Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy

Table 1 List of potential modifier genes for X-linked adrenoleukodystrophy investigated in various studies

Series No.	Gene name	Variants studied	No. of cases	Inference	Ref.
Genes associated with VLCFA metabolism
I	ABCD2	rs11172566	117	No significance	Maier et al[34]
		rs11172661		No significance
I	ABCD2	A/T(5’UTR)	280	No significance	Matsukawa et al[35]
		M94V		No significance
II	ABCD3	rs4148058	280	No significance	Matsukawa et al[35]
		rs2147794		No significance
		rs16946		No significance
		rs681187		No significance
		rs662813		No significance
		rs337592		No significance
III	ABCD4	rs17182959	280	No significance	Matsukawa et al[35]
		rs17158118		No significance
		rs17782508		No significance
		rs2301345		No significance
		rs4148077		No significance
		rs4148078		No significance
		rs3742801		No significance
IV	Cytochrome P450 4F subfamily (CYP4F2)	rs21086622	152	Minor allele A associated with CALD (P = 0.036)	van Engen et al[38]
		rs3093207		No significance
		rs1272		No significance
		rs3093200		No significance
		rs3093194		No significance
		rs3093166		No significance
		rs4808400		No significance
		rs3093153		No significance
		rs3093135		No significance
		rs3093105		No significance
Genes associated with methionine metabolism
I	Cystathionine β-Synthase (CBS)	c.844_845ins68	86	Associated with pure AMN	Linnebank et al[46]
I	Cystathionine β-Synthase (CBS)	c.844_845ins68	172	No significance	Semmler et al[48]
II	Methionine synthase (MTR)	c.2756A>G	86	No significance	Linnebank et al[45]
II	Methionine synthase (MTR)	c.2756A>G	172	No significance	Semmler et al[48]
III	Methylenetetrahydrofolate reductase (MTHFR)	c.677C>T	86	No significance	Linnebank et al[45]
III	Methylenetetrahydrofolate reductase (MTHFR)	c.677C>T	172	No significance	Semmler et al[48]
		c.1298A>C		No significance
IV	Dihydrofolate reductase (DHFR)	c.594+59del19bp	172	No significance	Semmler et al[48]
V	5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase (MTRR)	c.60A>G	172	No significance	Semmler et al[48]
VI	Transcobalamin 2 (TC2)	c. 776C>G	86	GG genotype prevalent in AMN with demyelination compared to pure AMN (P = 0.001)	Linnebank et al[45]
VI	Transcobalamin 2 (TC2)	c. 776C>G (GG)	172	GG genotype associated with demyelination (P = 0.036)	Semmler et al[48]
VII	Reduced folate carrier 1 (RFC1)	c.80G>A	172	No significance	Semmler et al[48]
Genes associated with inflammation
I	TNF-α	G- 308A	15	No significance	McGuinness et al[64]
II	Cluster of differentiation (CD1)	CD1A-CD1E	139	No significance	Barbier et al[44]
III	Human leukocyte antigen (HLA)	HLA-DRB1*16	29	HLA-DRB1*16 associated with X-ALD (P < 0.02)	Berger et al[40]
		HLA-DRB1*15		No significance
III	Human leukocyte antigen (HLA)	HLA-DBR1*	70	No significance	Schmidt et al[41]
III	Human leukocyte antigen (HLA)	HLA-DRB1*16	106	No significance	McGuinness et al[65]
		HLA-DRB1*15
IV	Interleukin 6 (IL6)		68	No significance	Schmidt et al[41]
V	Myelin Oligodendrocyte glycoprotein (MOG)	(TAAA)n	68	226bp (TAAA)n polymorphism associated with the presence of Anti-MOG antibody. (P < 0.05).	Schmidt et al[41]
V	Myelin oligodendrocyte glycoprotein (MOG)	G15A	44	No significance	Gomez-Lira et al[42]
		CTC 5 repeats		No significance
		G511C		No significance
		G520A		No significance
		551+68 A→G		No significance
		551+77 C→T		No significance
Other genes
I	Superoxide oxide dismutase (SOD2)	rs4880		T-allele associated with cerebral involvement in non-CCALD cases	Brose et al[49]
		rs2758352		No significance
		rs2842980		No significance
		rs2758329		No significance
II	Apolipoprotein E (APOE)	rs7412 rs429358	83	APOE4 associated with cerebral involvement	Orchard et al[52]
III	Cytochrome P450 family 7 subfamily A member 1 (CYP2A1)	rs3824260 (c.-533T>C)	Study carried out on a patient diagnosed with AMN with c.659T>C mutation in ABCD1 gene in patient and mother	CC allele observed in patient whereas CT in mother	Płatek et al[50]
		rs3808607 (c.-267C>A)		AA allele observed in patient whereas CA in mother
IV	3 β-hydroxysteroid dehydrogenase type 7 (HSD3B7)	rs9938550 (c.748A>G)		GG allele observed in both
		rs2305880 (c.1068T>C)		CC allele observed in patient
V	Bile acyl-CoA synthetase (SLC27A5)	rs4810274 (c.1668-6T>C)		CC observed in patient
VI	Aldo-keto reductase family 1 member D1 (AKR1D1)	c.-71G>C		GC observed in patient
VII	Cytochrome P450 Family 27 Subfamily A Member 1 (CYP27A1)	rs397795841 (c.-357dupC)		Homozygous mutation in both

AMN: Adrenomyeloneuropathy; CALD: Cerebral adrenoleukodystrophy; CCALD: Childhood cerebral adrenoleukodystrophy; VLCFA: Very-long-chain fatty acid; X-ALD: X-linked adrenoleukodystrophy.