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

Cold Spring Harb Mol Case Stud. 2021 Dec 9;7(6):a006143. doi: 10.1101/mcs.a006143. Print 2021 Dec.


Undiagnosed genetic disease imposes a significant burden on families and health-care 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 polymerase III (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 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 an 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.

Keywords: abnormal CNS myelination; aggressive behavior; bilateral single transverse palmar creases; central hypotonia; cerebral hypomyelination; clinodactyly of the 5th finger; failure to thrive in infancy; malar flattening; microcephaly; recurrent otitis media; short chin; tapered finger.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Collagen Type II
  • Eyelids / abnormalities
  • Humans
  • Intellectual Disability*
  • Limb Deformities, Congenital*
  • Microcephaly*
  • Tracheoesophageal Fistula*


  • COL2A1 protein, human
  • Collagen Type II

Supplementary concepts

  • Oculodigitoesophagoduodenal syndrome