Gonosomal Mosaicism for a Novel COL5A1 Pathogenic Variant in Classic Ehlers-Danlos Syndrome.

Francesco Bassanese,Carmela Fusco,Salvatore Savasta,Lucia Micale,Matteo Granatiero,Marco Castori,Federica Russo,Luigia Cinque,Thomas Foiadelli

doi:10.3390/genes12121928

Abstract

(1) Background: Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by joint hypermobility and skin hyperextensibility with atrophic scarring. Many cEDS individuals carry variants in either the COL5A1 or COL5A2 genes. Mosaicism is relatively common in heritable connective tissue disorders but is rare in EDS. In cEDS, a single example of presumed gonosomal mosaicism for a COL5A1 variant has been published to date. (2) Methods: An 8-year-old girl with cEDS was analyzed by next-generation sequencing (NGS). Segregation was performed by Sanger sequencing in her unaffected parents. In the father, the mosaicism of the variant was further analyzed by targeted NGS and droplet digital PCR (ddPCR) in the blood and by Sanger sequencing in other tissues. (3) Results: The NGS analysis revealed the novel germline heterozygous COL5A1 c.1369G>T, p.(Glu457*) variant in the proband. Sanger chromatogram of the father’s blood specimen suggested the presence of a low-level mosaicism for the COL5A1 variant, which was confirmed by NGS and estimated to be 4.8% by ddPCR. The mosaicism was also confirmed by Sanger sequencing in the father’s saliva, hair bulbs and nails. (4) Conclusions: We described the second case of cEDS caused by paternal gonosomal mosaicism in COL5A1. Parental mosaicism could be an issue in cEDS and, therefore, considered for appropriate genetic counseling.

Highlights

The Ehlers-Danlos syndromes (EDS) are a group of clinically varied and genetically heterogeneous hereditary soft connective tissue disorders mainly featuring doughy/velvety, soft, thin and/or variably hyperextensible skin; easy bruising with capillary fragility and joint hypermobility of various degrees
COL5A1 variants are scattered throughout the gene, and the majority of them lead to
COL5A1 variants are scattered throughout the gene, and the majority of them lead to COL5A1 haploinsufficiency, usually resulting from nonsense-mediated mRNA decay (NMD) [4–6]

Summary

Introduction

The Ehlers-Danlos syndromes (EDS) are a group of clinically varied and genetically heterogeneous hereditary soft connective tissue disorders mainly featuring doughy/velvety, soft, thin and/or variably hyperextensible skin; easy bruising with capillary fragility and joint hypermobility of various degrees. Additional features include skin fragility, abnormal wound healing and scarring formation, congenital contortionism, propensity to acquired dislocations and the fragility of vessels and internal organs [1]. The 2017 EDS classification describes 13 EDS types identified by clinical characteristics, inheritance pattern and molecular findings in 19 distinct genes [1]. Recent studies have described another genetically distinct classic-like EDS type caused by biallelic deleterious variants in the AEPB1 gene [2], while additional cases have allowed to reclassify the so-called osteogenesis imperfecta/EDS overlap in COL1-related overlap disorder [1]. Generalized joint hypermobility and skin hyperextensibility with atrophic scarring are the major hallmarks, whereas easy bruising, doughy skin, skin fragility, cutaneous pseudotumors, subcutaneous

Methods

Results

Conclusion