Scoliosis and vertebral anomalies: Additional abnormal phenotypes associated with chromosome 16p11.2 rearrangement

Abstract

The typical chromosome 16p11.2 rearrangements are estimated to occur at a frequency of approximately 0.6% of all samples tested clinically and have been identified as a major cause of autism spectrum disorders, developmental delay, behavioral abnormalities, and seizures. Careful examination of patients with these rearrangements revealed association with abnormal head size, obesity, dysmorphism, and congenital abnormalities. In this report, we extend this list of phenotypic abnormalities to include scoliosis and vertebral anomalies. We present detailed characterization of phenotypic and radiological data of 10 new patients, nine with the 16p11.2 deletion and one with the duplication within the coordinates chr16:29,366,195 and 30,306,956 (hg19) with a minimal size of 555 kb. We discuss the phenotypical and radiological findings in our patients and review 5 previously reported patients with 16p11.2 rearrangement and similar skeletal abnormalities. Our data suggest that patients with the recurrent 16p11.2 rearrangement have increased incidence of scoliosis and vertebral anomalies. However, additional studies are required to confirm this observation and to establish the incidence of these anomalies. We discuss the potential implications of our findings on the diagnosis, surveillance and genetic counseling of patients with 16p11.2 rearrangement.

TBX6Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis

“…In the congenital scoliosis subgroup, we identified 5 of 6 persons (83%) as having the hemizygous T-C-A haplotype (Table 2). The only exception (Patient PT03) was of African ancestry, 13 and the T-C-A haplotype is rare among such persons (prevalence, <1% among Africans, as compared with 44% among Asians and 33% among persons of European descent) (Table S5 in the Supplementary Appendix). Patient PT03 had the nonreference allele of SNP rs111939223 (present in 4% of Yoruba Africans but absent in Asians and Europeans), which is located at a predicted messenger RNA polyadenylation site of TBX6 .…”

“…These persons were initially referred for clinical chromosomal microarray testing owing to various medical problems. 13-15 …”

“…6 It is a likely cause of common diseases, including autism and obesity. 7-9 Vertebral malformations have been observed in a small proportion of persons with 16p11.2 copy-number variants (including deletion and duplication), 10-12 a finding that suggests the potential involvement of 16p11.2 copy-number variants (specifically, deletions) 13 in congenital scoliosis.…”

Diagnostic strategy in segmentation defect of the vertebrae: a retrospective study of 73 patients

“…This classification is based on clinical and radiological features in order to guide the diagnostic work-up 6. Single SDV (S-SDV) has been associated with numerous disorders, such as Alagille syndrome, Goldenhar syndrome and 16p11.2 microdeletion encompassing TBX6 7. S-SDV is a rather non-specific symptom included in malformation findings and often not specific enough to orientate the aetiological diagnosis.…”

Sequencing of the TBX6 Gene in Families With Familial Idiopathic Scoliosis

“…In addition, the 16p11.2 region encompasses several structural variants [19,20]. There is a higher incidence of scoliosis and vertebral anomalies in patients with recurrent 16p11.2 rearrangements [21,22]. Given both the association between TBX6 genetic variants and CS and the relationship between CS and IS, the current study utilizes traditional Sanger sequencing technology to examine the TBX6 gene in a subset of 13 trios with FIS.…”