ClinGen Dosage Sensitivity Curation Page

RS1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
24138048 Kim and Mukai (2013) reviewed the clinical features and genotype-phenotype correlation observed in several different studies, including multi-generational families of individuals with XLRS1 (total of ~350 individuals with XLRS1; PMID: Sauer 1997; Tantri 2003; The Retinoschisis Consortium, 1998; Eksandh 2000; Renner 2008; Vincent 2013; Rodriguez 2005; Pimenides 2005; Riveiro-Alverez 2009; Shinoda 2000; Hewitt 2005; Shinoda 2000), and concluded the clinical phenotype and mutational spectrum of XLRS are highly variable across individuals, even those with the same genotype within the same family. At the time of publication, more than 205 different variants including reduced and loss of function variants in the RS1 gene had been reported in patients with XLRS. The majority were missense variants in exons 4?6, with nonsense and splice-site variants, deletions, and insertions also observed. The reported variants correspond to approximately 63% missense, 11% deletions, 16% indels, 8% splicing, 1 duplication, and 1 complex rearrangement. They described several molecular genetic studies, which demonstrated the underlying cause of RS1 protein dysfunction associated with missense variants in the RS1 gene was due to intracellular retention of the mutant protein and, thus, disease severity would not be expected to be variant specific. Other variants were also reported to produce a defective or reduced and/or non-functional protein, or absence of the protein.
32300273 Chen et al. (2020) describe 90 unrelated patients with molecularly confirmed XLRS and who underwent clinical and genetic analyses. The 90 probands (3?52 years old, mean age 17+/- 13 years) showed a variety of clinical phenotypes, including 80% with macular retinoschisis, 48% had peripheral retinoschisis, 16% macular atrophy, and 3% had a normal macular structure. A total of 68 variants were identified, including 15 novel variants. Most variants (65%) were missense; the remaining null variants included nonsense, splicing effect, frameshift indel, and large genomic exon level deletions. The 62 patients with missense variants have apparently milder visual defects than the 28 patients with null variants.

Haploinsufficiency phenotype comments:

X-linked juvenile retinoschisis (XLRS; OMIM 312700) is one of the most common genetic causes of juvenile progressive retinal-vitreal degeneration in males and has a worldwide prevalence ranging from 1 in 5,000 to 25,000. Heterozygous (carrier) females cannot be identified by clinical examination as they typically have a normal fundus appearance and visual function. Very rarely, examination of the peripheral retina may show white flecks or areas of schisis. The phenotypic expression in females is also influenced by uniparental isodisomy, nonrandom inactivation of the X chromosomes, monosomy X, and having a mutation in the RS1 gene on both X chromosomes (see GeneReviews). XLRS is characterized by early-onset visual loss and bilateral foveal schisis from the splitting of inner retinal layers, present in 98?100% of patients. Affected males show schisis (splitting) of the neural retina leading to reduced visual acuity. Carrier females may also express the disease and display similar clinical findings. The onset of clinical symptoms usually occurs within the first decade, as early as 3 months in some cases. Additional evidence includes: PMID: 9326935 Sauer et al. (1998) identified RS1 (aka XLRS1) as the gene responsible for retinoschisis. Mutational analyses in nine unrelated families identify one nonsense, one frameshift, one splice acceptor, and six missense variants in RS1; all of which segregate with disease. PMID: 9618178 The Retinoschisis Consortium (1998) screened 234 familial and sporadic retinoschisis cases and identified 82 different variants in 214 (91%) cases. The mutational spectrum was missense (75%), small intragenic deletions (7%), nonsense (6%), framseshift (6%) and splice site (6%).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.