BMPER variants associated with a novel, attenuated subtype of diaphanospondylodysostosis

Abstract

Diaphanospondylodysostosis (DSD), caused by loss of bone morphogenetic protein-binding endothelial regulator (BMPER), has been considered a lethal skeletal dysplasia characterized by severe deficiency of vertebral body and sacral ossification, reduced rib number and cystic kidneys. In this study, however, we have demonstrated that variants in BMPER may cause a milder disorder, without renal anomalies, that is compatible with long-term survival. Four siblings, three males and one female, presented with severe congenital scoliosis associated with rib and vertebral malformations as well as strikingly delayed ossification of the pedicles. The female was stillborn from an unrelated cause. Stabilization of the scoliosis with expandable titanium rods was successful in the three boys, all of whom have short stature. An autosomal recessive mode of inheritance was hypothesized. Single nucleotide polymorphism microarray analysis was performed for three of the siblings to identify autosomal genes with shared allele patterns, suggesting possible linkage. Exome sequencing of one sibling was then performed. Rare variants were identified in 347 genes with shared alleles. Only one of these genes had bi-allelic variants in a gene strongly expressed in paraxial mesenchyme: BMPER, which is the cause of DSD, an autosomal recessive disorder. The disorder described herein could represent an attenuated form of DSD or could be designated a separate entity such as spondylopedicular dysplasia.

Extending the phenotype of BMPER-related skeletal dysplasias to ischiospinal dysostosis

“…Previous reports ascertained biallelic BMPER mutations in six patients with DSD [ 9 , 13 ] and three siblings with attenuated DSD [ 12 ]. In this report we show that ISD a disorder phenotypically similar, but much milder, than DSD is also caused by biallelic mutations in the BMPER gene.…”

“…Parental consanguinity in one patient suggested autosomal recessive inheritance, but the causative gene has been hitherto unknown [ 2 ]. Diaphanospondylodysostosis (DSD) is a lethal/semilethal skeletal dysplasia, the phenotype of which is similar to, but more severe than, that of ISD [ 5 – 12 ] (Additional file 1 : Tables S1 and Additional file 2 : Table S2). Funari et al identified mutations in the BMPER in four patients with DSD [ 13 ], and since then two additional DSD patients and three siblings with so-called attenuated form of DSD with BMPER mutations have been published [ 9 , 12 ] (Table 1 , Fig.…”

Agonists and Antagonists of TGF-β Family Ligands

“…Cross talk with various BMP modulators, ECM components, and cell-surface proteins may thus provide a basis for the activities of Cv2/Bmper as agonist or antagonist of BMP ligands. Mutations in BMPER have been linked to an autosomal recessive perinatal lethal skeletal disorder, diaphanospondylodysostosis, in humans (Funari et al 2010;Ben-Neriah et al 2011;Zong et al 2015).…”

Further evidence for causation of ischiospinal dysostosis by a pathogenic variant in BMPER and expansion of the phenotype

“…Biallelic pathogenic variants in BMPER are also known to cause diaphanospondylodysostosis (DSD) (OMIM #608022), a perinatally lethal condition (Funari et al ). Attenuated DSD with features overlapping with ISD and DSD has been reported in a family with biallelic variants in BMPER (Zong et al ). All the three conditions have overlapping features and demonstrate the spectrum of severity of the BMPER related conditions.…”