Reexamining genetic disorders with array CGH

Recent advances in genomics have dramatically increased our capacity to analyze abnormal cells, revealing a multitude of changes in genomic DNA, such as mutations and copy number alterations. Array comparative genomic hybridization (aCGH) has become a valuable, genome-wide screening tool for the detection of chromosomal aberrations in the form of copy number imbalances in the field of cytogenetics. Array CGH is a relatively simple molecular technique based on the co-hybridization of fluorescently-labeled sample and control genomic DNAs onto a glass slide or a chip. The major advantage of aCGH is that it offers improved resolution compared to traditional techniques and is more robust than mRNA expression arrays. Recent studies demonstrated the ability of aCGH to detect submicroscopic chromosomal imbalances in the range of a few megabases. Consequently, research laboratories rely more and more on this method to identify the root cause of genetic disorders. Malformations affecting cardiac and central nervous systems are, for example, common birth defects and several chromosomal aberrations and other deletions/multiplications have been so far identified. Regretfully, only a few single genes have been found to be associated with isolated congenital heart disorder.

Mediator complex subunit 13-like protein (MED13L) is a subunit of the large Mediator complex responsible for the co-activation of DNA-binding transcription factors and nearly all RNA polymerase II-dependent genes. MED13/MED13L interaction with RNA polymerase II is tightly regulated by its association with cyclin-dependent kinase 8 (CDK8), which controls transcription initiation and re-initiation. Formation of a complex between MED13/MED13L and CDK8 also regulates transcription via chromatin modification and further interactions with elongation factors (M.A. Davis et al., 2013). MED13L may specifically regulate transcription of targets of the Wnt and SHH signaling pathways. It is involved in the early development of the brain and the heart, and defects in this gene have been linked with congenital cardiac deficits, in particular transposition of the great arteries.

Dr. Abidemi Adegbola and colleagues from Icahn School of Medicine at Mount Sinai identified eight patients with common characteristics including dysmorphism, behavioral difficulties, intellectual disability, motor developmental delay and speech impairment. Using Enzo’s CGH labeling kit, they labeled genomic DNA extracted from these patients’ peripheral blood and performed copy number profiling using human genome CGH 180K oligonucleotide arrays from Agilent Technologies. They discovered novel MED13L exon deletions and duplications. However, none of these patients had congenital heart defects providing some evidence to argue against MED13L-heart phenotype. Instead, it seems that underneath the MED13L syndrome, there is a gradient with some variants capable of causing stark phenotypes including dysmorphism, global developmental delay and congenital heart illness while others trigger “milder” phenotypes with non-syndromic intellectual disability and lack of congenital cardiac defects. It implies that genetic background and other unpredictable factors could also account for the severity of the affliction.

Altogether, these data prove that new variants of MED13L as well as variants in other key complex components will be, more than likely, identified and associated with comparable phenotypes and that using current genetic tools such as aCGH along with a thorough family history and genetic background check-up could go a long way towards an improved and detailed overview of not only MED13L-linked genetic disorders but also other birth defects.

Enzo Life Sciences will be attending the European Human Genetics Conference 2015 organized by the European Society of Human Genetics (ESHG). Please join us in Glasgow, June 6-9, at booth 242 and discover one of the leading CGH labeling kit on the market. Enzo Life Sciences also offers a comprehensive product portfolio for advancing your research in genetics and molecular biology including PCR/qPCR products; some of which are listed below:

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