Genome sequencing identifies three molecular diagnoses including a mosaic variant in the COL2A1 gene in an individual with Pol III–related leukodystrophy and Feingold syndrome

Abstract

Undiagnosed genetic disease imposes significant burden on families and healthcare resources, especially in cases with a complex phenotype. Here we present a child with suspected leukodystrophy in the context of additional features, including hearing loss, clinodactyly, rotated thumbs, tapered fingers, and simplified palmar crease. Trio genome sequencing (GS) identified three molecular diagnoses in this individual: compound heterozygous missense variants associated with Pol III-related leukodystrophy, a 4 Mb de novo copy number loss including the MYCN gene associated with Feingold syndrome, and a mosaic single nucleotide variant (SNV) associated with COL2A1-related disorders. These variants fully account for the individual's features, but also illustrate the potential for superimposed and unclear contributions of multiple diagnoses to a individual's overall presentation. This report demonstrates the advantage of GS in detection of multiple variant types, including low-level mosaic variants, and emphasizes the need for comprehensive genetic analysis and detailed clinical phenotyping to provide individuals and their families with the maximum benefit for clinical care and genetic counseling.

A Novel Mutation c.3392G>T of COL2A1 Causes Spondyloepiphyseal Dysplasia Congenital by Affecting Pre-mRNA Splicing

“…Mosaicism has been previously reported in at least seven families with COL2A1 -related disease ( Winterpacht et al, 1993 ; Spranger et al, 1994 ; Forzano et al, 2007 ; Désir et al, 2012 ; Nagendran et al, 2012 ; Yamamoto et al, 2020 ; Muirhead et al, 2021 ). In these studies, parents in a somatic mosaic status with the COL2A1 mutation were clinically unaffected or showed a milder phenotype while offspring with heterozygous mutations tended to show a severe phenotype, the most severe cases even died neonatally ( Forzano et al, 2007 ; Nagendran et al, 2012 ).…”