TY - GEN
T1 - ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants
AU - Bauwens, Miriam
AU - Garanto, Alejandro
AU - Sangermano, Riccardo
AU - Naessens, Sarah
AU - Weisschuh, Nicole
AU - De Zaeytijd, Julie
AU - Khan, Mubeen
AU - Sadler, Françoise
AU - Balikova, Irina
AU - Van Cauwenbergh, Caroline
AU - Rosseel, Toon
AU - Bauwens, Jim
AU - De Leeneer, Kim
AU - De Jaegere, Sarah
AU - Van Laethem, Thalia
AU - De Vries, Meindert
AU - Carss, Keren
AU - Arno, Gavin
AU - Fakin, Ana
AU - Webster, Andrew R.
AU - de Ravel de l’Argentière, Thomy J.L.
AU - Sznajer, Yves
AU - Vuylsteke, Marnik
AU - Kohl, Susanne
AU - Wissinger, Bernd
AU - Cherry, Timothy
AU - Collin, Rob W.J.
AU - Cremers, Frans P.M.
AU - Leroy, Bart P.
AU - De Baere, Elfride
PY - 2019/1/23
Y1 - 2019/1/23
N2 - Purpose: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. Methods: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. Results: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. Conclusion: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.
AB - Purpose: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. Methods: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. Results: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. Conclusion: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.
KW - ABCA4-associated disease
KW - AON
KW - deep-intronic
KW - missing heritability
KW - noncoding
UR - http://www.mendeley.com/research/abca4associated-disease-model-missing-heritability-autosomal-recessive-disorders-novel-noncoding-spl-1
UR - http://www.scopus.com/inward/record.url?scp=85060523094&partnerID=8YFLogxK
U2 - 10.1038/s41436-018-0420-y
DO - 10.1038/s41436-018-0420-y
M3 - Article
C2 - 30670881
VL - 21
SP - 1761
EP - 1771
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
PB - Nature Publishing Group
ER -