Whole-exome sequencing in the investigation of retinal dystrophy

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• 作者：Sarah Hull ; FRCOphth^a ; ^b ; ^{s.hull@ucl.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Gavin Arno ; PhD^a ; ^b ; Nicholas Owen ; DPhil^a ; Vincent Plagnol ; PhD^a ; Anthony Robson ; PhD^a ; ^b ; Prof Michel Michaelides ; FRCOphth^a ; ^b ; Prof Graham Holder ; PhD^a ; ^b ; Prof Andrew Webster ; FRCOphth^a ; ^b ; Prof Anthony Moore ; FRCOphth^a ; ^b ; ^c
• 刊名：The Lancet
• 出版年：2016
• 出版时间：25 February 2016
• 年：2016
• 卷：387
• 期：supp_S1
• 页码：S52
• 全文大小：58 K

文摘

Juvenile onset retinal dystrophy presents at age 16 years or younger. It is genetically heterogeneous, and causal genes can be associated with distinctive clinical features. Next generation sequencing techniques including whole-exome sequencing (WES) provide an unbiased platform for investigating patients. The aim of this study was to perform WES on patients with early onset retinal dystrophy and conduct in-depth phenotyping to determine key clinical and molecular characteristics and correlations.

Methods

Patients were ascertained from the inherited retinal clinics of a large tertiary referral centre. WES was performed on more than 100 probands. Likely pathogenic variants were confirmed with Sanger sequencing and family segregation. All patients underwent clinical examination, retinal imaging and electrophysiological testing, and targeted systemic investigations. Written, informed consent was obtained from all participants. The study received approval from the local ethics committee.

Findings

Unusual features of genes previously reported to have systemic manifestations were observed in 12 families. These features included IFT140-related retinal dystrophy in two families with no skeletal or renal manifestations of IFT140-related Mainzer-Saldino syndrome, COL18A1-related retinal dystrophy in a patient with normal neuroradiological imaging (unexpected for Knobloch syndrome), and IQCB1 in two patients with leber congenital amaurosis but normal renal function. In addition, identification of mutations in HPS6 in a family thought to have isolated foveal hypoplasia prompted further investigations that identified a bleeding diathesis consistent with Hermansky-Pudlak syndrome.

Interpretation

Early molecular diagnosis in early onset retinal dystrophy facilitates genetic counselling and directs appropriate investigations. WES provides an unbiased method for investigating patients compared with candidate gene sequencing and can identify atypical phenotypic presentations of syndromic genes as described in this cohort of patients. Thus, patient-specific investigations for potential systemic complications can be performed.

Funding

National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Foundation Fighting Blindness, Fight For Sight, Moorfields Eye Hospital Special Trustees, Rosetrees Trust, Foundation Fighting Blindness Career Development Award (MM).