Commentary on A Patient with Coarse Facial Features and Molecular Odyssey: Lessons Learned and Best Practice.

Abstract

The authors describe a 6-year-old female with macrocephaly, limited joint mobility, short stature, and normal cognitive development. Biochemical genetic studies demonstrated elevated urinary dermatan sulfate and decreased N-acetylgalactosamine-6-sulfatase (arylsulfatase B) activity. This collection of clinical features and biochemical abnormalities is specific for mucopolysaccharidosis (MPS) type VI (Maroteaux–Lamy syndrome). Targeted NGS analysis and whole-exome analysis identified a heterozygous pathogenic missense variant in ARSB. MPS VI is an autosomal recessive disorder, therefore biallelic variants would be required to cause an enzyme deficiency as well as the accumulation of urinary dermatan sulfate, necessitating a search for a second variant. Further dosage analysis and whole-genome sequencing did not identify a second variant in ARSB. Subsequent WGS analysis by a different laboratory identified an additional novel, heterozygous 97 bp duplication in ARSB, and this was confirmed by Sanger sequencing. The implementation of NGS into clinical laboratories has revolutionized genetic testing. Even early on, reports surfaced about missed variants leading to continued improvements in reagents and analysis pipelines (1). Indels of >50 bp are often missed by short-read sequencing and the integration of long-read analyses into clinical testing will likely improve the identification of these difficult variants. Missed variants can cause delays in treatment or limit familial testing. Additionally, in this case, if a molecular-first approach had been used and biochemical testing not initiated, the patient may have been considered a carrier.