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

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

Johanna L Schmidt  1 , Amy Pizzino  1 , Jessica Nicholl  2 , Allison Foley  3 , Yue Wang  4 , Jill A Rosenfeld  4 , Lindsey Mighion  5 , Lora Bean  5 , Cristina da Silva  5 , Megan T Cho  6 , Rebecca Truty  7 , John Garcia  7 , Virginia Speare  8 , Kirsten Blanco  8 , Zoe Powis  8 , Grace M Hobson  9 , Susan Kirwin  9 , Bryan Krock  10 , Hane Lee  11   12 , Joshua L Deignan  11 , Maggie A Westemeyer  13 , Ryan L Subaran  14 , Isabelle Thiffault  15 , Ellen A Tsai  16 , Terry Fang  16 , Guy Helman  17   18 , Adeline Vanderver  1   19
Affiliations

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

Johanna L Schmidt et al. Am J Med Genet A. 2020 Aug.

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.

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Conflict of interest statement

CONFLICT OF INTEREST

A. F. is a coordinator in clinical trials sponsored by BioMarin Pharmaceuticals. Y. W. reports that the Department of Molecular & Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted by Baylor Genetics. Y. W. receives salary support from Baylor Genetics. J. A. R. reports that the Department of Molecular & Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted by Baylor Genetics. J. A. R. receives salary support from Baylor Genetics. L. M., L. B., Cd. S. are employees of Emory Genetics Lab. M. T. C. at the time of this work, was an employee of GeneDx, a wholly owned subsidiary of OPKO Health, Inc. R. T. and J. G. are employees and stockholders of Invitae. MW is an employee and stockholder of Natera. V. S., K. B., and Z. P. are employees of Ambry Genetics. J. E. H. is an employee of Qiagen. J. R. P. is an employee of Tempus. E. A. T. and T. C. F. are employed by Biogen. A. V. receives research support from Biogen, Gilead, Ionis, Illumina, Eli Lilly, and Shire/Takeda. The remaining authors do not report any conflicts of interest.

Figures

FIGURE 1
FIGURE 1
(a) Relative frequency of cases identified in exome sequencing cohorts. The remainder of the genes (SLC17A5, CYP27A1, SUMF1, PSAP, DARS2, HEPACAM, MLC1, PSAP, RNASET2, ALDH3A2, ASPA, FUCA1, DARS, FAM126A, ACOX1, LMNB1, CLCN2, SCP2 in decreasing order of frequency) each represented less than 2% of the total population. (b) Relative frequency of cases identified in exome, gene panel and single gene sequencing cohorts. The remainder of the genes (LMNB1, GBE1, HSD17B4, EARS2, CYP27A1, SUMF1, SOX10, CSF1R, SLC17A5, HEPACAM, DARS2, MLC1, ALDH3A2, PSAP, FUCA1, FAM126A, PSAP, RNASET2, DARS, ACOX1, CLCN2, SCP2 in decreasing order of frequency) each represented less than 2% of the total population
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