TY - JOUR
T1 - The identification of a RNA splice variant in TULP1 in two siblings with early-onset photoreceptor dystrophy
AU - Verbakel, Sanne K.
AU - Fadaie, Zeinab
AU - Klevering, B. Jeroen
AU - van Genderen, Maria M.
AU - Feenstra, Ilse
AU - Cremers, Frans P.M.
AU - Hoyng, Carel B.
AU - Roosing, Susanne
N1 - Funding Information:
The work of F.P.M.C., S.R. and Z.F. is supported by the Foundation Fighting Blindness USA Project Program Award grant no. PPA‐0517‐0717‐RAD (to F.P.M.C. and S.R.). The work of F.P.M.C. and S.R. is also supported by the Rotterdamse Stichting Blindenbelangen, the Stichting Blindenhulp, the Stichting tot Verbetering van het Lot der Blinden, and the Stichting Blinden‐Penning (to F.P.M.C and S.R.).
Funding Information:
Funding information The work of F.P.M.C., S.R. and Z.F. is supported by the Foundation Fighting Blindness USA Project Program Award grant no. PPA-0517-0717-RAD (to F.P.M.C. and S.R.). The work of F.P.M.C. and S.R. is also supported by the Rotterdamse Stichting Blindenbelangen, the Stichting Blindenhulp, the Stichting tot Verbetering van het Lot der Blinden, and the Stichting Blinden-Penning (to F.P.M.C and S.R.).
Publisher Copyright:
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Background: Early-onset photoreceptor dystrophies are a major cause of irreversible visual impairment in children and young adults. This clinically heterogeneous group of disorders can be caused by mutations in many genes. Nevertheless, to date, 30%–40% of cases remain genetically unexplained. In view of expanding therapeutic options, it is essential to obtain a molecular diagnosis in these patients as well. In this study, we aimed to identify the genetic cause in two siblings with genetically unexplained retinal disease. Methods: Whole exome sequencing was performed to identify the causative variants in two siblings in whom a single pathogenic variant in TULP1 was found previously. Patients were clinically evaluated, including assessment of the medical history, slit-lamp biomicroscopy, and ophthalmoscopy. In addition, a functional analysis of the putative splice variant in TULP1 was performed using a midigene assay. Results: Clinical assessment showed a typical early-onset photoreceptor dystrophy in both the patients. Whole exome sequencing identified two pathogenic variants in TULP1, a c.1445G>A (p.(Arg482Gln)) missense mutation and an intronic c.718+23G>A variant. Segregation analysis confirmed that both siblings were compound heterozygous for the TULP1 c.718+23G>A and c.1445G>A variants, while the unaffected parents were heterozygous. The midigene assay for the c.718+23G>A variant confirmed an elongation of exon 7 leading to a frameshift. Conclusion: Here, we report the first near-exon RNA splice variant that is not present in a consensus splice site sequence in TULP1, which was found in a compound heterozygous manner with a previously described pathogenic TULP1 variant in two patients with an early-onset photoreceptor dystrophy. We provide proof of pathogenicity for this splice variant by performing an in vitro midigene splice assay, and highlight the importance of analysis of noncoding regions beyond the noncanonical splice sites in patients with inherited retinal diseases.
AB - Background: Early-onset photoreceptor dystrophies are a major cause of irreversible visual impairment in children and young adults. This clinically heterogeneous group of disorders can be caused by mutations in many genes. Nevertheless, to date, 30%–40% of cases remain genetically unexplained. In view of expanding therapeutic options, it is essential to obtain a molecular diagnosis in these patients as well. In this study, we aimed to identify the genetic cause in two siblings with genetically unexplained retinal disease. Methods: Whole exome sequencing was performed to identify the causative variants in two siblings in whom a single pathogenic variant in TULP1 was found previously. Patients were clinically evaluated, including assessment of the medical history, slit-lamp biomicroscopy, and ophthalmoscopy. In addition, a functional analysis of the putative splice variant in TULP1 was performed using a midigene assay. Results: Clinical assessment showed a typical early-onset photoreceptor dystrophy in both the patients. Whole exome sequencing identified two pathogenic variants in TULP1, a c.1445G>A (p.(Arg482Gln)) missense mutation and an intronic c.718+23G>A variant. Segregation analysis confirmed that both siblings were compound heterozygous for the TULP1 c.718+23G>A and c.1445G>A variants, while the unaffected parents were heterozygous. The midigene assay for the c.718+23G>A variant confirmed an elongation of exon 7 leading to a frameshift. Conclusion: Here, we report the first near-exon RNA splice variant that is not present in a consensus splice site sequence in TULP1, which was found in a compound heterozygous manner with a previously described pathogenic TULP1 variant in two patients with an early-onset photoreceptor dystrophy. We provide proof of pathogenicity for this splice variant by performing an in vitro midigene splice assay, and highlight the importance of analysis of noncoding regions beyond the noncanonical splice sites in patients with inherited retinal diseases.
KW - early-onset retinal dystrophy
KW - intronic variant
KW - TULP1
KW - whole exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85067291261&partnerID=8YFLogxK
U2 - 10.1002/mgg3.660
DO - 10.1002/mgg3.660
M3 - Article
C2 - 30950243
AN - SCOPUS:85067291261
SN - 2324-9269
VL - 7
JO - Molecular Genetics and Genomic Medicine
JF - Molecular Genetics and Genomic Medicine
IS - 6
M1 - e660
ER -