Autosomal recessive variations of TBX6, from congenital scoliosis to spondylocostal dysostosis

Abstract

Proximal 16p11.2 microdeletions are recurrent microdeletions with an overall prevalence of 0.03%. In patients with segmentation defects of the vertebra (SDV), a burden of this microdeletion was observed with TBX6 as a candidate gene for SDV. In a published cohort of patients with congenital scoliosis (CS), TBX6 haploinsufficiency was compound heterozygous with a common haplotype. Besides, a single three-generation family with spondylocostal dysostosis (SCD) was reported with a heterozygous stop-loss of TBX6. These observations questioned both on the inheritance mode and on the variable expressivity associated with TBX6-associated SDV. Based on a national recruitment of 56 patients with SDV, we describe four patients with variable SDV ranging from CS to SCD associated with biallelic variations of TBX6. Two patients with CS were carrying a proximal 16p11.2 microdeletion associated with the previously reported haplotype. One patient with extensive SDV was carrying a proximal 16p11.2 microdeletion associated with a TBX6 rare missense change. One patient with a clinical diagnosis of SCD was compound heterozygous for two TBX6 rare missense changes. The three rare variants were affecting the chromatin-binding domain. Our data illustrate the variable expressivity of recessive TBX6 ranging from CS to SCD.

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease

“…Additional functional and multi-racial evidence were subsequently provided to establish the TBX6 compound inheritance model in sporadic CS patients (Wu et al 2015). This model was further repeatedly observed in a Japanese and a European CS cohort independently (Lefebvre et al 2016; Takeda et al 2017). …”

Intrauterine phenotypic features associated with 16p11.2 recurrent microdeletions

“…To the best of our knowledge, prenatal ultrasound findings of vertebral malformations (2 cases), cardiovascular malformations (1 case), FGR (2 cases), and absent nasal bone (1 case) have only been described in 6 cases . Other congenital malformations associated with the 16p11.2 recurrent microdeletion have been postnatally defined in previous studies.…”

“…TBX6 genetically interacts with the notch ligand delta‐like 1 and has been recognized as a key gene involved in vertebral malformations in mice and humans . Although heterozygous null mutations of TBX6 reduce its gene expression level by nearly one‐half, its gene‐dosage effect is not sufficient to cause vertebral malformations . The pathogenic effect of TBX6 on vertebral malformations is more complicated than simple haploinsufficiency.…”

“…The pathogenic effect of TBX6 on vertebral malformations is more complicated than simple haploinsufficiency. The combination of a rare TBX6 null mutation and a T‐C‐A risk haplotype or a rare missense mutation could significantly reduce the TBX6 gene expression level and confer a high risk of vertebral malformations . This mechanism may partially explain the heterogeneity of vertebral malformations in different individuals with the microdeletion.…”

Summary of the first inaugural joint meeting of the International Consortium for scoliosis genetics and the International Consortium for vertebral anomalies and scoliosis, March 16–18, 2017, Dallas, Texas

“…Of these, mono-allelic mutations in TBX6, a transcription factor necessary for Notch signaling, and a high risk TBX6 haplotype, are associated with a range of phenotypes, from a severe lethal form of spondylothoracic dysostosis to congenital scoliosis. (Wu et al, 2015; Lefebvre et al, 2017)—allelic TBX6 mutations are also associated with Mullerian derived structural abnormalities such as Mayer-Rokitansky-Kuster syndrome (congenital absence of vagina, absent uterus, presence of fallopian tubes, and ovaries) (Sandbacka et al, 2013). Phenotype-genotype correlation is beginning to emerge, according to the nature of DNA variants/mutations.…”