Monogenic short stature

Gene: RSPRY1

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 11 Dec 2025, 1:25 p.m. | Last Modified: 11 Dec 2025, 1:25 p.m.

Panel Version: 1.27

Green List (high evidence)

Comment on list classification: At least 5 unrelated families have been reported in the literature with biallelic variants in this gene, presenting with spondyloepimetaphyseal dysplasia. Sufficient to rate Green at the next GMS panel update.

Created: 14 Mar 2025, 12:51 p.m. | Last Modified: 14 Mar 2025, 12:51 p.m.

Panel Version: 8.142

Comment on publications: PMID: 39940902 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

Created: 14 Mar 2025, 12:49 p.m. | Last Modified: 14 Mar 2025, 12:49 p.m.

Panel Version: 8.141

- PMID: 30063090 (2018) - WES revealed a novel homozygous, c.377delT; p.(Ile126fs*), frameshift variant in exon 2 in one family. Dideoxy-sequencing revealed a homozygous splice site variant c.516+2T>A; p.(?) in a second family. All patients had short stature, skeletal deformities, facial dysmorphism and intellectual disability.

- PMID: 38562122 (2024) - family with two sisters presenting with short stature, facial dysmorphism, progressive vertebral defects, small epiphysis, cupping and fraying of metaphyses, brachydactyly, and short metatarsals harbored a homozygous missense variant c.1652G>A;p.(Cys551Tyr) in the RSPRY1 gene. Cognitive assessments indicated mild impairment.

- PMID: 39940902 (2025) - discuss the previously reported family (PMID: 30063090) with spondyloepimetaphyseal dysplasia and a homozygous frameshift variant in the RSPRY1 gene (c.377delT, p.Ile126fs*). Functional studies demonstrate the molecular and cellular mechanisms that underpin this disorder via disruption of the TGF-β signalling pathway which plays a key role in skeletal homeostasis.

Created: 14 Mar 2025, 12:46 p.m. | Last Modified: 14 Mar 2025, 12:46 p.m.

Panel Version: 8.138

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, OMIM:616723

Publications

• 26365341
• 30063090
• 38562122
• 39940902

Comment on list classification: Gene identified in literature PMID:30914295 as missing in PanelApp compared to other curated gene list for ID genes.

Faden et al (PMID: 26365341) reported on a consanguineous Bedouin Saudi family in which 4 sibs had progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability finding a a homozygous 1 bp duplication in RSPRY1 that predicts frameshift and premature truncation (GenBank: NM_133368.1; c.1279dupA [p.Thr427Asnfs∗10]

Using a "gene-matcher" tool they also studied a Peruvian boy with a homozygous missense variant (GenBank: NM_133368.1; c.121G>T [p.Gly41Cys]) in a conserved residue (GERP 5.22, Phast 658) in RSPRY1. The boy presented with a similar phenotype, who was born of parents from a small isolated region and presented with significant speech delay; he was diagnosed with autism spectrum disorder at 5 years of age. At age 8 years, he exhibited short stature, dysmorphic facial features, low-set ears, short trunk with hyperlordosis, varus and valgus knee deformities, and overriding toes. Skeletal survey showed delayed epiphyseal maturation, flattening of femoral heads, thoracic platyspondyly, and short fourth metatarsals.

Table 1 Faden et al (PMID: 26365341) all effected individuals are recorded as having ID.

The authors performed functional work on mice looking at limb abnormalities and found the expression of Rspry1 correlates strikingly with the skeletal defects observed in affected individuals and is also consistent with the presence of brain and craniofacial phenotypes, because expression was detected in embryonic and postnatal brain and in developing craniofacial tissues

Rating gene as Amber as only two unrelated cases reported.

Created: 30 May 2019, 2:27 p.m.