Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next-generation sequencing

Am J Med Genet A. 2020 Aug;182(8):1906-1912. doi: 10.1002/ajmg.a.61641. Epub 2020 Jun 23.

Abstract

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A-related leukodystrophy, Peroxisomal biogenesis disorders, POLR3-related Leukodystrophy, Vanishing White Matter, and Pelizaeus-Merzbacher Disease. Despite the relative frequency of these conditions, carrier-screening laboratories regularly test only 20 of the 55 leukodystrophy-related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.

Keywords: carrier screening; frequency; leukodystrophy; next-generation sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmune Diseases of the Nervous System / genetics*
  • Autoimmune Diseases of the Nervous System / pathology
  • Demyelinating Diseases / epidemiology
  • Demyelinating Diseases / genetics*
  • Demyelinating Diseases / pathology
  • Exome / genetics
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lysosomal Storage Diseases / epidemiology
  • Lysosomal Storage Diseases / genetics
  • Magnetic Resonance Imaging
  • Male
  • Myelin Sheath / genetics
  • Myelin Sheath / metabolism
  • Nervous System Malformations / genetics*
  • Nervous System Malformations / pathology
  • Pelizaeus-Merzbacher Disease / epidemiology
  • Pelizaeus-Merzbacher Disease / genetics*
  • Pelizaeus-Merzbacher Disease / pathology
  • RNA Polymerase III / genetics*
  • Tubulin / genetics*
  • White Matter / diagnostic imaging
  • White Matter / pathology

Substances

  • TUBB4A protein, human
  • Tubulin
  • POLR3A protein, human
  • RNA Polymerase III

Supplementary concepts

  • Aicardi-Goutieres syndrome