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Dianna K H Wheaton, Kaylie Webb-Jones, Sara J Bowne, Lori S Sullivan, Stephen P Daiger, Rui Chen, Joost Felius, David G Birch, Lori Dao, Angela M Scheuerle; Severe Early-onset LCA-like Retinal Dystrophy due to Compound Heterozygous PRPH2 Mutations. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2890. doi: https://doi.org/.
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To characterize the phenotype and genotype of an early-onset, LCA-like dystrophy in an infant with congenital anomalies and developmental delay. Testing identified pathogenic mutations in three retinal dystrophy genes including the first observation of compound heterozygous PRPH2 mutations.
At birth, the small for gestational age male exhibited micrognathia, a high palate, and obstructive apnea. Nystagmus, observed at age 6 months led to a provisional diagnosis of LCA. Dysphagia resulted in G-tube placement at 7 months. Exams at 9 months included a pediatric ophthalmology exam, a visual function assessment (Teller acuity, electroretinogram [ERG]), and a medical genetics consult to define the diagnosis. Retinal dystrophy genetic testing by next-generation sequencing was requested via research (163 genes) and diagnostic (53 genes) lab protocols.
The ophthalmology exam detailed a hypoplastic optic nerve (OD), trace retinal pallor, fine intermittent rotary nystagmus, and exotropia (OD). Teller acuity was abnormal for age at 20/145, rod ERG responses were normal whereas cone 30Hz flicker amplitudes were reduced 99% and delayed. The medical genetics exam detailed additional dysmorphic (microcephaly, prominent forehead, deep-set eyes, low set ears) and physical findings (hypotonia, Franceschetti oculo-digital sign, inability to sit/stand independently). Cardiovascular, pulmonary and abdominal exams were normal. Family history was unremarkable for anomalies or impairments of sight/hearing. Lab assays were normal for karyotype (46XY), SNP chromosome microarray, targeted sequencing of HADHA (LCHAD) and peroxisomal disorder analytes. Both retinal dystrophy genetic testing protocols identified two pathogenic PRPH2 mutations c.629C>G (p.Pro210Arg; dominant) and c.37C>T (p.Arg13Trp; di-genic), and as well as a pathogenic ROM1 c.339dupG (p.Leu114fs; di-genic). A heterozygous, pathogenic USH2A mutation c.1606T>C was also identified. Parental testing confirmed the independent inheritance of the two PRPH2 mutations.
PRPH2 mutations are typically associated with adult-onset retinal dystrophy of variable phenotype ranging from pattern dystrophy to retinitis pigmentosa. The severe, early-onset phenotype observed in this PRPH2-induced retinal dystrophy is likely due to the PRPH2/ROM1 digenic mutations occurring concurrently with an additional dominant acting PRPH2 mutation.
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