Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant

Nathalie M Bax; Riccardo Sangermano; Susanne Roosing; Alberta A H J Thiadens; Lies H Hoefsloot; L Ingeborgh van den Born; Milan Phan; B Jeroen Klevering; Carla Westeneng-van Haaften; Terry A Braun; Marijke N Zonneveld-Vrieling; Ilse de Wijs; Merve Mutlu; Edwin M Stone; Anneke I den Hollander; Caroline C W Klaver; Carel B Hoyng; Frans P M Cremers

doi:10.1002/humu.22717

Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant

Nathalie M Bax, Riccardo Sangermano, Susanne Roosing, Alberta A H J Thiadens, Lies H Hoefsloot, L Ingeborgh van den Born, Milan Phan, B Jeroen Klevering, Carla Westeneng-van Haaften, Terry A Braun, Marijke N Zonneveld-Vrieling, Ilse de Wijs, Merve Mutlu, Edwin M Stone, Anneke I den Hollander, Caroline C W Klaver, Carel B Hoyng, Frans P M Cremers

Medical retina and Uveitis

Research output: Contribution to journal › Article › Research › peer-review

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.

Original language	English
Pages (from-to)	43-7
Number of pages	5
Journal	Human Mutation
Volume	36
Issue number	1
DOIs	https://doi.org/10.1002/humu.22717
Publication status	Published - Jan 2015

Keywords

ATP-Binding Cassette Transporters/genetics
Exons
Female
Genetic Association Studies/methods
Genetic Heterogeneity
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Introns
Macular Degeneration/congenital
Male
Pedigree
Retinitis Pigmentosa/genetics
Sequence Analysis, DNA
Sequence Deletion
Stargardt Disease

Access to Document

10.1002/humu.22717

Cite this

Bax, N. M., Sangermano, R., Roosing, S., Thiadens, A. A. H. J., Hoefsloot, L. H., van den Born, L. I., Phan, M., Klevering, B. J., Westeneng-van Haaften, C., Braun, T. A., Zonneveld-Vrieling, M. N., de Wijs, I., Mutlu, M., Stone, E. M., den Hollander, A. I., Klaver, C. C. W., Hoyng, C. B., & Cremers, F. P. M. (2015). Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant. Human Mutation, 36(1), 43-7. https://doi.org/10.1002/humu.22717

@article{8b80f9a1de024519b9c450e7c92bd2b6,

title = "Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant",

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. ",

keywords = "ATP-Binding Cassette Transporters/genetics, Exons, Female, Genetic Association Studies/methods, Genetic Heterogeneity, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Introns, Macular Degeneration/congenital, Male, Pedigree, Retinitis Pigmentosa/genetics, Sequence Analysis, DNA, Sequence Deletion, Stargardt Disease",

author = "Bax, {Nathalie M} and Riccardo Sangermano and Susanne Roosing and Thiadens, {Alberta A H J} and Hoefsloot, {Lies H} and {van den Born}, {L Ingeborgh} and Milan Phan and Klevering, {B Jeroen} and {Westeneng-van Haaften}, Carla and Braun, {Terry A} and Zonneveld-Vrieling, {Marijke N} and {de Wijs}, Ilse and Merve Mutlu and Stone, {Edwin M} and {den Hollander}, {Anneke I} and Klaver, {Caroline C W} and Hoyng, {Carel B} and Cremers, {Frans P M}",

note = "{\textcopyright} 2014 WILEY PERIODICALS, INC.",

year = "2015",

month = jan,

doi = "10.1002/humu.22717",

language = "English",

volume = "36",

pages = "43--7",

number = "1",

}

Bax, NM, Sangermano, R, Roosing, S, Thiadens, AAHJ, Hoefsloot, LH, van den Born, LI, Phan, M, Klevering, BJ, Westeneng-van Haaften, C, Braun, TA, Zonneveld-Vrieling, MN, de Wijs, I, Mutlu, M, Stone, EM, den Hollander, AI, Klaver, CCW, Hoyng, CB & Cremers, FPM 2015, 'Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant', Human Mutation, vol. 36, no. 1, pp. 43-7. https://doi.org/10.1002/humu.22717

TY - JOUR

T1 - Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant

AU - Bax, Nathalie M

AU - Sangermano, Riccardo

AU - Roosing, Susanne

AU - Thiadens, Alberta A H J

AU - Hoefsloot, Lies H

AU - van den Born, L Ingeborgh

AU - Phan, Milan

AU - Klevering, B Jeroen

AU - Westeneng-van Haaften, Carla

AU - Braun, Terry A

AU - Zonneveld-Vrieling, Marijke N

AU - de Wijs, Ilse

AU - Mutlu, Merve

AU - Stone, Edwin M

AU - den Hollander, Anneke I

AU - Klaver, Caroline C W

AU - Hoyng, Carel B

AU - Cremers, Frans P M

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

KW - ATP-Binding Cassette Transporters/genetics

KW - Exons

KW - Female

KW - Genetic Association Studies/methods

KW - Genetic Heterogeneity

KW - Genetic Predisposition to Disease

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Introns

KW - Macular Degeneration/congenital

KW - Male

KW - Pedigree

KW - Retinitis Pigmentosa/genetics

KW - Sequence Analysis, DNA

KW - Sequence Deletion

KW - Stargardt Disease

U2 - 10.1002/humu.22717

DO - 10.1002/humu.22717

M3 - Article

C2 - 25363634

SN - 1059-7794

VL - 36

SP - 43

EP - 47

JO - Human Mutation

JF - Human Mutation

IS - 1

ER -

Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant

Abstract

Keywords

Access to Document

Fingerprint

Cite this