Evagene adds four non-classical inheritance models

1. X-linked dominant with sex-differential severity

Classical XLD assumes similar severity in heterozygous females and hemizygous males. In practice, the clinically encountered X-linked dominant disorders split into five observable live-born patterns, and the recurrence-risk conversation turns on which pattern applies:

• Equal — similar severity in both sexes; classical XLD.
• Males worse — males substantially more severely affected than heterozygous females, but both viable.
• Male-lethal, reproduces — affected males do not survive to term; carrier mothers show a 1:1:1 live-born ratio of affected daughters, unaffected daughters, and unaffected sons. Incontinentia pigmenti (IKBKG), focal dermal hypoplasia (PORCN), and OFD1 fit this pattern.
• Male-lethal, no reproduction — affected males not seen in live births or recorded offspring. Rett syndrome (MECP2), CDKL5-related disorder, and related Rett-class conditions sit here.
• Males unaffected — metabolic-interference protection means males are phenotypically spared. Craniofrontonasal syndrome (EFNB1) and Epilepsy and Mental Retardation Limited to Females (EFMR; PCDH19) are the canonical examples.

For each sub-mode, Evagene's risk engine produces sex-specific offspring probabilities calibrated to what the clinician should expect to count in the live-born generation. The sub-mode is stored on the disease record and pre-populated for canonical disorders through catalogue lookup. The full derivation is in the risk models guide.

2. Mitochondrial (mtDNA) inheritance

Mitochondrial DNA mutations transmit exclusively down the maternal line. Evagene now implements this directly, with three features tuned to the clinical phenotypes rather than to textbook Mendelian logic:

• Strict maternal transmission — fathers do not transmit mtDNA variants; unaffected daughters of a carrier mother still transmit.
• Sex-differential penetrance — configurable per disease. Leber's hereditary optic neuropathy (LHON) shows marked male preponderance; MELAS affects both sexes more symmetrically. Each record carries male_penetrance and female_penetrance parameters.
• Heteroplasmy scaling — phenotype severity tracks the mutant-load fraction in the transmitting mother's tissues, with a mitochondrial_heteroplasmy_level parameter at the disease level and a runtime override.

Canonical disorders covered: LHON, MELAS, MERRF, NARP, Leigh syndrome (mtDNA subset), Kearns-Sayre syndrome, Pearson syndrome. See the mitochondrial section of the risk models guide, plus the individual diseases catalogue entries.

3. Digenic two-locus inheritance

For a subset of disorders, the phenotype requires a simultaneous variant at two separate loci. The classical digenic pedigree pattern — unaffected but related parents with multiple affected offspring, then ~25% transmission onwards — is straightforward to miss if each locus is analysed under autosomal recessive assumptions.

Evagene's digenic engine models the joint genotype at both loci and returns the correct offspring probability. Three canonical configurations are supported:

• both_het — one pathogenic variant at each locus; Aa;Bb × aa;bb yields 25% affected offspring.
• one_het_one_hom — asymmetric configurations where one locus requires homozygosity and the other heterozygosity.
• both_hom — homozygosity required at both loci.

Canonical disorders covered: Usher syndrome type 2 (classical USH2A / GPR98 interaction), certain forms of retinitis pigmentosa, and primary congenital glaucoma. Both loci are assumed autosomal and unlinked; genuinely linked digenic loci require a dedicated linkage analysis. The full derivation is in the digenic section of the risk models guide.

4. Imprinting and uniparental disomy (UPD)

Imprinting disorders defeat the usual recurrence-risk heuristics because the molecular mechanism determines the number, not the pedigree alone. Evagene's imprinting / UPD engine weights recurrence by four mechanisms:

• Deletion — typically sporadic; low recurrence unless a parent is a structural-variant carrier.
• Uniparental disomy (UPD) — typically sporadic; recurrence dominated by the rare cases of parental meiotic instability.
• Imprinting-centre defect — can carry substantial recurrence risk depending on the configuration.
• Point mutation in the imprinted gene — follows classical Mendelian recurrence for the underlying autosomal-dominant or -recessive pattern.

For imprinting-centre defects, the parent-of-origin rule applies: the transmitting parent's sex determines which syndromic phenotype emerges in offspring. A paternally-inherited defect at 15q11-13 presents as Prader-Willi; a maternally-inherited defect at the same locus presents as Angelman syndrome. Evagene encodes this directly — the offspring-risk output depends on both the molecular mechanism and the transmitting parent's sex.

Canonical disorders covered: Prader-Willi, Angelman, Beckwith-Wiedemann syndrome, Silver-Russell syndrome, transient neonatal diabetes mellitus (TNDM). The imprinting section of the risk models guide lists the full mechanism-weight tables.

Where this lands clinically

The target audience for these additions is clinical geneticists, genetic counsellors, and reproductive-medicine specialists. The common thread is families whose pedigree pattern does not fit the classical Mendelian three, and where the correct recurrence-risk number depends on the specific molecular or developmental mechanism rather than on the pedigree shape alone.

• A woman whose brother had a mitochondrial encephalopathy and who is considering a pregnancy — now has an explicit mitochondrial offspring-risk output, not an ad-hoc narrative.
• A couple whose first child had Angelman syndrome confirmed by IC-defect methylation analysis — gets a mechanism-weighted recurrence risk, not a textbook figure.
• A family with multiple daughters affected by a Rett-like picture and no affected sons — is explicitly modelled under the male-lethal-no-reproduction XLD sub-mode.
• Siblings with Usher type 2 and unaffected parents — fits the digenic two-locus pattern directly, with the correct 25% offspring risk rather than a contradictory recessive calculation.

Related pages

• 17 April 2026 release notes — polygenic, nine cancer family-history models, CanRisk export
• Decision matrix: which risk model for which counselling question?
• Reproductive counselling and non-classical inheritance — for genetic counsellors
• Mendelian inheritance calculator
• Complex-disease pedigree software
• Rett syndrome pedigree