Background Chromosome microarray (CMA) analysis typically focuses on coding DNA (RefSeq and OMIM genes). Although non-coding intergenic and intronic variants may be critical in disease pathogenesis, copy number variants (CNV) in these regions are usually interpreted as variants of unknown clinical significance.
Objective We present a case of a lethal neonatal condition in which the pathogenic CNV lies in a distant, upstream non-coding region.
Design/method Chromosome microarray was performed in a newborn female with a prenatal diagnosis of AVSD, who presented with severe neonatal respiratory distress out of keeping with her cardiac issues.
Results CMA analysis revealed a de novo 1.5 Mb deletion at 16q24.1. None of the 16 RefSeq genes mapping within the deleted region appeared causative. However, this deletion is located 157 kb upstream of FOXF1, a gene responsible for congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). The observed deletion encompasses a recently characterised distant regulator/enhancer of the FOXF1 gene. The pathological diagnosis of ACDMPV was confirmed posthumously.
Conclusion This case highlights the importance of relevant clinical information for CMA interpretation, and the importance of the analysis of flanking regions if an identified CNV does not initially appear pathogenic. As our knowledge of epigenetics and the genomic landscape improves, an increasing number of non-coding CNVs are poised to gain clinical relevance. We suggest that a database of well-characterised non-coding regulatory regions be developed and incorporated into CMA analysis.
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