Genotype–phenotype associations in a large PRPH2‐related retinopathy cohort

• Published in: Human mutation Vol. 41; no. 9; pp. 1528 - 1539
• Main Authors: Reeves, Melissa J., Goetz, Kerry E., Guan, Bin, Ullah, Ehsan, Blain, Delphine, Zein, Wadih M., Tumminia, Santa J., Hufnagel, Robert B.
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01.09.2020
• Subjects: clinical variant interpretation; Complementary DNA; Etiology; eyeGENE; genotype; Genotypes; Nucleotide sequence; Pathogenicity; Peripherin; phenotype; Phenotypes; PRPH2; Retinal degeneration; Retinopathy; phenotype; clinical variant interpretation; PRPH2; retinopathy; eyeGENE; genotype
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.24065

Molecular variant interpretation lacks disease gene‐specific cohorts for determining variant enrichment in disease versus healthy populations. To address the molecular etiology of retinal degeneration, specifically the PRPH2‐related retinopathies, we reviewed genotype and phenotype information obtained from 187 eyeGENE® participants from 161 families. Clinical details were provided by referring clinicians participating in the eyeGENE® Network. The cohort was sequenced for variants in PRPH2. Variant complementary DNA clusters and cohort frequency were compared to variants in public databases to help us to determine pathogenicity by current American College of Medical Genetics and Genomics/Association for Molecular Pathology interpretation criteria. The most frequent variant was c.828+3A>T, which affected 28 families (17.4%), and 25 of 79 (31.64%) variants were novel. The majority of missense variants clustered in the D2 intracellular loop of the peripherin‐2 protein, constituting a hotspot. Disease enrichment was noted for 23 (29.1%) of the variants. Hotspot and disease‐enrichment evidence modified variant classification for 16.5% of variants. The missense allele p.Arg172Trp was associated with a younger age of onset. To the best of our knowledge, this is the largest patient cohort review of PRPH2‐related retinopathy. Large disease gene‐specific cohorts permit gene modeling for hotspot and disease‐enrichment analysis, providing novel variant classification evidence, including for novel missense variants. American College of Medical Genetics and Genomics classification of variants, ClinVar concordance, Fisher's exact test of Genome Aggregation Database (gnomAD) allele frequency (AF) versus proband AF, and eyeGENE® proband allele frequencies versus gnomAD allele frequencies: (a) gnomAD AF of ClinVar variants according to ClinVar classification. There were 29 variants classified as pathogenic in ClinVar, of which two were also found in gnomAD: c.425G>A p.Arg142Gln and c.623G>A p.Gly208Asp. (b) eyeGENE® proband AF and gnomAD AF for the common variants between these two datasets. The variants with p < .00063 in the Fisher's exact test were annotated.