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Heterozygous Deep‐Intronic Variants and Deletions in ABCA 4 in Persons with Retinal Dystrophies and One Exonic ABCA 4 Variant
Author(s) -
Bax Nathalie M.,
Sangermano Riccardo,
Roosing Susanne,
Thiadens Alberta A.H.J.,
Hoefsloot Lies H.,
den Born L. Ingeborgh,
Phan Milan,
Klevering B. Jeroen,
Westenengvan Haaften Carla,
Braun Terry A.,
ZonneveldVrieling Marijke N.,
Wijs Ilse,
Mutlu Merve,
Stone Edwin M.,
den Hollander Anneke I.,
Klaver Caroline C.W.,
Hoyng Carel B.,
Cremers Frans P.M.
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22717
Subject(s) - abca4 , biology , genetics , proband , exon , stargardt disease , compound heterozygosity , splice , mutation , gene , microbiology and biotechnology , phenotype
Variants in ABCA 4 are responsible for autosomal‐recessive S targardt disease and cone‐rod dystrophy. Sequence analysis of ABCA 4 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 ABCA 4 . 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 ABCA 4 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 V 1 and V 4 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.