Unexpected genomic architecture in a sporadic case of C1-INH Hereditary Angioedema: the hidden heritability

Hereditary Angioedema (HAE) due to C1-esterase inhibitor (C1-INH) deficiency or dysfunction (C1-INH-HAE), is an autosomal dominant genetic disease characterized by recurrent cutaneous and submucosal swelling episodes most often caused by heterozygous pathogenic Single Nucleotide Variants (SNVs), small insertions or deletions (indels) or Copy Number Variants (CNVs) in the SERPING1 gene, coding for C1-INH. Rare subtypes of HAE not associated with SERPING1 pathogenic variants (nC1-INH-HAE) have been described. This case report aimed to characterize a 55-year-old proband, without a family history of hereditary diseases, presenting with a clinical diagnosis of C1-INH-HAE, primary Sjögren syndrome, and unexplained neuropathic symptoms. Firstly, targeted Next-Generation Sequencing and Multiple Ligation-dependent Probe Amplification (MLPA) were performed on the proband’s genomic DNA to analyze the SERPING1 gene. Secondly, Chromosomal Microarray Analysis (CMA) and Fluorescence In Situ Hybridization analysis were performed to confirm the cytogenomics results. MLPA detected a heterozygous variant corresponding to the whole SERPING1 gene deletion on chromosome 11, a very rare cause of C1-INH-HAE. CMA defined breakpoints and disclosed an additional pathogenic CNV on chromosome 17, involving PMP22 gene, and causing Neuropathy, Hereditary, With Liability To Pressure Palsies disease. The clinical consequences of SERPING1 and PMP22 haploinsufficiency are associated with the unusual constellation of clinical symptoms, unraveling an unexpected cytogenomics architecture with two co-occurring disease-causing CNVs in a previously genetically undiagnosed patient.