RDH12-Related Dominant Retinopathy (MONDO:0800100): Comprehensive Disease Characterization

Causal gene: RDH12 (retinol dehydrogenase 12; HGNC:19977; NCBI Gene 145226; Ensembl ENSG00000139988; UniProt Q96NR8; chromosome 14q24.1).

Scope note. This report concerns the autosomal dominant retinopathy caused by heterozygous RDH12 variants (MONDO:0800100), an allelic but distinct entity from the far more common autosomal recessive RDH12-associated Leber congenital amaurosis/early-onset severe retinal dystrophy (LCA13; OMIM #612712). Because the dominant form is rare, much of the molecular and mechanistic literature is shared between the two and is drawn from the recessive/cell/animal literature; the distinction is made explicit throughout. Evidence source types are labeled: [human clinical], [in vitro], [model organism], [computational].

1. Disease Information

Overview. RDH12-related dominant retinopathy is a rare inherited retinal dystrophy (IRD) transmitted in an autosomal dominant fashion and caused by specific heterozygous C-terminal frameshift variants in RDH12. Clinically it is a comparatively mild, late(r)-onset rod–cone dystrophy / retinitis pigmentosa with variable expressivity and incomplete penetrance — in sharp contrast to the severe, blinding, childhood-onset recessive disease caused by biallelic RDH12 loss-of-function. The first dominant family (Fingert et al. 2008, 18779497 [human clinical]) had "a mild form of RP" with "late onset and relatively mild severity … dramatically different from the other disease associated with mutation in this gene, autosomal recessive Leber congenital amaurosis." The most completely characterized dominant pedigree (Muthiah et al. 2022, 34031043 [human clinical]) reclassified the phenotype as a rod–cone dystrophy with variable expression.

Key identifiers. - MONDO: MONDO:0800100 (RDH12-related dominant retinopathy). - Gene OMIM: RDH12 608830. Phenotype OMIM: no distinct dominant phenotype MIM number is currently assigned; the recessive allelic disorder is "Leber congenital amaurosis 13" OMIM #612712. The dominant RP is described in the literature but not given its own MIM phenotype number (consistent with the template note "OMIM: not recorded"). - Orphanet: No dominant-specific ORPHA code; related umbrella entities are retinitis pigmentosa (ORPHA:791) and Leber congenital amaurosis (ORPHA:65). - ICD-11: 9B70 Retinitis pigmentosa / hereditary retinal dystrophy (9B70.0). ICD-10: H35.52 (pigmentary retinal dystrophy). - MeSH: Retinitis Pigmentosa (D012174); Retinal Dystrophies (D058499). - HGNC: 19977. UniProt: Q96NR8.

Synonyms / alternative names. Autosomal dominant RDH12-related retinal dystrophy; autosomal dominant RDH12 retinopathy; RDH12-associated autosomal dominant retinitis pigmentosa; RDH12 rod–cone dystrophy (dominant).

Information source. Disease-level aggregated resources (OMIM, ClinVar, gnomAD, Ensembl) plus individual-patient case series/pedigree studies (Fingert 2008; Muthiah 2022). No EHR-scale datasets exist for this ultra-rare entity.

2. Etiology

Primary cause — genetic. The disease is monogenic/Mendelian, caused by heterozygous pathogenic variants in RDH12. Reported dominant alleles are C-terminal single-nucleotide frameshifts clustering around codons 253–260: - c.776delG (776delG) — original dominant family (Fingert et al. 2008, 18779497) [human clinical]. - c.763delG — four-generation British pedigree (Muthiah et al. 2022, 34031043) [human clinical]. - c.759del, p.(Phe254Leufs*24) — dominant RP patient used to derive iPSC line UCLi014-A (Sarkar et al. 2021, 34216980) [human clinical / in vitro].

Risk factors. - Genetic: The causal heterozygous RDH12 frameshift is the sole established determinant. A positive family history is the dominant risk indicator. No susceptibility loci or validated modifier genes are reported for the dominant form. - Environmental/other: No proven environmental, occupational, infectious, lifestyle, age, or sex risk factors. Light exposure is a biologically plausible modulator (RDH12 detoxifies light-generated retinaldehyde; Rdh12⁻/⁻ mice show light-induced photoreceptor apoptosis — Maeda et al. 2006, 17032653 [model organism]), but no clinical evidence links ambient light to dominant-disease severity.

Protective factors. None established. Genotype itself is protective relative to the recessive disease: within the recessive spectrum, homozygosity for the hypomorphic p.Leu99Ile allele is associated with milder, later disease (Daich Varela et al. 2024, 37714431 [human clinical]).

Gene–environment interactions. Not formally characterized. The inferred interaction is light/oxidative load × RDH12 dysfunction → aldehyde-driven photoreceptor stress (inferred, not demonstrated in dominant patients).

3. Phenotypes

The dominant phenotype is a mild rod–cone dystrophy / retinitis pigmentosa (Muthiah 2022, 34031043; Fingert 2008, 18779497) [human clinical]. Key features, with suggested HPO terms:

Note: The dominant disease generally lacks the devastating early features of recessive RDH12-LCA (congenital/early childhood blindness, universal macular atrophy from age 2, non-recordable ERG in infancy, dense bone-spicule pigmentation) documented in Fahim et al. 2019 (30979730) and Daich Varela & Michaelides 2022 (35491887) [human clinical].

Quality-of-life impact. Progressive peripheral field loss and night blindness impair mobility and night driving; relatively preserved central acuity means reading/face recognition are often retained longer than in the recessive disease. No disease-specific EQ-5D/SF-36/PROMIS data exist for the dominant form; IRDs broadly reduce vision-related QoL (NEI-VFQ).

4. Genetic / Molecular Information

Causal gene. RDH12 (HGNC:19977; OMIM 608830; Ensembl ENSG00000139988; chr14:67,701,886–67,734,451, GRCh38 [computational, gnomAD]). Encodes a 316-aa NADPH-dependent retinal reductase of the short-chain dehydrogenase/reductase (SDR) superfamily (UniProt Q96NR8; Pfam PF00106/adh_short; InterPro IPR002347).

Pathogenic variants (dominant). Heterozygous frameshift C-terminal variants: c.776delG, c.763delG, c.759del p.(Phe254Leufs24). These lie in the final coding region and are predicted to escape nonsense-mediated decay (NMD), producing a stable, altered truncated protein [computational inference]. - ACMG classification: dominant alleles are rare/private and functionally supported; recessive frameshifts here are classified Pathogenic/Likely pathogenic in ClinVar. - Allele frequency: dominant alleles are essentially absent from population databases (Fingert: not in 158 controls; gnomAD does not list these as recurrent) — consistent with private, family-specific mutations. - Origin: germline, segregating through pedigrees (AD). No somatic involvement. - Functional consequence: predicted gain of function / dominant-negative (Muthiah 2022, 34031043): "predicted to result in a gain of function, that causes disease in a gene typically associated with biallelic (recessive) variants." Supported by gnomAD constraint [computational]: pLI = 7.8×10⁻⁵, LOEUF (oe_lof upper) = 0.889, obs/exp LoF = 0.617 — RDH12 tolerates heterozygous LoF*, so haploinsufficiency is not the mechanism.

Variant landscape (gene-wide, mostly recessive). ClinVar lists 674 variants for RDH12 [computational], dominated by frameshift and missense alleles distributed across the coding sequence (e.g., c.43del p.Leu15Cysfs4; c.146T>C p.Leu49Ser; c.295C>A p.Leu99Ile; c.701G>A p.Arg234His; c.759del p.Phe254Leufs24). The recessive common allele p.Leu99Ile (c.295C>A) was the most frequent variant (52/… alleles) in a South American cohort (Daich Varela et al. 2024, 37714431) [human clinical].

Modifier genes / epigenetics / chromosomal abnormalities. None established for the dominant disease. No DNA-methylation/histone or large structural (CNV/translocation) mechanisms are implicated; a heterozygous RDH12 deletion has been reported in the recessive/compound setting (Sarkar et al. 2020, 32322264).

Suggested ontology terms. Gene product GO: GO:0004745 (NAD(P)+-retinol dehydrogenase / all-trans-retinol dehydrogenase activity), GO:0052650 (all-trans-retinol dehydrogenase (NADP+) activity), GO:0042574 (retinal metabolic process), GO:0007601 (visual perception).

5. Environmental Information

No established environmental, toxic, radiation, occupational, dietary, lifestyle, or infectious causes/triggers. The only biologically relevant exogenous factor is light, which generates the all-trans-retinal substrate that RDH12 detoxifies (inferred modulator; CHEBI:17898 all-trans-retinal). No infectious agents are involved. [No data available for this disease specifically.]

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

1. A heterozygous C-terminal frameshift in RDH12 (e.g., c.763delG, c.776delG, c.759del) results in an mRNA that escapes nonsense-mediated decay (last-exon rule) (inferred).
2. This leads to expression of a stable mutant RDH12 protein with an altered/extended C-terminus (the C-terminus contains the amphipathic membrane-association region) (inferred; protein-level data limited).
3. The mutant protein acts via a predicted gain-of-function / dominant-negative mechanism — it is not simple haploinsufficiency, because gnomAD shows RDH12 tolerates heterozygous LoF (pLI≈0) and recessive-allele carriers are unaffected [computational support]. The mutant is inferred to mislocalize and/or poison normal retinoid handling in the photoreceptor inner segment (inferred).
4. Reduced effective RDH12 reductase activity results in impaired reduction of all-trans-retinal (atRAL) → all-trans-retinol (atROL) in the inner segment [in vitro: Belyaeva 2005 15865448; Sarkar 2021 34445569].
5. atRAL and reactive lipid-peroxidation aldehydes (e.g., 4-HNE) accumulate, which leads to cytotoxicity and disrupted retinoid homeostasis [in vitro: Lee 2008 18396173].
6. Aldehyde accumulation induces oxidative stress and the ER unfolded-protein response (upregulation of sXBP1, CHOP/DDIT3, ATF4) [in vitro: Sarkar 2021 34445569].
7. Oxidative + ER stress results in photoreceptor apoptosis, branching to rod-predominant degeneration first (night blindness, peripheral field loss) and cone/macular involvement (central atrophy, reduced cone density) [model organism: zebrafish rdh12; human clinical: Muthiah 2022].
8. Progressive photoreceptor loss manifests clinically as a slowly progressive rod–cone dystrophy/RP with macular atrophy — milder than the recessive disease because residual wild-type RDH12 and partial function persist (inferred).

Branch (recessive comparison): biallelic LoF → near-complete loss of RDH12 → severe early atRAL/aldehyde toxicity → fulminant childhood macular atrophy and LCA (Fahim 2019, 30979730).

Mechanistic detail by category

• Molecular pathways / biochemistry: Visual (retinoid) cycle; RDH12 reduces atRAL using NADPH (~2000-fold NADP(H) preference; highest catalytic efficiency for all-trans-retinal kcat/Km ≈ 900 min⁻¹ µM⁻¹) (Belyaeva 2005, 15865448) [in vitro]. KEGG "Retinol metabolism" (hsa00830); Reactome "The canonical retinoid cycle in rods."
• Cellular processes: apoptosis (GO:0006915), response to oxidative stress (GO:0006979/GO:0034599), ER unfolded-protein response (GO:0030968), autophagy alteration (reduced atg12), photoreceptor outer-segment phagocytosis disruption.
• Protein dysfunction: loss of enzymatic reductase activity in mutants; for dominant alleles, a gain-of-function/dominant-negative stable product (vs misfolding/degradation seen with some missense recessive alleles).
• Metabolic changes: accumulation of all-trans-retinal (CHEBI:17898) and toxic aldehydes (4-hydroxynonenal, CHEBI:58266); disturbed retinyl ester/retinoic acid balance (Lee 2008, 18396173).
• Immune involvement: none primary.
• Tissue-damage mechanism: oxidative stress + aldehyde toxicity + ER stress → photoreceptor cell death.
• Molecular profiling: iPSC lines (34216980) and HEK/ARPE-19 models (34445569; 41683787) provide expression/functional data; no patient tissue transcriptomics/proteomics/metabolomics for the dominant form.

Cell types (CL): photoreceptor cell (CL:0000210), rod (CL:0000604), cone (CL:0000573); adjacent retinal pigment epithelial cell (CL:0002586). Subcellular (GO CC): photoreceptor inner segment (GO:0001917), endoplasmic reticulum membrane (GO:0005789), smooth ER / membrane-anchored.

7. Anatomical Structures Affected

• Organ level: Eye (UBERON:0000970); specifically the retina (UBERON:0000966) and macula lutea (UBERON:0005396). Primary disease is confined to the eye; no systemic/secondary organ involvement (non-syndromic).
• Tissue/cell level: Neural retina — photoreceptor layer; rod and cone photoreceptors (CL:0000604, CL:0000573); secondary RPE changes and inner retinal remodeling. Peripapillary sparing and macular/parafoveal atrophy are characteristic patterns.
• Subcellular: Photoreceptor inner segment (RDH12 localization; GO:0001917), ER (stress response).
• Localization & laterality: Bilateral and symmetric (HP:0012832 Bilateral). Regional: parafoveal/perifoveal and peripapillary (macula UBERON:0005396; optic disc region).

8. Temporal Development

• Onset: Adult/late onset for the dominant disease — "late onset and relatively mild severity" (Fingert 2008, 18779497). Variable; some mutation carriers are detectable only subclinically (e.g., on adaptive optics) reflecting incomplete penetrance (Muthiah 2022, 34031043). Pattern is insidious/chronic. (Contrast recessive: congenital/early-childhood onset, mean 4.1 yr — Fahim 2019, 30979730.)
• Progression: Slowly progressive over decades; stages = early (ring of hyper-AF, mild field constriction) → intermediate (enlarging perifoveal atrophy, ONL thinning) → advanced (extensive outer-retinal atrophy, significant field loss) with relative central-acuity preservation until late. Lifelong chronic disease; no remission.
• Critical periods / intervention window: Because photoreceptors persist for decades, there is a wide therapeutic window for the dominant disease (in contrast to the narrow infantile window in recessive disease, where early macular atrophy limits gene-replacement benefit).

9. Inheritance and Population

• Inheritance: Autosomal dominant (AD) for MONDO:0800100 (Fingert 2008; Muthiah 2022). The gene far more commonly causes autosomal recessive LCA13.
• Penetrance: Incomplete / age-dependent; penetrance determination is modality-dependent (subclinical carriers detected only by adaptive optics) (Muthiah 2022, 34031043).
• Expressivity: Variable (Muthiah 2022).
• Anticipation: None reported (not a repeat-expansion disorder).
• Germline mosaicism / founder effects / consanguinity: No founder effect or consanguinity role for the dominant alleles (private mutations; AD does not require consanguinity). Consanguinity is relevant only to the recessive disease.
• Carrier frequency: Not applicable in the AD sense (dominant alleles are private). For recessive disease, heterozygous LoF carriers exist in gnomAD but are unaffected.
• Epidemiology / prevalence: No reliable prevalence/incidence estimate exists for the dominant form — it is described in only a handful of pedigrees worldwide (ultra-rare). As gene-level context, RDH12 accounts for 3.4%–10.5% of LCA/EOSRD (Fahim 2019, 30979730) — but these are predominantly recessive cases.
• Demographics: Reported dominant families are of European (British/US) ancestry; too few to infer ethnic predilection, geographic clustering, sex ratio (expected ~1:1 for AD), or age distribution.

10. Diagnostics

• Clinical/imaging tests (core):
• Fundus autofluorescence (FAF): parafoveal/peripapillary hyper-AF ring, perifoveal hypo-AF (Muthiah 2022).
• Spectral-domain OCT: foveal total-retinal and ONL thinning; outer-retinal disruption.
• Adaptive optics scanning light ophthalmoscopy: reduced cone density (sensitive for subclinical carriers).
• Full-field & pattern ERG: rod–cone pattern of dysfunction; peripheral macular dysfunction.
• Visual fields (perimetry): peripheral constriction.
• Fundus photography: variable pigmentary changes/macular atrophy.
• Laboratory/biomarkers: No blood/urine biomarker or enzyme assay; diagnosis is clinical + genetic. (Research biomarker: all-trans-retinal/aldehyde handling, not clinical.)
• Genetic testing (definitive): Single-gene / IRD gene-panel next-generation sequencing, whole-exome (WES) and whole-genome sequencing (WGS) identify the heterozygous RDH12 frameshift; segregation analysis across the pedigree confirms dominant transmission (Muthiah 2022 used NGS incl. WGS). Chromosomal microarray/karyotype/FISH/mtDNA/repeat-expansion testing are not indicated (point-level frameshift mechanism). RNA studies can confirm NMD escape (research).
• Clinical criteria / differential diagnosis: No disease-specific criteria. Differentials: other dominant RP genes (RHO, PRPH2, RP1, PRPF31, NR2E3), cone–rod dystrophy genes (GUCA1A, CRX), and — critically — recessive RDH12-LCA/EOSRD (distinguished by congenital/severe early onset, universal early macular atrophy, non-recordable infantile ERG, biallelic variants). Genotyping + segregation resolves these.
• Screening: Cascade genetic testing of at-risk relatives in known pedigrees (with adaptive-optics/FAF to detect subclinical carriers). No population newborn/carrier screening (ultra-rare, AD, private alleles).

11. Outcome / Prognosis

• Survival/mortality: Not life-limiting; normal life expectancy. No disease-specific mortality (eye-restricted disorder).
• Morbidity/function: Chronic visual disability — progressive peripheral field loss and nyctalopia with relatively preserved central acuity; prognosis is markedly better than the recessive disease, which causes childhood legal blindness. Within recessive RDH12, p.Leu99Ile homozygotes reach legal blindness at an older age (Daich Varela 2024, 37714431) [human clinical].
• Disease course/complications: Slowly progressive outer-retinal atrophy; possible late cystoid macular changes/cataract (general RP complications). No spontaneous recovery.
• Prognostic factors: Specific variant, age, extent of macular atrophy on OCT/FAF, cone density on AO, residual field/ERG amplitude. No validated molecular prognostic biomarker.
• QoL measures: No dominant-form-specific instruments reported; NEI-VFQ-25 applicable clinically.

12. Treatment

No approved disease-specific therapy exists for RDH12 retinopathy (Daich Varela & Michaelides 2022, 35491887: "There is currently no treatment available for RDH12-retinopathy") [human clinical review].

• Supportive/rehabilitative (standard of care): low-vision aids, orientation & mobility training, occupational therapy, refraction/glare control (tinted lenses), management of cataract/cystoid macular edema, genetic counseling. NCIT: C15277 (Rehabilitation Therapy), C15296 (Supportive Care).
• Pharmacotherapy / mechanism-based (experimental, in vitro): Aldehyde/retinaldehyde scavengers — pregabalin attenuated atRAL-induced ER stress in mutant RDH12 cells (Sarkar 2021, 34445569) [in vitro]; conceptually related scavengers (e.g., primary-amine trap drugs). Antioxidants/ER-stress modulators are candidate strategies. No clinical trials for the dominant form. NCIT: C47484 (Pregabalin); C275 (Antioxidant).
• Gene therapy: AAV-mediated RDH12 gene augmentation is in preclinical development (patents held by Ali and Thompson groups per Fahim 2019, 30979730; in-vitro rAAV-RDH12 functional studies, Pavlova et al. 2026, 41683787) [in vitro / preclinical]. Caveat: gene augmentation (adding wild-type) treats loss-of-function recessive disease but may be insufficient for a dominant gain-of-function allele, which may instead require allele-specific knockdown/editing (ASO, siRNA, CRISPR). NCIT: C15431 (Gene Therapy); C117202 (AAV Vector).
• Cell therapy / other advanced modalities: iPSC-derived retinal models exist for drug screening (34216980) but no clinical cell therapy. Not applicable: immunotherapy, targeted small molecules, surgery (beyond cataract).
• Pharmacogenomics: Not applicable.

13. Prevention

• Primary prevention: Not possible for a germline Mendelian disorder. Genetic counseling for affected AD families (50% transmission risk) with options for prenatal diagnosis and preimplantation genetic testing (PGT-M). NCIT: C15265 (Genetic Counseling).
• Secondary prevention: Cascade genetic testing and ophthalmic surveillance (FAF/OCT/AO) of at-risk relatives for early detection; monitor for treatable complications (cataract, CME).
• Tertiary prevention: Low-vision rehabilitation; avoidance of excessive light exposure is biologically rational (RDH12 clears light-generated aldehydes) though unproven clinically.
• Immunization / public-health / behavioral / prophylaxis: Not applicable.

14. Other Species / Natural Disease

• Taxonomy / orthologs: RDH12 is conserved in vertebrates — human (NCBI Gene 145226; Homo sapiens NCBI:txid9606), mouse Rdh12 (NCBI Gene 77974; Mus musculus NCBI:txid10090), zebrafish rdh12 (Danio rerio NCBI:txid7955). Orthology: Alliance of Genome Resources / HomoloGene.
• Natural disease in other species: No well-established naturally occurring RDH12 retinopathy is cataloged in companion animals (no prominent OMIA entry); disease knowledge is from engineered models rather than spontaneous animal disease.
• Comparative biology: The retinoid (visual) cycle and RDH12's atRAL-reductase role are evolutionarily conserved; however, mice do not recapitulate human severity (redundancy with other RDHs, lower retinoid flux), a key cross-species difference.
• Transmission: Not applicable (non-infectious, non-zoonotic).

15. Model Organisms

• Mouse (mammalian): Rdh12-knockout mice (MGI) — mild phenotype that fails to recapitulate human disease: slowed atRAL reduction and delayed dark adaptation, accelerated 11-cis-retinal production, and increased susceptibility to light-induced photoreceptor apoptosis (Maeda et al. 2006, 17032653); grossly normal retinal histology at 10 months with normal ERG and retinoid levels (Kurth et al. 2007, 17130236) [model organism]. Limitation: no spontaneous severe degeneration → poor efficacy model; useful for light-damage and retinoid-flux studies.
• Zebrafish: CRISPR-Cas9 rdh12 mutant (rdh12^u533, c.17_23del; p.(Val6AlafsTer5)) shows disrupted outer-segment phagocytosis, rhodopsin mislocalization, reduced atg12/sod2 — early rod-predominant degeneration (Sarkar et al. 2021, 34445569) [model organism]. Better captures degeneration/oxidative-ER-stress phenotype.
• Cellular / in vitro: HEK-293 and ARPE-19 lines expressing WT vs mutant RDH12 for atRAL-toxicity, oxidative/ER-stress, and rAAV-RDH12 functional assays (34445569; 41683787); purified-enzyme kinetics (15865448).
• iPSC / organoids: Patient-derived iPSC line UCLi014-A from a dominant-RP patient (heterozygous c.759del p.(Phe254Leufs24)) and UCLi015-A from a recessive-LCA patient (Sarkar et al. 2021, 34216980) — enabling retinal-organoid disease modeling, mechanism comparison, and drug screening [in vitro]. This dominant-patient iPSC line is the most directly relevant model for MONDO:0800100.*
• Model databases: MGI (mouse), ZFIN (zebrafish), Cellosaurus (iPSC lines), Alliance of Genome Resources.

Summary of Evidence Types & Key Citations

• Human clinical: 18779497 (Fingert 2008, first dominant family, 776delG); 34031043 (Muthiah 2022, c.763delG, deep phenotyping, GoF prediction); 34216980 (dominant-patient iPSC, c.759del); 30979730 (recessive natural history; RDH12 = 3.4–10.5% of LCA/EOSRD); 37714431 (South American cohort, p.Leu99Ile); 35491887 (review, no treatment).
• In vitro: 15865448 (enzyme kinetics); 18396173 (4-HNE/aldehyde toxicity); 34445569 (oxidative/ER stress, pregabalin rescue + zebrafish); 41683787 (rAAV-RDH12).
• Model organism: 17032653 (light-induced apoptosis KO mouse); 17130236 (KO mouse normal histology).
• Computational / population genetics: gnomAD constraint (pLI≈0, LOEUF 0.89) — RDH12 tolerant of heterozygous LoF, arguing against haploinsufficiency.

Limitations

• The dominant entity is ultra-rare (a few pedigrees); phenotype, penetrance, natural history, and epidemiology are based on small samples.
• The gain-of-function/dominant-negative mechanism is predicted/inferred, not experimentally proven at the protein level for the dominant alleles.
• Most mechanistic/therapeutic data derive from recessive, cell, or animal contexts and are extrapolated to the dominant disease.
• No prevalence/incidence, QoL, or clinical-trial outcome data specific to the dominant form.

Future Directions

• Protein-level studies (localization, stability, dominant-negative testing) of c.763delG/c.776delG/c.759del, ideally in patient iPSC-derived retinal organoids (UCLi014-A).
• Allele-specific silencing/editing strategies appropriate to a dominant GoF allele, and testing aldehyde scavengers/antioxidants.
• Natural-history registries and standardized imaging/functional outcome measures for the dominant phenotype.