Dataset Information

Modification of the PROM1 disease phenotype by a mutation in ABCA4.

ABSTRACT: Background: The extensive phenotypic heterogeneity of monogenic diseases can be largely traced to intragenic variation; however, recent advances in clinical detection and gene sequencing have uncovered the emerging role of non-allelic variation (i.e. genetic trans-modifiers) in shaping disease phenotypes. Identifying these associations are not only of significant diagnostic value, but also provides scientific insight into the expanded molecular etiology of rare diseases. This reports describes the discordant clinical manifestation of a family segregating mutations in ABCA4 and PROM1. Methods: Three patients across a two generation family underwent multimodal imaging and functional testing of the retina including color photography, fundus autofluorescence (AF), spectral domain-optical coherence tomography (SD-OCT) and full-field electroretinography (ffERG). Genetic characterization was carried out by direct Sanger and whole exome sequencing. Results: Clinical examination revealed similar retinal degenerative phenotypes in the proband and her mother. Despite being younger, the proband's phenotype was more advanced and exhibited additional features related to Stargardt disease not found in the mother. Whole exome sequencing identified a pathogenic missense variant in PROM1, c.400C > T, p.(Arg134Cys), as the underlying cause of retinal disease in both the proband and mother. Sequencing of the ABCA4 locus uncovered a single disease-causing variant, c.5714 + 5G > A in the daughter segregating from the father who, surprisingly, also exhibited very subtle disease changes associated with STGD1 despite being a heterozygous carrier. Conclusions: Harboring an additional heterozygous ABCA4 mutation increases severity and confers STGD1-like features in patients with PROM1 disease which provides supporting evidence for their shared pathophysiology and potential treatment prospects.

SUBMITTER: Lee W

PROVIDER: S-EPMC6777736 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Modification of the PROM1 disease phenotype by a mutation in ABCA4.

Lee Winston W Paavo Maarjaliis M Zernant Jana J Stong Nicholas N Laurente Zachary Z Bearelly Srilaxmi S Nagasaki Takayuki T Tsang Stephen H SH Goldstein David B DB Allikmets Rando R

Ophthalmic genetics 20190801 4

Background: The extensive phenotypic heterogeneity of monogenic diseases can be largely traced to intragenic variation; however, recent advances in clinical detection and gene sequencing have uncovered the emerging role of non-allelic variation (i.e. genetic trans-modifiers) in shaping disease phenotypes. Identifying these associations are not only of significant diagnostic value, but also provides scientific insight into the expanded molecular etiology of rare diseases. This repor ...[more]

PMID: 31576780

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Project description:PURPOSE:To characterize patients affected by a uniquely severe, rapid-onset chorioretinopathy (ROC) phenotype of ABCA4 disease. DESIGN:Comparative cohort study. PARTICIPANTS:Sixteen patients were selected from a large clinically diagnosed and genetically confirmed cohort (n = 300) of patients diagnosed with ABCA4 disease. MAIN OUTCOME MEASURES:Phenotypic characteristics were assessed on color fundus photographs, short-wavelength autofluorescence (488-nm), and near-infrared autofluorescence (NIR-AF, 787-nm) images. Subfoveal thickness measurements were obtained from enhanced-depth imaging OCT. Generalized retinal function was determined with full-field electroretinogram (ffERG) testing, and lipofuscin accumulation was assessed by quantitative autofluorescence (qAF). RESULTS:All patients exhibited advanced disease features, including pigment migration in the macula and retinal vessel attenuation at an early age, and reported a symptomatic onset, on average, at 7.4 years (average for ABCA4 disease is 21.9 years, P < 0.0001). Deterioration of the macula was observed to begin with an intense, homogeneous signal on short-wavelength autofluorescence, which corresponds to an attenuated NIR-AF signal and progresses to a patchy, coalescing pattern of chorioretinal atrophy within the subsequent decade. Measurement of choroidal thickness revealed a more rapid thinning of choriocapillaris with age of Sattler's layer compared with the rate in most other patients with ABCA4 disease (P < 0.001). Levels of qAF in the macula before atrophy were above both the 95% confidence intervals for healthy individuals and patients with Stargardt disease (STGD1) (>1000 qAF units). Severe attenuation of cone responses and notable decreases in rod responses were detected by ffERG. Sequencing of the ABCA4 gene revealed exclusively deleterious, null mutations, including stop codons; frameshift deletions; variants in canonical splice sites, which completely abolish splicing; and known deleterious missense alleles. CONCLUSIONS:The ROC phenotype is a unique classification of ABCA4 disease, which is caused by deleterious null biallelic ABCA4 mutations and is characterized by the rapid deterioration of retinal pigment epithelium and photoreceptor layers in the macula and significant choroidal thinning within the first 2 decades of life.

Project description:BackgroundMore than 1500 variants in the ATP-binding cassette, sub-family A, member 4 (ABCA4), locus underlie a heterogeneous spectrum of retinal disorders ranging from aggressive childhood-onset chorioretinopathy to milder late-onset macular disease. Genotype-phenotype correlation studies have been limited in clinical applicability as patient cohorts are typically small and seldom capture the full natural history of individual genotypes. To overcome these limitations, we constructed a genotype-phenotype correlation matrix that provides quantifiable probabilities of long-term disease outcomes associated with specific ABCA4 genotypes from a large, age-restricted patient cohort.MethodsThe study included 112 unrelated patients at least 50 years of age in whom 2 pathogenic variants were identified after sequencing of the ABCA4 locus. Clinical characterization was performed using the results of best corrected visual acuity, retinal imaging, and full-field electroretinogram testing.ResultsFour distinct prognostic groups were defined according to the spatial severity of disease features across the fundus. Recurring genotypes were observed in milder prognoses, including a newly defined class of rare hypomorphic alleles. PVS1 (predicted null) variants were enriched in the most severe prognoses; however, missense variants were present in a larger-than-expected fraction of these patients. Analysis of allele combinations and their respective prognostic severity showed that certain variants, such as p.(Gly1961Glu), and both rare and frequent hypomorphic alleles, were "clinically dominant" with respect to patient phenotypes irrespective of the allele in trans.ConclusionThese results provide much-needed structure to the complex genetic and clinical landscape of ABCA4 disease and add a tool to the clinical repertoire to quantitatively assess individual genotype-specific prognoses in patients.FUNDINGNational Eye Institute, NIH, grants R01 EY028203, R01 EY028954, R01 EY029315, P30 19007 (Core Grant for Vision Research); the Foundation Fighting Blindness USA, grant no. PPA-1218-0751-COLU; and Research to Prevent Blindness.

Dataset Information

Modification of the PROM1 disease phenotype by a mutation in ABCA4.

Publications

Modification of the <i>PROM1</i> disease phenotype by a mutation in <i>ABCA4</i>.

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