Exome sequencing analysis identifies frequent oligogenic involvement andFLNBvariants in adolescent idiopathic scoliosis

Abstract

BackgroundAdolescent idiopathic scoliosis (AIS) is a genetically heterogeneous disease characterised by three-dimensional deformity of the spine in the absence of a congenital spinal anomaly or neurological musculoskeletal disorder. The clinical variability and incomplete penetrance of some genes linked with AIS indicate that this disease constitutes an oligogenic trait.ObjectiveWe aimed to explore the oligogenic nature of this disease and identify novel AIS genes.MethodsWe analysed rare damaging variants within AIS-associated genes by using exome sequencing in 40 AIS trios and 183 sporadic patients.ResultsMultiple variants within AIS-associated genes were identified in eight AIS trios, and five individuals harboured rare damaging variants in the FLNB gene. The patients showed more frequent oligogenicity than the controls. In the gene-based burden test, the top signal resided in FLNB. In functional studies, we found that the AIS-associated FLNB variants altered the protein’s conformation and subcellular localisation and its interaction with other proteins (TTC26 and OFD1) involved in AIS. The most compelling evidence of an oligogenic basis was that the number of rare damaging variants was recognised as an independent prognostic factor for curve progression in Cox regression analysis.ConclusionOur data indicate that AIS is an oligogenic disease and identify FLNB as a susceptibility gene for AIS.

Epigenetic and Genetic Factors Related to Curve Progression in Adolescent Idiopathic Scoliosis: A Systematic Scoping Review of the Current Literature

“…According to the research performed, a total of 40 papers [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ] met the inclusion criteria and were considered for review. Of these studies, twenty-one [ 18 , 19 , 21 , 24 , 31 , 33 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 44 , 45 ,…”

“…According to the Oxford level of evidence scale, ten [ 16 , 17 , 27 , 28 , 29 , 32 , 46 , 48 , 49 , 53 ] of the included studies had a level of evidence IV, twenty-six [ 18 , 19 , 20 , 21 , 23 , 24 , 26 , 31 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 44 , 45 , 47 , 50 , 51 , 52 , 54 , 55 ] studies had a level of evidence III, while the remaining studies had a level of evidence II [ 22 , 25 , 30 , 43 ].…”

“…The median age at the first visit ranged from 12.2 ± 1.2 to 18.5 ± 1.8 years and the median follow-up ranged from 12 months to 42 months. Asiatic populations (Chinese, Japanese, and Korean) [ 9 , 16 , 17 , 20 , 21 , 23 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 42 , 43 , 44 , 45 , 47 , 51 , 53 , 54 , 55 , 56 ] were the most studied by authors, but Caucasian populations (Europeans, Polish, and French-Canadian) [ 24 , 25 , 26 , 27 , 41 , 43 , 46 , 48 , 49 , 52 ], Russian [ 19 ], and Turkish [ 18 ] populations were also evaluated for possible associations. Two studies did not accurately describe the population demographics [ 30 , 43 ].…”

“…A detail of the type of scoliotic curve was reported in eleven [ 16 , 17 , 19 , 22 , 24 , 39 , 40 , 42 , 47 , 51 , 53 ] of the selected studies ( Table 1 ), for a total of 3949 thoracic curves (56.8%), 1019 lumbar curves (14.6%), 482 thoraco-lumbar curves (6.9%), 1304 double curves (18.7%), and 195 triple curves (2.8%).…”

Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report

“…They result due to gain-of-function of FLNB. Recently, co-inheritance of some FLNB variants with variants in other genes important in skeletogenesis, were also identified to have a role in the complex trait of adolescent idiopathic scoliosis [ 12 ]. However, the recessively inherited SCT is caused by biallelic missense, nonsense or frameshift truncating variants, which result in loss of function of FLNB [ 1 , 13 ].…”