TY - JOUR
T1 - Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma
AU - Pierrache, Laurence H.M.
AU - Kimchi, Adva
AU - Ratnapriya, Rinki
AU - Roberts, Lisa
AU - Astuti, Galuh D.N.
AU - Obolensky, Alexey
AU - Beryozkin, Avigail
AU - Tjon-Fo-Sang, Martha J.H.
AU - Schuil, Jose
AU - Klaver, Caroline C.W.
AU - Bongers, Ernie M.H.F.
AU - Haer-Wigman, Lonneke
AU - Schalij, Nicoline
AU - Breuning, Martijn H.
AU - Fischer, Gratia M.
AU - Banin, Eyal
AU - Ramesar, Raj S.
AU - Swaroop, Anand
AU - van den Born, L. Ingeborgh
AU - Sharon, Dror
AU - Cremers, Frans P.M.
N1 - Publisher Copyright:
© 2017 American Academy of Ophthalmology
PY - 2017/7
Y1 - 2017/7
N2 - Purpose To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma. Design Case series. Participants Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma. Methods We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography. Main Outcome Measures IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings. Results We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula. Conclusions IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype–phenotype correlations.
AB - Purpose To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma. Design Case series. Participants Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma. Methods We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography. Main Outcome Measures IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings. Results We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula. Conclusions IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype–phenotype correlations.
UR - http://www.scopus.com/inward/record.url?scp=85017464647&partnerID=8YFLogxK
U2 - 10.1016/j.ophtha.2017.03.010
DO - 10.1016/j.ophtha.2017.03.010
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C2 - 28412069
AN - SCOPUS:85017464647
SN - 0161-6420
VL - 124
SP - 992
EP - 1003
JO - Ophthalmology
JF - Ophthalmology
IS - 7
ER -