Exome analysis of prenatal and postnatal cases referred with skeletal dysplasia-overview of phenotypic and genomic and findings | Haworth A, et al | Genetics in Medicine | Mar. 2022

Abstract

Skeletal dysplasias are rare disorders representing approximately 5% of all congenital anomalies. They are highly heterogeneous and clinical findings are often non-specific, so accurate diagnosis often relies on expert interpretation of radiological findings. Until the last few years treatments have been limited and focused primarily on surgical interventions to manage life-threatening skeletal and neurological complications. However, recently the development of therapeutics, such as vosoritide and infigratinib for children with achondroplasia, and asfotase alpha for hypophosphatasia, has highlighted the need to provide an accurate and timely diagnosis to inform early intervention.

ES was performed by hybridisation capture using either: Agilent Clinical Research Exome (V2.0) or ExomeCG (Nonacus). Sequencing was carried out on Illumina NextSeq 500 or Novaseq platforms. Secondary analysis was performed using DRAGEN Bio-IT processor or Sentieon with tertiary analysis performed using the Congenica clinical decision support platform. Copy number variant detection (CNV) was undertaken on a subset of cases using an implementation of Exome depth in the Congenica platform. Of the 60 cases referred with a clinical diagnosis of possible skeletal dysplasia, a molecular diagnosis was obtained in 51.6% (31/60). A higher diagnostic yield was observed in prenatal (64%, 18/28) rather than postnatal cases (40%, 13/32).

Exome analysis of prenatal and postnatal cases referred with skeletal dysplasia-overview of phenotypic and genomic and findings