Evagene for Reproductive Medicine

The reproductive-medicine consultation

A woman in her early thirties, her partner with Ashkenazi Jewish ancestry, is planning a pregnancy. Her mother had breast cancer at 47; her maternal grandmother had ovarian cancer at 62; her older sister has had two affected sons with an undiagnosed neurological presentation and a third pregnancy ended in fetal demise. She wants to know: what is her own breast-cancer risk, what is the carrier risk she and her partner face across common recessive disorders, and what explains her sister's pregnancy losses — and what it might mean for her.

That single consultation touches every risk model Evagene supports. The pedigree carries all of it. Below is what Evagene does with each piece.

1. Ancestry-weighted carrier priors across the AR / XLR catalogue

For every individual with recorded ancestry, Evagene surfaces prior carrier probabilities across the autosomal-recessive and X-linked-recessive catalogue, weighted by that individual's ancestry proportions. Every row is attributed to one of three explicit sources, so the clinician always knows where the number came from:

Explicit population key — direct published carrier frequency (Cystic fibrosis in Northern European ~1 in 25; Tay-Sachs in Ashkenazi Jewish ~1 in 30).
Weighted mix — proportion-weighted combination when ancestry is mixed, with per-population contributions shown in the row.
Hardy-Weinberg estimate from incidence — derived as 2pq where no population-specific frequency is published, clearly flagged as an estimate rather than a published figure.

Safety default — ancestry-gated. If no ancestry is recorded on an individual, Evagene shows no personalised carrier number. This closes the common clinical-tool failure mode of presenting a "general population" figure as if it applied to a specific person. No ancestry, no prior — by design.

2. Non-classical inheritance modelling

The pedigrees that most often land in reproductive-medicine clinics are the ones that do not fit the classical Mendelian three. Evagene models the four patterns that matter most for reproductive counselling:

X-linked dominant with sex-differential severity

Five sub-modes cover the clinically observed live-born patterns: equal, males worse, male-lethal but reproduces (1:1:1 live-born ratio — incontinentia pigmenti, focal dermal hypoplasia, OFD1), male-lethal no reproduction (Rett syndrome, CDKL5, MECP2-related), and metabolic-interference males-unaffected (CFND / EFNB1, EFMR / PCDH19). Offspring-risk output is sex-split and sub-mode-aware.

Mitochondrial (mtDNA) inheritance

Strict maternal transmission. Sex-differential penetrance (LHON male preponderance; MELAS symmetric). Heteroplasmy scaling — phenotype severity tracks the mutant-load fraction in the transmitting mother's tissues. Canonical disorders: LHON, MELAS, MERRF, NARP, Leigh (mtDNA subset), Kearns-Sayre, Pearson. Offspring risks are maternal-line-only; affected fathers do not transmit; unaffected daughters of a carrier mother still transmit.

Digenic two-locus inheritance

Unaffected but related parents with multiple affected offspring, then ~25% transmission onwards — the classical digenic pattern. Supports both_het, one_het_one_hom, and both_hom configurations. Canonical disorders: Usher syndrome type 2, certain forms of retinitis pigmentosa, primary congenital glaucoma.

Imprinting and uniparental disomy (UPD)

Four mechanisms modelled with mechanism-weighted recurrence: deletion (typically sporadic), UPD (typically sporadic), imprinting-centre defect (substantially higher recurrence), and point mutation (classical Mendelian). For IC defects, the parent-of-origin rule applies: a paternal IC defect at 15q11-13 presents as Prader-Willi; a maternal IC defect at the same locus presents as Angelman syndrome. Canonical disorders: Prader-Willi, Angelman, Beckwith-Wiedemann, Silver-Russell, transient neonatal diabetes mellitus (TNDM). The offspring-risk output depends on both the molecular mechanism and the transmitting parent's sex.

3. Reproductive and breast-health fields for Gail, Tyrer-Cuzick, and CanRisk

Reproductive counselling often doubles as breast-cancer risk counselling, particularly for women who meet NICE moderate- or high-risk criteria. Evagene's Individual record carries the structured reproductive and breast-health fields that drive Gail, Tyrer-Cuzick, and the CanRisk export:

Age at menarche, age at menopause, age at first live birth, parity.
Cumulative hormone-therapy years.
Number of prior benign breast biopsies; atypical hyperplasia flag; LCIS flag.
Mammographic density (BI-RADS 1–4).
Height and weight for BMI.

Fields are optional; models that require a missing field display a clear warning rather than defaulting silently.

4. CanRisk / BOADICEA export for NICE-recommended workup

The NICE-recommended model for moderate- and high-risk women is BOADICEA, hosted at canrisk.org. Evagene ships a one-click export of a ##CanRisk 2.0 pedigree file populated with pedigree structure, ages at diagnosis, BRCA1 / BRCA2 / PALB2 / ATM / CHEK2 test statuses, Ashkenazi flag, and reproductive factors. The clinician uploads it at canrisk.org and runs BOADICEA there. BOADICEA is not bundled — licensed by the University of Cambridge; individual clinical use is free after registration, third-party web-service integration requires a separate commercial licence. The export path is the legally clean route to the gold-standard tool.

5. Germline mosaicism and the two-unaffected-parents case

When a couple presents after a second affected pregnancy from clinically unaffected parents, the recurrence-risk conversation has to distinguish between parental germline mosaicism (high recurrence), reduced-penetrance inheritance, and true independent de novo events. Evagene's germline mosaicism calculator computes a posterior across the competing hypotheses and integrates a somatic VAF from blood or sperm sequencing when available. Joint-parent logic ensures that confirming mosaicism in one parent exonerates the other, rather than leaving both under residual co-suspicion.

What this gives a reproductive-medicine service

One pedigree, read through every relevant model, without re-entry into separate tools.
Ancestry-gated carrier priors with explicit source attribution per row — a defensible number or no number, never a misleading "general" figure.
Recurrence-risk outputs calibrated to the specific molecular mechanism rather than to textbook numbers.
Structured reproductive and breast-health fields that carry through to Gail, Tyrer-Cuzick, and CanRisk / BOADICEA.
A legally clean path to BOADICEA for every NICE moderate- and high-risk woman in the service.