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Sarah Hull, Gulunay Kiray, John Chiang, Andrea L Vincent; Molecular and phenotypic investigation of a New Zealand cohort of childhood-onset retinal dystrophy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2383.
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© ARVO (1962-2015); The Authors (2016-present)
Inherited retinal diseases are clinically heterogeneous and are associated with nearly 300 different genes. In this retrospective, observational study of a consecutive cohort of patients with childhood-onset retinal dystrophy, molecular investigations and in-depth phenotyping were performed to determine key clinical and molecular characteristics.
A series of 51 patients from 47 families were ascertained from the New Zealand Database of Inherited Retinal Disease. Molecular investigations included arrayed primer extension, and next generation sequencing with a 280 retinal gene panel. Detailed clinical investigations included retinal imaging and electrophysiology.
Patients presented at a mean 17 months of age (median 3 months, range 0 months – 10 years). In 10 patients (10 families) presentation was consistent with Leber Congenital Amaurosis (LCA) with onset in infancy with nystagmus, roving eye movements and extinguished electroretinogram. Fundus appearance at presentation included no abnormality (n=2), mild pigmentary change (n=3), marked pigmentary change (n=1), and macular coloboma (n=4).Analysis has so far identified 58 likely pathogenic variants including 15 novel variants in 36 of 47 families (77%). Variants in 24 genes have been identified with the most common being CRB1 related disease in 4 families and RPE65 related disease in 3 families. Three sporadic retinal dystrophy patients were found to have variants in dominant genes CRX (n=2) and RHO and one male proband had a hemizygous variant in X-linked CACNA1F resulting in more accurate genetic counseling of inheritance.Variants in syndromic associated genes were identified in 4 families including ALMS1 associated with Alstrom syndrome (2 families), VPS13B associated with Cohen syndrome, and PPT1 associated with neuronal ceroid lipofuscinosis enabling systemic investigations and directed care. Of 10 families with LCA, 8 have been molecularly solved (80%) with variants found in 8 different genes.
Molecular investigations using a large retinal gene panel have achieved a reasonable rate of diagnosis including unexpected findings in syndromic genes. Molecular diagnosis facilitates genetic counselling, prognostic expectations and systemic investigations. It is an essential prerequisite for gene-specific interventions particularly relevant for those 3 families diagnosed with RPE65 related disease.
This is a 2020 ARVO Annual Meeting abstract.
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