Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
Am J Hum Genet
; 97(4): 608-15, 2015 Oct 01.
Article
en En
| MEDLINE
| ID: mdl-26365341
ABSTRACT
Skeletal dysplasias are highly variable Mendelian phenotypes. Molecular diagnosis of skeletal dysplasias is complicated by their extreme clinical and genetic heterogeneity. We describe a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family, comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability. Combined autozygome/exome analysis identified a homozygous frameshift mutation in RSPRY1 with resulting nonsense-mediated decay. Using a gene-centric "matchmaking" system, we were able to identify a Peruvian simplex case subject whose phenotype is strikingly similar to the original Saudi family and whose exome sequencing had revealed a likely pathogenic homozygous missense variant in the same gene. RSPRY1 encodes a hypothetical RING and SPRY domain-containing protein of unknown physiological function. However, we detect strong RSPRY1 protein localization in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification, consistent with a role in bone development. This study highlights the role of gene-centric matchmaking tools to establish causal links to genes, especially for rare or previously undescribed clinical entities.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Osteocondrodisplasias
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Enfermedades del Desarrollo Óseo
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Osificación Heterotópica
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Genes Recesivos
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Anomalías Musculoesqueléticas
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Mutación
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
Límite:
Adolescent
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Animals
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Child
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Female
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Humans
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Male
Idioma:
En
Revista:
Am J Hum Genet
Año:
2015
Tipo del documento:
Article
País de afiliación:
Arabia Saudita