ABCA4-Associated Stargardt Disease

Abstract

Autosomal recessive Stargardt disease (STGD1) is associated with variants in the ABCA4 gene. The phenotypes range from early-onset STGD1, that clinically resembles severe cone-rod dystrophy, to intermediate STGD1 and late-onset STGD1. These different phenotypes can be correlated with different combinations of ABCA4 variants which can be classified according to their degree of severity. A significant fraction of STGD1 cases, particularly late-onset STGD1 cases, were shown to carry only a single ABCA4 variant. A frequent coding variant (p.Asn1868Ile) was recently identified which – in combination with a severe ABCA4 variant – is generally associated with late-onset STGD1. In addition, an increasing number of rare deep-intronic variants have been found and some of these are also associated with late-onset STGD1. The effect of these and other variants on ABCA4 RNA was tested using in vitro assays in human kidney cells using specially designed midigenes. With stem cells and photoreceptor progenitor cells derived from patient skin or blood cells, retina-specific splice defects can be assessed. With expert clinical examination to distinguish STGD1 cases from other maculopathies, as well as in-depth genomics and transcriptomics data, it is now possible to identify both mutant ABCA4 alleles in > 95% of cases.

Zusammenfassung

Der autosomal-rezessive Morbus Stargardt (STGD1) ist mit Varianten im ABCA4-Gen assoziiert. Es gibt unterschiedliche Phänotypen – frühzeitig auftretender STGD1, was der schweren Zapfen-Stäbchen-Dystrophie klinisch ähnelt, sowie intermediärer STGD1 und spät auftretender STGD1. Diese unterschiedlichen Phänotypen werden mit verschiedenen Kombinationen von ABCA4-Varianten assoziiert, die nach Schweregrad eingeteilt werden können. Viele STGD1-Fälle, insbesondere die spät auftretenden, hatten bis vor Kurzem nur eine einzige ABCA4-Variante getragen. Eine häufige codierende Variante (p.Asn1868Ile), die in Wechselwirkung mit einer schwerwiegenden ABCA4-Variante gewöhnlich mit spät auftretendem STGD1 assoziiert ist, ist kürzlich identifiziert worden. Auch wurden mehrere seltene Varianten in Intronen identifiziert, die auch assoziiert sind mit spät auftretendem STGD1. Die Wirkungen von diesen und anderen Varianten auf ABCA4-RNA wurden in In-vitro-Tests in humanen Nierenzellen und mit selbst entworfenen Midigenen untersucht. Retinaspezifische Splicing-Defekte wurden mit Stammzellen und Photorezeptor-Progenitor-Zellen untersucht, die wiederum von Haut- oder Blutzellen der Patienten abgeleitet worden waren. Mit einer fachmännischen klinischen Untersuchung, um STGD1 von anderen Makulopathien zu unterscheiden, sowie tiefgehenden genomischen und transkriptosomalen Daten ist es jetzt möglich, beide mutierte ABCA4-Allelen in mehr als 95% der Fälle zu erkennen.

Key words

Stargardt disease - variants - splice defects - deep-intronic variants - reduced penetrance

Schlüsselwörter

Morbus Stargardt - Varianten - Spleißdefekte - tief intronische Varianten - reduzierte Penetranz

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