rs12730935 — FLG 3702delG

FLG 3702delG — The Third Broken Allele

A single protein — filaggrin — is responsible for assembling the skin's outermost waterproof layer and generating the natural moisturizing factor (NMF)¹¹ natural moisturizing factor (NMF)
a hygroscopic mixture of amino acids, urocanic acid, pyrrolidone carboxylic acid, urea, and ions that keeps the stratum corneum hydrated and maintains the acidic skin pH (4.5–5.5) essential for barrier function that protects against allergen penetration, infection, and water loss. The FLG gene encodes a massive precursor — profilaggrin — which is proteolytically cleaved during terminal epidermal differentiation into 10–12 filaggrin monomers. The 3702delG variant (c.3702delG) deletes a single guanine nucleotide in the coding sequence at position 3702, shifting the reading frame and generating a premature stop codon within filaggrin repeat domain 3. This eliminates all downstream filaggrin sequence from that allele — making 3702delG a complete null allele²² complete null allele
any FLG loss-of-function mutation that abolishes filaggrin protein production from the affected chromosome regardless of the mechanism (nonsense, frameshift, or splice site).

3702delG is the third most common FLG null allele in European populations, identified in Irish and Scottish ichthyosis vulgaris families alongside the previously characterized R501X (rs61816761) and 2282del4 (rs558269137). Notably, R501X and 2282del4 both affect repeat domain 1, while 3702delG affects domain 3 — yet the downstream clinical consequence is identical: loss of all filaggrin protein from that allele.

The Mechanism

Loss of one functional FLG allele (heterozygous 3702delG) reduces total filaggrin output by approximately 50%, impairing stratum corneum assembly and NMF production. Reduced NMF means higher transepidermal water loss (TEWL)³³ transepidermal water loss (TEWL)
a measure of how much water evaporates through the skin; elevated TEWL is a reliable marker of barrier deficiency even in carriers without clinical eczema, elevated skin pH, and structural gaps between corneocytes. These gaps allow environmental allergens — house dust mite, pollen, food proteins — to reach the viable epidermis and trigger IgE-mediated sensitization through the skin, before dietary exposure to those allergens has occurred. This percutaneous sensitization⁴⁴ percutaneous sensitization
allergen sensitization through the skin rather than the gut or lungs — the primary mechanism linking FLG null carrier status to food allergy and asthma is the molecular foundation of the atopic march.

Inheritance is semidominant: heterozygotes (DI) have an intermediate phenotype, commonly identifiable only by palmar hyperlinearity and mild dryness. When a carrier of 3702delG also carries a second FLG null allele — R501X or 2282del4 — on the other chromosome, the compound heterozygous state is equivalent to complete filaggrin absence: the severe phenotype of ichthyosis vulgaris homozygosity is expressed with high penetrance.

The Evidence

3702delG was first identified by Sandilands et al. 2006⁵⁵ Sandilands et al. 2006
Sandilands A et al. Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis. J Invest Dermatol. 2006 in Irish families with ichthyosis vulgaris. A proband compound heterozygous for R501X/3702delG showed a severe phenotype clinically indistinguishable from R501X homozygosity, establishing that centrally positioned null mutations in the filaggrin repeat array are fully pathogenic. The broader comprehensive filaggrin gene analysis⁶⁶ comprehensive filaggrin gene analysis
Sandilands A et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet. 2007 characterized 3702delG as one of six prevalent European FLG null alleles, with an Irish case-control study demonstrating heterozygote odds ratio of 7.44 (95% CI not specified) for childhood eczema across the five most common European mutations combined.

The 3702delG allele is essentially absent outside Northwest European populations: it was not detected in control populations from Western Siberia, Spain, or East Asian cohorts, in contrast to R501X and 2282del4, which are found at lower but non-negligible frequencies in several populations globally. This geographic restriction reflects the Northwest European ancestry of the founding haplotype on which 3702delG arose.

The clinical framework established for R501X and 2282del4 applies equally to 3702delG, because the functional outcome is identical: FLG null alleles as a group confer OR 3.12 (95% CI 2.57–3.79) for atopic eczema⁷⁷ FLG null alleles as a group confer OR 3.12 (95% CI 2.57–3.79) for atopic eczema
Rodríguez et al. 2009: meta-analysis of 24 studies confirming eczema and asthma risk across FLG null mutations and OR 3.29 (95% CI 2.84–3.82) for eczema-associated asthma. Importantly, asthma risk disappears when eczema is absent, confirming that the skin barrier defect — not a direct airway effect — is the primary driver. Carriers of any two FLG null alleles (homozygous or compound heterozygous) carry odds ratio exceeding 10 for eczema herpeticum⁸⁸ eczema herpeticum
severe disseminated herpes simplex virus infection of eczematous skin — a medical emergency relative to eczema patients without FLG mutations.

A randomized controlled trial⁹⁹ randomized controlled trial
Simpson et al. 2014 JACI: daily emollient from birth reduced cumulative AD incidence by ~50% in high-risk infants over 6 months demonstrated that consistent barrier augmentation from birth reduces eczema incidence by approximately 50% in high-risk infants, establishing a clear intervention window for families with FLG null allele carriers.

Practical Actions

The barrier-support strategy for 3702delG carriers is identical to that for R501X and 2282del4 carriers — because the mechanism and deficit are the same. Ceramide-dominant emollients containing the physiologic 3:1:1 ratio of ceramides to cholesterol to free fatty acids replicate what a functional stratum corneum would produce. Urea-containing formulations (5–10% urea) are particularly beneficial because urea is both an NMF component and can upregulate residual FLG expression in skin cells. Fragrance, methylisothiazolinone (MI/MCI), sodium lauryl sulfate, and propylene glycol in personal care products disproportionately disrupt compromised barriers and should be eliminated.

Heterozygous carriers without current eczema should focus on proactive barrier maintenance during physiological stress periods — low humidity, cold weather, frequent handwashing, or prolonged water exposure — rather than waiting for symptoms. For parents carrying 3702delG: daily emollient from birth in high-risk infants is supported by RCT evidence, and early oral introduction of allergenic foods (peanut, egg, fish) — following current LEAP-trial-derived guidelines — is particularly critical in FLG-carrier families to prevent percutaneous sensitization from establishing food allergy before oral tolerance can develop.

Interactions

3702delG (rs12730935) is the third major European FLG null allele, and its most clinically significant interaction is compound heterozygosity with either R501X (rs61816761) or 2282del4 (rs558269137). When 3702delG is carried on one chromosome and either of these alleles on the other, the individual has no functional FLG gene — functionally equivalent to FLG null homozygosity. The R501X/3702delG compound heterozygous phenotype was clinically confirmed as indistinguishable from R501X homozygosity in the original characterization study. The management is identical to homozygosity: intensive twice-daily emollient therapy, dermatology referral, dupilumab consideration for moderate-to-severe eczema, and eczema herpeticum vigilance.

Proposed compound actions for supervisor: (1) When a user carries rs12730935 DI or DD AND rs61816761 AG or AA (3702delG + R501X compound heterozygous or R501X homozygous + 3702delG): complete FLG null state — intensive twice-daily ceramide-dominant emollient, dermatology referral, dupilumab evaluation, eczema herpeticum emergency recognition, early allergen introduction in offspring, barrier-disrupting ingredient elimination. Evidence level: established. (2) When a user carries rs12730935 DI or DD AND rs558269137 DI or DD (3702delG + 2282del4 compound heterozygous): complete FLG null state — identical management as above. Evidence level: established.