[Targeted sequencing identifies a hotspot mutation SNRNP200 p.S1087L correlates with novel phenotypes in retinitis pigmentosa].
OBJECTIVE
To identify the pathogenic mutation in a four-generation Chinese family with autosomal dominant retinitis pigmentosa (ADRP) and to analyze its associated clinical phenotypes.


METHODS
Twelve participants from the index family were recruited, including 5 patients, 6 asymptomatic siblings, and one spouse. All participants underwent ophthalmic examinations, including best-corrected visual acuity (BCVA), visual field (VF) testing, fundus photography, and full-field flash electroretinography (ERG). Targeted sequence capture array technique with next-generation of high throughput sequencing(NGS) was performed to detect variants in 189 hereditary retinal disease (HRD) related genes, comprising 179 identified HRD-causing genes and 10 potential causative genes which were involved in pre-messenger RNA(pre-mRNA) splicing. Variants detected by targeted sequencing were filtered by bioinformatic analyses, validated by Sanger sequencing and intra-familiar analysis.Genotype-phenotype correlation was also analyzed.


RESULTS
SNRNP200 p.S1087L was identified as the disease causative mutation for this family by targeted sequencing and optimized bioinformatic analyses. This family demonstrated early onset of the disease by presenting nyctalopia among 6 to 8 years old, performed rapid disease progression and severely impaired visual function by displaying loss of VF among 14 to 17 years old and decreased central vision among 21 to 28 years old. The fundus presentations and ERG results showed typical RP presentations.


CONCLUSIONS
SNRNP200 p.S1087L is identified as a hotspot mutation but correlates with distinct phenotypes in the present family, including early onset of the disease, rapid disease progression, and severely impaired visual function. This study also give evidence to that molecular diagnostic platform for HRD can improve the detection rate of causative genes/mutations in HRD patients, thus providing important approaches for further investigation of the genetic causes for HRD.
Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine,Nanjing 210029, China.
Xue
X
Chen
Xiang
X
Gao
Kan-xing
KX
Zhao
Xin-yuan
XY
Pan
Xiu-mei
XM
Zhang
Xiu-ying
XY
Wang
Song-tao
ST
Yuan
Qing-huai
QH
Liu
Email: dr.zhaochen@gmail.com.
Chen
C
Zhao
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics*; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics*; D055815:Young Adult
D017411:Ribonucleoproteins, Small Nuclear; C545711:SNRNP200 protein, human