newborns with multiple congenital anomalies defined as two or more birth defects from more than one organ system. Cytogenetic studies were performed using OGT CytoSure 8 × 60 K microarray. We found ten rearrangements in ten newborns. Of these, one recurrent syndromic microduplication was observed, whereas all other changes were unique. Six rearrangements were definitely pathogenic, including one submicroscopic and five that could be seen on routine karyotype analysis. Four other copy number variants were likely pathogenic. The candidate genes that may explain the phenotype were discussed. In conclusion, high-resolution array comparative hybridization can be applied successfully in newborns with multiple congenital anomalies as the method detects a significant number of pathogenic changes, resulting in early diagnoses. We hypothesize that small changes previously considered benign or even inherited rearrangements should be classified as potentially pathogenic at least until a subsequent clinical assessment would exclude a developmental delay or dysmorphism.

Genomic Testing for Prenatal Clinical Evaluation of Congenital Anomalies

“…CAs can be the result of genetic factors, environmental factors, or a combination of both [8,9], although the underlying etiology often remains unknown. It is estimated that genetic factors represent an important cause of CAs and may result from different genetic mechanisms: the most common are aneuploidies, deletions, and duplications of DNA segments (collectively known as CNV), and single gene disorders [8,9]. Some disorders have an epigenetic basis; genes can be silenced or activated by modifications that may depend on the parent of origin or other influences [4].…”

“…Although most CAs are isolated and sporadic; the genetic contribution has long been recognized, and specific genes involved are increasingly being identified. However, the majority of isolated CAs are thought to be caused by a complex interplay of genetic and environmental factors and follow the so-called multifactorial or polygenic inheritance [4,8,9]. On the other hand, multiple CAs are often part of a syndrome, of chromosomal or monogenic etiology.…”

Genetic Analysis Algorithm for the Study of Patients with Multiple Congenital Anomalies and Isolated Congenital Heart Disease

“…In addition, around 1 in 200 infants has MCA [ 5 ]. These patients have serious medical, as well as familial and social implications, including early and high lethality [ 6 , 7 ].…”

The frequency of CNVs in a cohort population of consecutive fetuses with congenital anomalies after the termination of pregnancy

“…The etiology of CAs is complex; CAs can result from genetic factors, environmental factors, or a combination of both (D'Amours et al., ; Szczałuba et al., ). It is estimated that genetic factors represent an important cause of CAs and may be due to different genetic mechanisms: aneuploidies, deletions, and duplications of DNA segments (collectively known as copy number variations—CNVs), and single gene disorders (D'Amours et al., ; Szczałuba et al., ). Due to the genetic complexity, the targeted genetic diagnostics is usually problematic and challenging.…”

“…It has long been estimated that an important proportion of patients with CAs have submicroscopic chromosomal changes not detectable by conventional karyotyping (D'Amours et al., ; Szczałuba et al., ). In the last decade the availability of a comparative genomic hybridization using microarray technology (aCGH), enabled detection of CNVs down to few kb in size.…”