Major Contribution of Genomic Copy Number Variation in Syndromic Congenital Heart Disease: The Use of MLPA as the First Genetic Test

Abstract

Congenital heart disease (CHD) is the most common congenital disorder among live births. When associated with extracardiac abnormalities, it is characterized as a syndromic heart disease (syndromic CHD) and corresponds to 25% of all liveborn infants with a heart defect. The etiology in about 65% of the cases still remains unknown, and in about 35% of the patients, it is associated with genetic factors. In the present study, MLPA and SNP-array techniques were used to investigate a group of 47 patients with syndromic CHD. In total, 16 defects (34%) were identified, of which 12 (25.5%) were classified as pathogenic or probably pathogenic. The most frequent abnormalities were 22q11.2 deletion (22q11.2 deletion syndrome) and 7q11.23 deletion (Williams-Beuren syndrome). We also show that rarer malformations may be associated with syndromic CHD, such as 14q32.33 deletion as well as 17q25.3, 15q11.2 (BP1-BP2), 22q13.31, and 12p13.31 (SLC2A3) duplications. The present study demonstrates that CNVs are important causal factors and should be studied in patients with syndromic CHD. Furthermore, the use of MLPA as a first screening test was appropriate, as this less expensive technology detected 11 of the 12 pathogenic abnormalities (91.6%).

MLPA � first-tier Screening Assay in Newborns with Nonsyndromic Congenital Heart Disease

“…In our study the MLPA detection rate was 16.67% (10/60 cases), comparable to the 3.2-33.33% rates indicated in previous studies [1,6,8,10] that investigated CNVs associated to CHD in children, this variation being probably a consequence of patient selection criteria and MLPA kit used, rather than technique limitations. The apparently low detection rate should be interpreted in the light of current knowledge, as there may be up to 400 genes involved in CHD pathogenesis, many of which still not identified [12], therefore genetic testing of individuals with isolated apparently nonsyndromic CHDs is still a low-yield exercise [12], but improvements are predicted for the near future.…”

“…DiGeorge syndrome or 22q11.2 deletion syndrome is the second main cause of CHD [1,16], and expectedly, it was the most frequently diagnosed disorder in our study, with an incidence of 5% (3/60 patients), all being heterozygous. Our diagnosis rate was smaller than that of Monteiro et al [1], but they included only syndromic patients.…”

“…As subtle phenotypic characteristics are often difficult to be seen early on in life [2], especially in neonates, CHDs may be among the first symptoms in pathologies involving CHD as part of the clinical spectrum. Several studies have shown the importance of CNVs in a significant number of CHD patients [1,6,8,10,11], but all existing studies focused their attention on children or fetuses, none trying to establish a diagnosis at birth or in the neonatal period. Early determination of a CHDs' genetic origin is important, as these children bare an increased risk of postoperative complications [12], and thus, the awareness of possible associated extracardiac abnormalities may be decisive for the optimal therapeutic management [6], be it surgical [13] or drug administration [3,14].…”

“…Congenital heart disease (CHD) is the most frequent malformative pathology seen in newborns, with an incidence of 10/1000 births [1]. Part of a genetic syndrome, or stand alone, CHDs are considered a major cause of morbidity and mortality, as 24-50% of neonates who die because of a birth defect actually have a heart defect [2,3].…”

“…Multiplex ligation-dependent probe amplification (MLPA) is a valuable tool for the *email: valeriu.moldovan@umfst.ro https://doi.org/10.37358/RC.20.2.7912 detection of known CNVs, with a relatively low cost and a straightforward technique. The MLPA method has been previously used to diagnose CHDs in children, but not in neonates, and the diagnosis rate varied [1,6,8], being mainly dependent on patient selection and the MLPA kit used.…”