Background: Disproportional short stature (DSS) is the most frequent clinical presentation of skeletal dysplasias, which are a heterogeneous group of more than 450 disorders of bone. Skeletal survey is important to establish the diagnosis and to guide the genetic test, but has several limitations, especially in mild and atypical cases.
Objective and hypotheses: To identify the genetic aetiology of DSS by exome sequencing.
Method: Whole exome sequencing was performed in six patients with disproportional short stature without a definitive classification into a skeletal dysplasia category, and their affected (n=6) and unaffected (n=5) available relatives. All pedigrees suggested an autosomal dominant pattern of inheritance. Exons and splice sites were captured with the Agilent SureSelect XT, and were sequenced on an Illumina HiSeq.
Results: The mean coverage of the captured regions was 170×. Our analysis focused on functional variants absent in controls that segregate in the families. We identified a causative variant predicted as pathogenic in three patients. Case 1 with height SDS of −2.0 has a novel heterozygous mutation in NPR2 gene (c.2905G>C/p.V969L). Heterozygous mutations in NPR2 are a cause of short stature without a distinct phenotype. Case 2 (height SDS of −4.5) has a heterozygous mutation in FBN1 gene (c.5183C>T/p.A1728V). Mutations in FBN1 were associates with gelophysic and acromicric dysplasia, but this patient lacks some of the cardinal features of these conditions. Case 3 with a height SDS of −2.5 and bilateral osteonecrosis of the femoral epiphysis has a heterozygous mutation in COL2A1 gene (c.1852G>A/p.G618S). Mutations in COL2A1 cause several skeletal disorders with highly variable phenotype.
Conclusion: We identified three heterozygous mutations in three different genes that explain the disproportional short stature phenotype observed in our patients. Because of the mild and unspecific phenotype, only a genomic approach allowed the identification of the etiology of short stature in these patients.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology