Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype–phenotype correlations and impact on genetic counseling

Abstract

Communicated by Daniel F. Schorderet X-linked forms of retinitis pigmentosa (RP) (XLRP) account for 10 to 20% of families with RP and are mainly accounted for by mutations in the RP2 or RP GTPase regulator (RPGR) genes. We report the screening of these genes in a cohort of 127 French family comprising: 1) 93 familial cases of RP suggesting X-linked inheritance, including 48 out of 93 families with expression in females but no male to male transmission; 2) seven male sibships of RP; 3) 25 sporadic male cases of RP; and 4) two cone dystrophies (COD). A total of 5 out of the 93 RP families excluded linkage to the RP2 and RP3 loci and were removed form the cohort. A total of 14 RP2 mutations, 12 of which are novel, were identified in 14 out of 88 familial cases of RP and 1 out of 25 sporadic male case (4%). In 13 out of 14 of the familial cases, no expression of the disease was noted in females, while in 1 out of 14 families one woman developed RP in the third decade. A total of 42 RPGR mutations, 26 of which were novel, were identified in 80 families, including: 69 out of 88 familial cases (78.4%); 2 out of 7 male sibship (28.6%); 8 out of 25 sporadic male cases (32.0%); and 1 out of 2 COD. No expression of the disease was noted in females in 41 out of 69 familial cases (59.4%), while at least one severely affected woman was recognized in 28 out of 69 families (40.6%). The frequency of RP2 and RPGR mutations in familial cases of RP suggestive of X-linked transmission are in accordance to that reported elsewhere . Interestingly, about 30% of male sporadic cases and 30% of male sibships of RP carried RP2 or RPGR mutations, confirming the pertinence of the genetic screening of XLRP genes in male patients affected with RP commencing in the first decade and leading to profound visual impairment before the age of 30 years. Hum Mutat 28(1), [81][82][83][84][85][86][87][88][89][90][91] 2007.

Phenotypic progression in X-linked retinitis pigmentosa secondary to a novel mutation in the RPGR gene

“…Affected females had refraction from À7.00 D to À20.00 D, ETDRS visual acuity from 75 to 55 letters, foveal thickness from 144 to 212 mm, and V4e Goldmann field area from 15778 mm 2 to 5072 mm 2 There was a significant correlation between age and visual acuity (r ¼ À0.8, P ¼ 0.018), and between age and visual field area (r ¼ À0.94, P ¼ 0.005).…”

“…2 Traditionally, most RPGR mutations would be considered to be recessive with clinically normal female carriers or heterozygotes. However, some X-linked mutations have a dominant effect with an abnormal phenotype in heterozygous females.…”

“…2 However, as with other X-linked diseases, some females have symptoms and signs of RP, and are better regarded as being affected, as opposed to being carriers. 5 In these two families, complete penetrance was seen in both males and females.…”

The human retinitis pigmentosa GTPase regulator gene variant database

“…RPGR ORF15 mutations were also found in two canine models of retinal atrophy . In recent years, more new RPGR mutations and a new RPGR isoform (RPGR 9a) have been reported [Chakarova et al, 2006;Garcia-Hoyos et al, 2006;Sullivan et al, 2006;Neidhardt et al, 2007;Pelletier et al, 2007;Prokisch et al, 2007;Shu et al, 2007]. A total of 293 mutations in RPGR have been identified to date, 55% of which occur in the repetitive glutamic acid-and glycine-rich domain within exon ORF15.…”

Intellectual disability associated with retinal dystrophy in the Xp11.3 deletion syndrome: ZNF674 on trial. Guilty or innocent?

“…[1][2][3][4] Two genes, RP2 5 (MIM300757) and Retinitis pigmentosa GTPase regulator 6,7 (MIM312610), account for at least 80-90% of XLRD. 4,8 In 1994, Aldred et al 9 reported a large kindred cosegregating XLRD and intellectual disability (ID). Subsequently, affected patients were found to carry a 1.27-Mb microdeletion in Xp11.3-p11.23 and the disease was regarded as a contiguous gene deletion syndrome.…”