## 3 Results
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Term** & **Count** & **\%** & **\(p\) Value** & **Genes** & **Fold** **Enrichment** \\ \hline  & & & & _INVS_, _DNAH1_, _DNAH7_, _TUBAL3_, _DCTN1_, _DNAH6_, _IQGAP1_, _CAMSAP2_, _GOLGA2_, _TEKT1_, _DVLI_, _KIT13B_, _TEKT2_, _CEP107_, _KF121B_, _FSD1_, _KF11A_, _PCNT_, _DYNC2H1_, _MATUS2_, _KCNLAB2_, _SHROOM1_, _HAUS5_, _EML2_, _DLGI_, _SYNJ1_, _KATNAL2_, _INCENP_, _KF26A_, _KIFC1_, _FEZ1_, _EHADH_, _TTLL11_, _EIF3A_, _GAS8_ \\ \hline slit diaphragm & 5 & 0.44 & 6.761 \(\times\) 10 4 & _TRPC6_, _KIRREL2_, _NPHS1_, _MAGI2_, _IQGAP1_ & 10.66 \\ \hline intermediate filament & 17 & 1.48 & 8.88 \(\times\) 104 & _FLG_, _DSP_, _KRTP13-4_, _KRT2_, _KRTP26-1_, _KRTP27-1_, _KKTT9_, _KFKT10_, _GFAP_, _KRT28_, _KRT37_, _PKP2_, _KRTRAP6-1_, _SYNC_, _NES_, _KRT6A_, _PRPH_ \\ \hline Z disc & 17 & 1.48 & 1.42 \(\times\) 103 & _PPP1R12A_, _SYNO2_, _AHNAZ_, _ATP2B4_, _SLC4A1_, _NEB_, _ANK3_, _ADRAA1_, _IGFN1_, _RYR3_, _MYPN_, _TTN_, _OBSCN_, _HRC_, _PDE4B_, _SYNC_, _CRYAB_ \\ \hline spindle & 17 & 1.48 & 1.85 \(\times\) 103 & _INVS_, _DIDOI_, _SPAG8_, _NUMA1_, _DCTN1_, _DCTN3_, _HEPACAM2_, _HAUS5_, _EML2_, _INCENP_, _KIFC1_, _NUP85_, _CLTC1_, _ANKRD53_, _CEP170_, _E4F1_, _KBTBD8_ \\ \hline cytoplasm & 347 & 30.28 & 3.04 \(\times\) 103 & _INVS_, _DIDOI_, _SPAG8_, _NUMA1_, _DCTN1_, _DCTN3_, _HEPACAM2_, _HAUS5_, _EML2_, _INCENP_, _KIFC1_, _NUP85_, _CLTC1_, _ANKRD53_, _CEP170_, _E4F1_, _KBTBD8_ \\ \hline  & & & *_RPL5_, _ANKLE1_, _MTRR_, _HDAC10_, _RGSL1_, _ABCA12_, _BACH2_, _WDR87_, _ENDOV_, _TRK1_, _CYPD27_, _MPBP1_, _PPP4A_, _CT96C_, _PLC1_, _TRIM6A_, _RTNT1A_, _KF12B_, _ADCB_, _SDS_, _BSX_, _KRZT2_, _MTUS2_, _AEAP1_, _SCR1B_, _LCE12_, _MAPK19_, _EML2_, _PPP1R3G_, _NPP4B_, _KATNAL2_, _TEP1_, _FEZ1_, _ZSCAN26_, _WDPCP_, _TTLL11_, _FLYWCH1_, _ALPK2_, _PFN1_, _RIN1_, _TRIB2_, _KPRP_, _SPTBNS_, _PARBP_, _DHX8_, _PCDH15_, _CIORF198_, _AGAPI_, _XPC_ \\ \hline lateral & & & & *_REPL5_, _ANKLE1_, _MTRR_, _HDAC10_, _RGSL1_, _ABCA12_, _BACH2_, _WDR87_, _ENDOV_, _TRK1_, _CYPD27_, _MPBP1_, _PPP4A_, _CT96C_, _PLCI_, _TRIM6A_, _RTNT2B_, _HCGR5C_, _PHC1_, _TRIM6A_, _RTNT2B_, _HCGR5C_, _KRZT2_, _MTUS2_, _AEAP1_, _SCR1B_, _ACCB12_, _MAPK19_, _KRZT20_, _KRZT21_, _MK219_, _KRZT22_, _Next, we performed GOA on each family individually, to determine whether the cytoskeletal functional categories seen in the combined gene list were driven by a single family or many families. Overall, a cytoskeletal GO term was detected among the significantly enriched terms in every family except Family H, J, and O (Supplementary Files S2). Every family possessed at least one variant in a cytoskeletal gene. We next selected variants of interest for genotyping to determine whether the variant segregated with the AIS phenotype within each relevant family. Specific variants were genotyped if they were present in functional categories of interest (cytoskeletal or extracellular matrix GO terms), and if additional affected and unaffected members of the family were enrolled in our study. Ten genes (_ANKRD11, COL21A1, COL6A5, FGD1, NPHP4, OBSCN, TNXB, CTNNA3, NTRK1_, and _PDE4 DIP_) containing multiple variants across families were genotyped. Of these, variants within _TNXB_, _CTNNA3_, _NTRK1_, and _PDE4 DIP_ showed segregation of the variant with the IS phenotype in additional affected and unaffected family members (Supplementary Files S2). _TNXB_ (tenascin XB) localizes to the major histocompatibility region on chromosome 6 and encodes an ECM glycoprotein and has been associated to classic Ehlers-Danlos syndrome (EDS), a connective tissue disorder with scoliosis as one characteristic of the phenotype [72]. The _TNXB_ variants within our dataset (Family G: TNXB:NM_019105:exon24:c.C8192G:p.P2731R; Family S: TNXB:NM_019105:exon12:c.G444A: p.V148 ZM) do not appear in the EDS variant database to date [73; 74; 75]. _CTNNA3_ (Catenin \(\alpha\) 3) encodes a protein within the vinculin family of cell-cell adhesion proteins, and has been linked with certain types of cardiomyopathyopathy [76].