Parental mosaicism in Marfan and Ehlers–Danlos syndromes and related disorders

Abstract

Marfan syndrome (MFS) is a heritable connective tissue disorder (HCTD) caused by pathogenic variants in FBN1 that frequently occur de novo. Although individuals with somatogonadal mosaicisms have been reported with respect to MFS and other HCTD, the overall frequency of parental mosaicism in this pathology is unknown. In an attempt to estimate this frequency, we reviewed all the 333 patients with a disease-causing variant in FBN1. We then used direct sequencing, combined with High Resolution Melting Analysis, to detect mosaicism in their parents, complemented by NGS when a mosaicism was objectivized. We found that (1) the number of apparently de novo events is much higher than the classically admitted number (around 50% of patients and not 25% as expected for FBN1) and (2) around 5% of the FBN1 disease-causing variants were not actually de novo as anticipated, but inherited in a context of somatogonadal mosaicisms revealed in parents from three families. High Resolution Melting Analysis and NGS were more efficient at detecting and evaluating the level of mosaicism compared to direct Sanger sequencing. We also investigated individuals with a causal variant in another gene identified through our “aortic diseases genes” NGS panel and report, for the first time, on an individual with a somatogonadal mosaicism in COL5A1. Our study shows that parental mosaicism is not that rare in Marfan syndrome and should be investigated with appropriate methods given its implications in patient’s management.

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

“…More recent, Yokoi et al (2021) [18] identified a mosaicism of COL3A1 in a clinically asymptomatic mother of siblings with vascular EDS estimated at 6% by NGS. Very recently, Chesneau et al (2021) [8] reported the first case of an individual with somatogonadal mosaicism in COL5A1 identified by NGS. Although the mosaicism was estimated with a frequency of 10-15% in the blood, a clinical examination did not reveal any signs of cEDS in the father.…”

“…However, the rate of mosaicism seems to vary among different disorders and depends on the prevalence of de novo cases: the higher the prevalence of de novo cases, the higher the frequency of mosaicism should be. In the field of hereditary connective tissue disorders, the frequency of mosaic is approximately 16% in osteogenesis imperfecta [ 8 ], while only a few cases were reported on Marfan syndrome [ 14 ].…”

“…Mosaicism is often considered as an inheritance exception to the Mendelian laws, as well as a factor driving the intra- and interfamilial variability in autosomal-dominant traits. It is relatively common in collagen-related inherited disorders, such as osteogenesis imperfecta [ 8 ]. Nevertheless, genetic mosaicism has only rarely been documented in the 13 recognized types of EDS.…”

Parental mosaic cutaneous‐gonadal GJB2 mutation: From epidermal nevus to inherited ichthyosis‐deafness syndrome

“…By evaluating unaffected parents and an affected child (trio) using next‐generation sequencing, it was shown that post‐zygotic parental mosaicisms are responsible for 1–2% of de novo developmental delay syndromes 12 . Similarly, 5% of de novo Marfan syndrome cases were attributed to parental somato‐gonadal mosaicism 13 . Evaluation of the parental gonadal mosaicism risk is particularly relevant in patients with clinically apparent skin disease, considering their frequency and visibility.…”

First report of inherited protein S deficiency caused by paternal <I>PROS1</I> mosaicism

“…13 In recent years, some cases of various diseases that were originally considered to be caused by de novo variants have actually been attributed to parental somatic or gonadal mosaicism. [13][14][15] Since the sensitivity of variation detection in Sanger sequencing, considered the standard for evaluating PROS1 variants, is limited to approximately 15-20%, 8,9 heterozygous variants can be detected, but mosaicisms are likely to be undetectable. Thus, another more sensitive method, such as dPCR or pyrosequencing, is needed for the genetic evaluation of parental mosaicism.…”