The n e w e ng l a n d j o u r na l of m e dic i n e
C or r e sp ondence
Rapid Sequencing-Based Diagnosis of Thiamine
Metabolism Dysfunction Syndrome
To the Editor: Approximately 30 years after the
start of the Human Genome Project, we se-
quenced the genome of an infant with encepha-
lopathy in just over 11 hours. The results led to
a clinical diagnosis of thiamine metabolism dys-
function syndrome 2 (THMD2) 16.5 hours after
a blood sample was obtained and 13 hours af-
ter we initiated sequencing, which informed treat-
ment of the infant, thereby illustrating the ful-
fillment of the promise of the Human Genome
Project to transform health care.
A 5-week-old, previously healthy male infant
was admitted after 2 hours of inconsolable,
atypical crying and irritability (Fig. 1). Examina-
tion revealed downward eye deviation when he
cried. Computed tomography of the head showed
multiple large, bilateral hypodensities. Ten years
earlier, his parents, who were first cousins, had
had a child with a similar neurologic presenta-
tion that rapidly progressed to epileptic enceph-
alopathy; the child died at 11 months of age
without an etiologic diagnosis, despite extensive
evaluation.
Infantile encephalopathy is associated with
approximately 1500 genetic diseases, many of
which are clinically indistinguishable but have
unique, effective treatments. Without prompt
treatment, permanent neurologic injury or death
occurs in many infants with these diseases. A
resemblance to common conditions, such as hy-
poxic ischemic encephalopathy, can lead to inap-
propriate or delayed treatment. These consider-
ations prompted us to seek a diagnosis through
genome sequencing. With written informed con-
sent from the parents, we obtained blood sam-
ples 17 hours after admission (Fig. 1) and per-
formed genome sequencing, using standard and
prototypic methods in parallel.2,3 We used the
n engl j med 384;22  nejm.org  June 3, 2021
The New England Journal of Medicine
Downloaded from nejm.org at Memorial Sloan Kettering Library on June 14, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
criteria of the American Society of Medical Ge-
netics to evaluate the pathogenicity of a frame-
shift variant (c.597dup; p.His200fs) in SLC19A3
(ClinVar accession number, VCV000533549​.­2) and
make a provisional diagnosis of THMD2 14 hours
33 minutes after his blood sample arrived at the
genome center. (SLC19A3 encodes a thiamine
transporter.) This provisional diagnosis was clini-
cally confirmed 49 minutes later.
Video electroencephalography showed numer-
ous seizures occurring in the interim. Thiamine
and biotin administration was started 37.5 hours
after admission, and phenobarbital administra-
tion was started 2 hours later. One 15-second
seizure was recorded thereafter. Six hours later,
the patient was alert, calm, and bottle feeding.
Standard, trio genome sequencing confirmed
the diagnosis. After a further 24 hours passed
without seizures, the patient was discharged. He
is now thriving at 7 months of age.
Early infantile, “Leigh-like” THMD2 is char-
acterized by rapid neurologic deterioration and,
if untreated, childhood death.4,5 We believe that
the patient’s sibling died in infancy from THMD2,
given the carrier status of both parents and the
this week’s letters
2159 Rapid Sequencing-Based Diagnosis of Thiamine
Metabolism Dysfunction Syndrome
2161 Cross-Reactive Neutralizing Antibody Responses
Elicited by SARS-CoV-2 501Y.V2 (B.1.351)
2163 Mutant UBA1 and Severe Adult-Onset
Autoinflammatory Disease
2165 β-Thalassemias
 The n e w e ng l a n d j o u r na l of m e dic i n e

A Clinical Course
10:49 p.m. 8:11 a.m.
Presented to Electroencephalogram 8:23 a.m.
emergency
11:18 p.m. showed frequent
Findings on head CT abnormal, Genomics, medical genetics, and
department with seizures neonatology personnel discuss
patient admitted to NICU
irritability and diagnosis and treatment
inconsolable 9:30 a.m.
crying for 2 hr NICU rounds, detailed 9:44 a.m.
family history obtained Biotin and thiamine
ordered
12:30 p.m.
Genomics, medical genetics, and 12:13 p.m.
neonatology personnel discuss patient First doses
of biotin 6:00 p.m. 6:29 a.m.
2:00 p.m. and thiamine Irritability and Patient
RGS authorized, administered seizures resolved; discharged
consent obtained feeding started home

DOL 41 DOL 42 DOL 43 DOL 46

B Diagnostic Course
12:30 p.m. 8:23 a.m. Diagnosis Autosomal recessive
Genomics, medical genetics, and 6:30 a.m. Genomics, medical thiamine metabolism
neonatology personnel Sequencing genetics, and dysfunction syndrome 2
discuss patient complete; neonatology Gene Thiamine transporter 2,
bioinformatics personnel discuss SLC19A3
3:52 p.m. analysis started diagnosis and
Blood sample drawn Variant Homozygous, pathogenic
treatment c.597dup
7:24 a.m.
5:01 p.m. Variants and pheno- Predicted p.His200SerfsTer25
Blood sample arrived types uploaded to Consequence
at genome center molecular diagnostic
artificial intelligence
5:50 p.m. 7:34 a.m.
Sample preparation 7:23 p.m. Analysis by molecular
commenced Sequencing diagnostic artificial
started intelligence completed;
provisional diagnosis

Figure 1. Clinical and Diagnostic Course in the Patient and His Sibling.
The homozygous frameshift variant in the thiamine transporter 2 gene SLC19A3 that was detected in the patient had previously been
­reported as pathogenic both in a child with a similar presentation1 and in the ClinVar database (accession number, VCV000533549​.­2).
Circles along the timeline indicate events that occurred during the clinical course (darker blue) and the diagnostic course (lighter blue).
Circles with vertical lines indicate points of interaction among neonatology, genomics, and medical genetics personnel. CT denotes
computed tomography, DOL day of life, NICU neonatal intensive care unit, and RGS rapid genome sequencing.

similarity of radiographic and neurologic find- in Australia, England, Germany, and Wales and in
ings (Fig. S1 in the Supplementary Appendix, avail- Medicaid pilot programs in California, Florida,
able with the full text of this letter at NEJM.org). and Michigan.
This case illustrates the potential for de- Mallory J. Owen, M.B., Ch.B.
creased suffering and improved outcomes Rady Children’s Institute for Genomic Medicine
through the implementation of rapid genome San Diego, CA
mowen1@rchsd.org
sequencing in a multidisciplinary, integrated,
precision medicine delivery system.1 Such a sys- Anna-Kaisa Niemi, M.D., Ph.D.
Rady Children’s Hospital
tem includes identification of infants with sus- San Diego, CA
pected genetic diseases on the day of admission,
David P. Dimmock, M.B., B.S.
rapid genome sequencing as a first-tier test, com- Rady Children’s Institute for Genomic Medicine
munication of results in a manner that facili- San Diego, CA
tates prompt transition from empirical to etio- Mark Speziale, M.D., Ph.D.
logically informed treatment, and implementation Mark Nespeca, M.D.
within a learning health care system.1 Currently, Rady Children’s Hospital
rapid genome sequencing is being implemented San Diego, CA

n engl j med 384;22  nejm.org  June 3, 2021

The New England Journal of Medicine

Downloaded from nejm.org at Memorial Sloan Kettering Library on June 14, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
 Correspondence

Kevin K. Chau, M.S. Chris M. Kunard, M.S.

Luca Van Der Kraan, B.S. Kevin P. Hall, D.Phil.
Meredith S. Wright, Ph.D. Illumina
Christian Hansen, B.S. San Diego, CA
Narayanan Veeraraghavan, Ph.D. Stephen F. Kingsmore, M.B., Ch.B., D.Sc.
Yan Ding, M.B., M.Sc. Rady Children’s Institute for Genomic Medicine
Jerica Lenberg, M.S. San Diego, CA
Shimul Chowdhury, Ph.D. skingsmore@rchsd.org

Charlotte A. Hobbs, M.D., Ph.D. Supported by Alexion, Ernest and Evelyn Rady, the J. Willard
and Alice S. Marriott Foundation, and a grant (UL1TR002550)
Sergey Batalov, M.S. from the National Institutes of Health.
Zhanyang Zhu, Ph.D. Disclosure forms provided by the authors are available with
Shareef A. Nahas, Ph.D. the full text of this letter at NEJM.org.

Rady Children’s Institute for Genomic Medicine 1. Kingsmore SF, Ramchandar N, James K, et al. Mortality in a
San Diego, CA neonate with molybdenum cofactor deficiency illustrates the
need for a comprehensive rapid precision medicine system. Cold
Sheldon Gilmer Spring Harb Mol Case Stud 2020;​6(1):​a004705.
Gail Knight, M.D. 2. Clark MM, Hildreth A, Batalov S, et al. Diagnosis of genetic
diseases in seriously ill children by rapid whole-genome sequenc-
Rady Children’s Hospital
ing and automated phenotyping and interpretation. Sci Transl
San Diego, CA
Med 2019;​11(489):​eaat6177.
Sebastien Lefebvre, M.S. 3. Dimmock DP, Clark MM, Gaughran M, et al. An RCT of
rapid genomic sequencing among seriously ill infants results in
John Reynders, Ph.D. high clinical utility, changes in management, and low perceived
Thomas Defay, Ph.D. harm. Am J Hum Genet 2020;​107:​942-52.
Alexion Pharmaceuticals 4. Tabarki B, Al-Hashem A, Alfadhel M. Biotin-thiamine-
Boston, MA responsive basal ganglia disease. In:​Adam MP, Ardinger HH,
Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, edi-
Jacqueline Weir, M.Sci. tors. GeneReviews [Internet]. Seattle:​University of Washington,
Seattle, 2013:​1993-2020 (https://www​.­ncbi​.­n lm​.­n ih​.­gov/​­books/​
Vicki S. Thomson, Ph.D. ­NBK169615/​­).
Louise Fraser, Ph.D. 5. Lee JS, Yoo T, Lee M, et al. Genetic heterogeneity in Leigh
Bryan R. Lajoie, Ph.D. syndrome: highlighting treatable and novel genetic causes. Clin
Genet 2020;​97:​586-94.
Tim K. McPhail, Ph.D.
Shyamal S. Mehtalia, M.S. DOI: 10.1056/NEJMc2100365

Cross-Reactive Neutralizing Antibody Responses

Elicited by SARS-CoV-2 501Y.V2 (B.1.351)

To the Editor: The severe acute respiratory syn-
drome coronavirus 2 (SARS-CoV-2) 501Y.V2 lin-
eage (also known as B.1.351), first identified in
South Africa in October 2020,1 has mutations
that confer increased resistance to plasma from
convalescent patients and vaccine recipients, as
well as to some monoclonal antibodies.2-4 How-
ever, the immune response to 501Y.V2 is un-
known. Similarly, the ability of antibodies elic-
ited by 501Y.V2 infection to cross-react with
other variants is unknown, but such cross-reac-
tivity would have implications for the ability of
second-generation vaccines based on the 501Y.V2
spike protein to protect against infection with
the original and emerging SARS-CoV-2 lineages.5
We characterized the SARS-CoV-2 infections
in a cohort of patients with coronavirus disease
2019 (Covid-19) who were hospitalized in the
Groote Schuur Hospital, Cape Town (Table S1 in
the Supplementary Appendix, available with the
full text of this letter at NEJM.org), after the
emergence and dominance of 501Y.V2 in South
Africa. Blood samples were obtained from 89
patients between December 31, 2020, and Janu-
ary 15, 2021; of these patients, 28 (31%) were
randomly selected for SARS-CoV-2 sequencing,
all of whom were shown by phylogenetic analy-
sis to be infected with 501Y.V2 (Fig. S1A). Fur-
thermore, at this time, the epidemic in Cape
Town (Fig. S1B) and in South Africa as a whole

n engl j med 384;22  nejm.org  June 3, 2021

The New England Journal of Medicine

Downloaded from nejm.org at Memorial Sloan Kettering Library on June 14, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.