Table 3 Candidate variant prioritization and definition of categories of cases with adolescent idiopathic scoliosis (AIS)

From: Whole genome sequencing in adolescent idiopathic scoliosis cohort implicates multiple biological pathways

Categories	Gene-AIS association	Predicted effect of mutation	Family	Mode of inheritance
1) Solved case	Knows AIS gene or AD Syndromic Gene	P/LP or strong VUS	Trio	De novo, Inherited Heterozygous, Inherited Homozygous, or Compound Heterozygous
1) Solved case	AR Syndromic Gene	P/LP or strong VUS	Trio	Inherited Homozygous or Compound Heterozygous
2) Nearly solved case, requires missing parent genotype	Knows AIS gene or AD Syndromic Gene	P/LP or strong VUS	Duo or Singleton	De novo, Inherited Heterozygous, Inherited Homozygous, or Compound Heterozygous
2) Nearly solved case, requires missing parent genotype	AR Syndromic Gene	P/LP or strong VUS	Duo or Singleton	Inherited Homozygous or Compound Heterozygous
3) Case with strong candidate variant	Knows AIS gene or AD Syndromic Gene	Moderate VUS	Trio	De novo, Inherited Heterozygous, Inherited Homozygous, or Compound Heterozygous
	Knows AIS gene or AD Syndromic Gene		Duo or Singleton	Inherited Homozygous or Compound Heterozygous
	AR Syndromic Gene	P/LP or strong VUS	Trio, Duo or Singleton	De novo or Inherited Heterozygous
	AR Syndromic Gene	Moderate VUS	Trio, Duo or Singleton	Inherited Homozygous or Compound Heterozygous
	AIS-Associated Gene	P/LP, Strong VUS, or Moderate VUS	Trio	Inherited Homozygous or Compound Heterozygous
	AIS-Associated Gene	P/LP or strong VUS	Duo or Singleton	Inherited Homozygous or Compound Heterozygous
4) Case with moderate candidate variant	Knows AIS gene or AD Syndromic Gene	Moderate VUS	Duo or Singleton	De novo or Inherited Heterozygous
	Knows AIS gene or AD Syndromic Gene	Low VUS	Trio, Duo or Singleton	Inherited Homozygous or Compound Heterozygous
	AR Syndromic Gene	Moderate VUS	Trio, Duo or Singleton	De novo or Inherited Heterozygous
	AR Syndromic Gene	Low VUS	Trio	Inherited Homozygous or Compound Heterozygous
	AIS-Associated Gene	P/LP or strong VUS	Trio, Duo or Singleton	De novo or Inherited Heterozygous
		Moderate VUS	Trio	De novo or Inherited Heterozygous
		Moderate VUS	Duo or Singleton	Inherited Homozygous or Compound Heterozygous
		Low VUS	Trio	Inherited Homozygous or Compound Heterozygous
	AIS-Unassociated Gene	P/LP or strong VUS	Trio, Duo or Singleton	Inherited Homozygous or Compound Heterozygous

Known AIS Genes: ADGRG6/GPR126, AKAP2, BNC2, CHD7, COL11A1, COL11A2, FAT3, FBN1, FBN2, HSPG2, KIF7, LBX1, and POC5. AD/AR Syndromic Genes: Genes associated with an OMIM-listed genetic syndrome where scoliosis is a reported symptom or common comorbidity. AIS-associated Genes: Genes with previous evidence for association with AIS, other skeletal abnormalities, or other known AIS genes. P/LP: Variants classified as pathogenic/likely pathogenic (P/LP) based on ACMG criteria. Strong VUS: Structural variants, copy number variants, protein truncating variants, and variants with ClinVar pathogenic/likely pathogenic classification. Moderate VUS: Variants predicted to be deleterious by at least 3 computational prediction tools, and at least by 2/3 of the computational tools that were available. Low VUS: Variants predicted to be deleterious by at least 3 computational prediction tools, and at least by 1/3 of the computational tools that were available.

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Table 3 Candidate variant prioritization and definition of categories of cases with adolescent idiopathic scoliosis (AIS)

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