Table 1.

Genetic variations that were associated with changes in human milk components, as well as the effect on the infant and suggested treatment. LoF, loss of function; BCRP, breast cancer resistance protein; ABCG2, ATP-driven, multidrug efflux transporter; ITD, iodide transport defect; SNP, single nucleotide polymorphism; HMO, human milk oligosaccharide.

Gene Name	Protein Name	Effect of Mutations on Human Milk	The Effect on the Infant or Related Disease	Treatment
SLC30A2	ZnT2	LoF homozygous mutation in ZnT2 were found in mothers producing zinc-deficient human milk [25,26,27,28,29,30,31,32,33].	Transient neonatal zinc deficiency (TNZD), a disorder that leads to severe zinc deficiency in exclusively breastfed infants	Zinc supplementation (5 mg/day) and continuing breastfeeding [32]. No supplementation is needed after weaning.
ABCG2	BCRP	Mothers harboring the c.421C > A polymorphism in ABCG2, secreted threefold more nifedipine to human milk [41].	Unknown
SLC5A5	Sodium iodide symporter (NIS)	Mother carrying homozygous T354P mutation in the NIS transporter was reported to produce iodine-deficient milk. Other known LoF mutations in SLC5A5: V59E [54], G93R [51], R124H [55], Δ143-323 [56], Q267E [57], V270E [58], C272X [59], Δ287-288 [60], T354P [61], G395R [62], Δ439-443 [63], G543E [64], fs515X [65], and Y531X [65].	The mother was diagnosed with ITD, treated with levothyroxine from the age of five years old, therefore, iodine supplementation was given after birth to prevent deficiencies in the infant.	Mother supplementation with 50 mg potassium iodide tablet daily starting on the fifth day postpartum to increase iodine concentration in human milk.
MTHFR	Methylene tetrahydrof-olate reductase	The MTHFR 677C > T SNP was associated with higher levels of human milk unmetabolized folic acid (UMFA) [41].	Unknown
MTHFD1	Methylene tetrahydrof-olate dehydroge-nase 1	rs1076991, rs2983733, rs2987981, rs8003379, and rs17824591 SNPs in the methylene tetrahydrofolate dehydrogenase 1 (MTHFD1) gene were found to be associated with very high human milk choline concentrations in three subjects [22].	Unknown
FADS1 and FADS2	Fatty acid desaturase 1/2	The minor allele homozygotes of rs174553 (GG), rs99780 (TT), and rs174583 (TT) were associated with significantly lower 14:0, arachidonic (ARA, 20:4 ) and eicosapentanoic acid (EPA, 20:5), but higher 20:2 (n − 6) fatty acid in human milk [66]. Mothers carrying the minor homozygous allele G/G of rs174575, showed lower ARA, EPA, and docosahexanoic acids (DHA, 22:6 (n − 3)) and 22:5 (n − 3) levels in human milk [66]. Mothers carrying FADS1 rs174561, FADS2 rs174575, and intergenic rs3834458 minor alleles were found to have lower proportions of DHA in human milk [23].	Mothers carrying genetic variants associated with lower FADS1 activity (regulating AA and EPA synthesis), higher FADS2 activity (regulating DHA synthesis), and with higher EPA/AA and DHA/AA ratios in colostrum showed a significant advantage in cognition at 14 months.
FUT2	Fucosyltra-nsferase 2	Nonsense mutation W143X that introduces a premature stop codon in the FUT2 gene (rs601338) abolished the ability to synthesize α (1-2)-fucosylated HMOs (non-secretor status). Non-secretors where found to express less HMOs compared to mothers with secretor status (active FUT2) [67,68,69,70]. In addition, maternal secretor status was shown to be associated with the human milk microbiota composition [71].	Infants fed by non-secretor mothers, were delayed in the establishment of their gut microbiota, specifically bifidobacterial-laden [72,73].