RESUMEN
Marfan syndrome (MFS) is a hereditary systemic connective tissue disorder with great clinical variability. It is caused by heterozygous pathogenic variants in the FBN1 gene. Cardinal manifestations involve the cardiovascular, ocular, and skeletal systems. Clinical diagnosis is based on the revised Ghent nosology. We present the case of a child with a Marfan systemic score of 9 whose genetic study revealed two pathogenic mosaic frameshift variants in the FBN1 gene. Mosaicism is very rare in patients diagnosed with MFS, and this is the first description of a patient with two pathogenic mosaic variants in the FBN1 gene. Both variants are present in cells derived from ectodermal (buccal swab) and mesodermal (leukocyte) tissues, suggesting a mutation prior to gastrulation. We propose a defective repair of the de novo variant in the complementary strand as the mechanism that led this individual to be a carrier of two different populations of mutant cells carrying adjacent variants.
RESUMEN
Despite new strategies, such as evaluating deep intronic variants and new genes in whole-genome-sequencing studies, the diagnostic yield of genetic testing in hypertrophic cardiomyopathy (HCM) is still around 50%. FHOD3 has emerged as a novel disease-causing gene for this phenotype, but the relevance and clinical implication of copy-number variations (CNVs) have not been determined. In this study, CNVs were evaluated using a comparative depth-of-coverage strategy by next-generation sequencing (NGS) in 5493 HCM probands and 2973 disease-controls. We detected three symmetrical deletions in FHOD3 that involved exons 15 and 16 in three HCM families (no CNVs were detected in the control group). These exons are part of the diaphanous inhibitory domain of FHOD3 protein, considered a cluster of mutations for HCM. The clinical characteristics of the affected carriers were consistent with those reported in FHOD3 in previous studies. This study highlights the importance of performing CNV analysis systematically in NGS genetic testing panels for HCM, and reinforces the relevance of the FHOD3 gene in the disease.