Expanding genotype-phenotype associations in biglycan-related Meester-Loeys syndrome

Abstract

Loss-of-function variants in BGN, an X-linked gene coding for biglycan, are associated with Meester-Loeys syndrome (MRLS), a syndromic form of aortic aneurysm/dissection. Since the initial publication of five families in 2017, we identified eleven additional MRLS families. All sixteen probands, except two, are male and had an average age at presentation of 38 years. Thirteen males and one female presented with aortic (n = 10) and/or arterial (n = 6) aneurysms/dissections, one male (11y) presented with syndromic features without cardiovascular symptoms (yet), and one female proband (42y) was identified as part of comprehensive prenatal testing. An additional 33 BGN variant-harbouring family members (M/F:6/27) were identified with cascade screening. Their phenotype ranged from no cardiovascular or connective tissue phenotype to death due to aortic dissection. Identified BGN mutations causing a stop codon insertion, frameshift, or splicing defect and partial BGN deletions were shown to result in loss-of-function by cDNA and Western Blot analysis of skin fibroblasts of seven probands, or were strongly predicted to lead to loss-of-function based on the nature of the variant. Interestingly, a male proband with a deletion encompassing exon 2-8 of BGN presented with a more severe skeletal phenotype. RNA sequencing revealed expres-sional activation of a downstream ATPase (ATP2B3; normally repressed in skin fibroblasts) driven by the remnant BGN promotor as a possible explanation. These observations indicate that extensive analysis at RNA, cDNA and protein level is required before concluding on the pathogenicity of BGN variants; and distinct mutational mechanisms may underlie the wide phenotypic spectrum of MRLS patients. Conflict of Interest: None declared C03.5 Rare heterozygous variants in PTCH1 are associated with bladder exstrophy-epispadias complex