Heterozygous Deep-Intronic Variants and Deletions inABCA4in Persons with Retinal Dystrophies and One ExonicABCA4Variant

Abstract

Variants in ABCA4 are responsible for autosomal-recessive Stargardt disease and cone-rod dystrophy. Sequence analysis of ABCA4 exons previously revealed one causative variant in each of 45 probands. To identify the "missing" variants in these cases, we performed multiplex ligation-dependent probe amplification-based deletion scanning of ABCA4. In addition, we sequenced the promoter region, fragments containing five deep-intronic splice variants, and 15 deep-intronic regions containing weak splice sites. Heterozygous deletions spanning ABCA4 exon 5 or exons 20-22 were found in two probands, heterozygous deep-intronic variants were identified in six probands, and a deep-intronic variant was found together with an exon 20-22 deletion in one proband. Based on ophthalmologic findings and characteristics of the identified exonic variants present in trans, the deep-intronic variants V1 and V4 were predicted to be relatively mild and severe, respectively. These findings are important for proper genetic counseling and for the development of variant-specific therapies.

Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort

“…Nevertheless, homozygous or compound heterozygous mutations are regularly detected in no more than 70–75% of STGD1 patients, while a significant number of patients carry only a single ABCA4 mutation or none at all [15,16,17,18,19]. On the other hand, several deep intronic variants in non-coding regions were reported to segregate with STGD1 affecting correct splicing mechanisms [19,20,21,22,23]. …”

The CommonABCA4Variant p.Asn1868Ile Shows Nonpenetrance and Variable Expression of Stargardt Disease When Present intransWith Severe Variants

“…Family H is part of a previously described multigeneration pedigree. 13,20 Proband H-II:3 and the unaffected sibling H-II:1 carry V1 and c.2919-?_3328þ?del, whereas the unaffected individual H-II:2, the spouse of H-II:1, is compound heterozygous for V1 and c.[5461-10T>C; 5603A>T]. For H-I:1, the variants were deduced by haplotype analysis.…”

“…16 In carriers of monoallelic ABCA4 variants, the second variant can reside in introns, outside of splice sites, not detected by standard sequencing methods. [17][18][19][20] A very small fraction of these unidentified defects comprise copy number variants that elude detection by PCR-based sequencing techniques. 18,[21][22][23] Identification of disease-causing alleles and insight into their associations with differences in disease presentation and severity are essential for the counseling of patients and become increasingly important, as research on therapeutic approaches is rapidly evolving.…”

Clinical Utility Gene Card for: autosomal recessive cone-rod dystrophy

“…Large gene rearrangements are rare; three deletions in ABCA4 have been identified spanning exon 5, 18 and exon 20-22, respectively. [1][2][3] In the KCNV2 gene, several deletions are described ranging from single basepairs deletions to complete gene deletions. 4,5…”