PURPOSE: Mutations at some retinitis pigmentosa (RP) loci are associated with variable penetrance and expressivity, exacerbating diagnostic challenges. The purpose of this study was to dissect the genetic underpinnings of nonsyndromic RP with variable age of onset in a large Mexican family. METHODS: We ascertained members of a large, multigenerational pedigree using a complete ophthalmic examination. We performed whole exome sequencing on two affected first cousins, an obligate carrier, and a married-in spouse. Confirmatory sequencing of candidate variants was performed in the entire pedigree, as well as genotyping and mRNA studies to investigate expression changes in the causal locus. RESULTS: We identified a 14-base pair (bp) deletion in PRPF31, a gene implicated previously in autosomal dominant (ad) RP. The mutation segregated with the phenotype of all 10 affected females, but also was present in six asymptomatics (two females and four males). Studies in patient cells showed that the penetrance/expressivity of the PRPF31 deletion allele was concordant with the expression levels of wild-type message. However, neither the known PRPF31 modulators nor cis-eQTLs within 1 Mb of the locus could account for the variable expression of message or the clinical phenotype. CONCLUSIONS: We have identified a novel 14-bp deletion in PRPF31 as the genetic driver of adRP in a large Mexican family that exhibits nonpenetrance and variable expressivity, known properties of this locus. However, our studies intimate the presence of additional loci that can modify PRPF31 expression.
PURPOSE: Mutations at some retinitis pigmentosa (RP) loci are associated with variable penetrance and expressivity, exacerbating diagnostic challenges. The purpose of this study was to dissect the genetic underpinnings of nonsyndromic RP with variable age of onset in a large Mexican family. METHODS: We ascertained members of a large, multigenerational pedigree using a complete ophthalmic examination. We performed whole exome sequencing on two affected first cousins, an obligate carrier, and a married-in spouse. Confirmatory sequencing of candidate variants was performed in the entire pedigree, as well as genotyping and mRNA studies to investigate expression changes in the causal locus. RESULTS: We identified a 14-base pair (bp) deletion in PRPF31, a gene implicated previously in autosomal dominant (ad) RP. The mutation segregated with the phenotype of all 10 affected females, but also was present in six asymptomatics (two females and four males). Studies in patient cells showed that the penetrance/expressivity of the PRPF31 deletion allele was concordant with the expression levels of wild-type message. However, neither the known PRPF31 modulators nor cis-eQTLs within 1 Mb of the locus could account for the variable expression of message or the clinical phenotype. CONCLUSIONS: We have identified a novel 14-bp deletion in PRPF31 as the genetic driver of adRP in a large Mexican family that exhibits nonpenetrance and variable expressivity, known properties of this locus. However, our studies intimate the presence of additional loci that can modify PRPF31 expression.
Authors: F Marlhens; C Bareil; J M Griffoin; E Zrenner; P Amalric; C Eliaou; S Y Liu; E Harris; T M Redmond; B Arnaud; M Claustres; C P Hamel Journal: Nat Genet Date: 1997-10 Impact factor: 38.330
Authors: T P Dryja; T L McGee; L B Hahn; G S Cowley; J E Olsson; E Reichel; M A Sandberg; E L Berson Journal: N Engl J Med Date: 1990-11-08 Impact factor: 91.245
Authors: Feng Wang; Hui Wang; Han-Fang Tuan; Duy H Nguyen; Vincent Sun; Vafa Keser; Sara J Bowne; Lori S Sullivan; Hongrong Luo; Ling Zhao; Xia Wang; Jacques E Zaneveld; Jason S Salvo; Sorath Siddiqui; Louise Mao; Dianna K Wheaton; David G Birch; Kari E Branham; John R Heckenlively; Cindy Wen; Ken Flagg; Henry Ferreyra; Jacqueline Pei; Ayesha Khan; Huanan Ren; Keqing Wang; Irma Lopez; Raheel Qamar; Juan C Zenteno; Raul Ayala-Ramirez; Beatriz Buentello-Volante; Qing Fu; David A Simpson; Yumei Li; Ruifang Sui; Giuliana Silvestri; Stephen P Daiger; Robert K Koenekoop; Kang Zhang; Rui Chen Journal: Hum Genet Date: 2013-10-24 Impact factor: 4.132
Authors: H Morimura; G A Fishman; S A Grover; A B Fulton; E L Berson; T P Dryja Journal: Proc Natl Acad Sci U S A Date: 1998-03-17 Impact factor: 11.205
Authors: M Al-Maghtheh; E Vithana; E Tarttelin; M Jay; K Evans; T Moore; S Bhattacharya; C F Inglehearn Journal: Am J Hum Genet Date: 1996-10 Impact factor: 11.025
Authors: Linda Köhn; Sara J Bowne; Lori S Sullivan; Stephen P Daiger; Marie S I Burstedt; Konstantin Kadzhaev; Ola Sandgren; Irina Golovleva Journal: Eur J Hum Genet Date: 2008-12-03 Impact factor: 4.246
Authors: Andy Boyd; Jean Golding; John Macleod; Debbie A Lawlor; Abigail Fraser; John Henderson; Lynn Molloy; Andy Ness; Susan Ring; George Davey Smith Journal: Int J Epidemiol Date: 2012-04-16 Impact factor: 7.196
Authors: Barbara E Stranger; Stephen B Montgomery; Antigone S Dimas; Leopold Parts; Oliver Stegle; Catherine E Ingle; Magda Sekowska; George Davey Smith; David Evans; Maria Gutierrez-Arcelus; Alkes Price; Towfique Raj; James Nisbett; Alexandra C Nica; Claude Beazley; Richard Durbin; Panos Deloukas; Emmanouil T Dermitzakis Journal: PLoS Genet Date: 2012-04-19 Impact factor: 5.917
Authors: Anna M Rose; Amna Z Shah; Giulia Venturini; Carlo Rivolta; Geoffrey E Rose; Shomi S Bhattacharya Journal: Ann Hum Genet Date: 2013-10-14 Impact factor: 1.670
Authors: N H Chapman; R A Bernier; S J Webb; J Munson; E M Blue; D-H Chen; E Heigham; W H Raskind; Ellen M Wijsman Journal: Hum Genet Date: 2018-10-01 Impact factor: 4.132
Authors: Danial Roshandel; Jennifer A Thompson; Rachael C Heath Jeffery; Dan Zhang; Tina M Lamey; Terri L McLaren; John N De Roach; Samuel McLenachan; David A Mackey; Fred K Chen Journal: Genes (Basel) Date: 2021-06-14 Impact factor: 4.096