Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes

Abstract

Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148-698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants (SNV) and copy number variants (CNV) that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes.

Deep Scleral Exposure: A Degenerative Outcome of End-Stage Stargardt Disease

“…36 The sibling pair Patient 11 and Patient 12 harbored a deep intronic variant, c.4539+2028C>T, and a deletion/insertion, c.6148–698_c.6670del/insTGTGCACCTCCCTAG, described in a previous report. 37 Patient 5 harbors another deep intronic variant, c.4539+2001G>A.…”

Genetic Spectrum of ABCA4-Associated Retinal Degeneration in Poland

“…Out of the 67 patients in this group, nine came from families showing a clear pseudo-dominant pattern, either with full or incomplete penetrance (Figure 1). Pseudo-dominance in this gene has been reported many times [6,31,32]. This plays a crucial role, especially in cases where clinical phenotype cannot be easily determined.…”

Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration

“…Substantial progress has been made with respect to both objectives: several deep intronic ABCA4 variants have been proven to affect splicing8 14 and preliminary data (not shown) indicate that such is also true of rare variants affecting ABCA4 expression. We have also shown that large CNVs, which elude detection by sequencing, are exceptionally rare in the ABCA4 locus and, as a result, account for only a small fraction of ‘missing’ alleles 15. WES of patients with 0 ABCA4 mutations has uncovered causal genes in ~70% of cases with ABCA4 -like phenotypes, including known retinal disease genes ( CRB1, CRX , etc)11 13 and new genes ( RAB28, RDH11 ) 10 12.…”