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Deoxyguanosine Kinase Deficiency

Synonyms: DGUOK Deficiency; DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form

, MD, FAAP, FACMG, , MD, FAAP, FACMG, and , PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: December 22, 2016.

Estimated reading time: 15 minutes


Clinical characteristics.

The two forms of deoxyguanosine kinase (DGUOK) deficiency are a neonatal multisystem disorder and an isolated hepatic disorder that presents later in infancy or childhood. The majority of affected individuals have the multisystem illness with hepatic disease (jaundice, cholestasis, hepatomegaly, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and psychomotor retardation) evident within weeks of birth. Those with isolated liver disease may also have renal involvement and some later develop mild hypotonia. Progressive hepatic disease is the most common cause of death in both forms.


Reduced mitochondrial (mt) DNA copy number in liver or muscle can be used to confirm mtDNA depletion. Detection of biallelic pathogenic variants in DGUOK establishes the diagnosis of DGUOK deficiency.


Treatment of manifestations: Care is best provided by a multidisciplinary team. Children with cholestatic liver disease may require formulas with enriched medium-chain-triglyceride content and fractional meals with enteral nutrition at night for adequate nutrition. Ongoing monitoring of gross motor development and skills with the intervention of appropriate therapies is appropriate in these children. Liver transplantation is controversial because of the frequent severe neurologic involvement due to the underlying mitochondrial disease.

Prevention of secondary complications: Avoidance of nutritional deficiencies; adherence to normal immunization schedule.

Surveillance: Routine monitoring of hepatic function, nutritional status, gross motor development and skills, and urine for proteinuria and aminoaciduria.

Genetic counseling.

DGUOK deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if the DGUOK pathogenic variants in the family are known.


Suggestive Findings

The diagnosis of deoxyguanosine kinase (DGUOK) deficiency (DGUOK-related hepatocerebral mitochondrial DNA depletion syndrome) should be suspected in individuals with a combination of the following clinical, supportive laboratory, and liver biopsy findings.

Clinical features

  • Multisystem disease. Neonatal-onset progressive liver disease (jaundice, cholestasis, hepatomegaly, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and psychomotor retardation)
  • Isolated hepatic disease. Later-infantile or childhood-onset hepatic disease that is progressive and/or induced by viral illness

Supportive laboratory findings

  • Lactic acidosis and hypoglycemia
  • Elevated transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
  • In some cases, elevated serum gammaglutamyltransferase (GGT), alpha fetoprotein (AFP), and ferritin [Dimmock et al 2008b]
  • In most cases, plasma amino acid profile showing elevated tyrosine, phenylalanine, and methionine [Leanza et al 2008, Mudd et al 2012].
    Note: (1) Elevated serum concentration of tyrosine or phenylalanine can be detected on newborn screening in the majority of neonates with multisystem DGUOK deficiency. (2) Infants with DGUOK deficiency do not excrete succinylacetone in the urine, whereas urinary excretion of succinylacetone is diagnostic for tyrosinemia type 1. (3) When transient, elevation of serum concentration of tyrosine may be falsely attributed to transient tyrosinemia of the newborn [Lee et al 2009].

Liver biopsy findings

  • Liver histology typically reveals cholestasis, but may show microsteatosis, fibrosis, giant cell hepatitis, or cirrhosis. Electron microscopy may reveal an increase in the number of mitochondria and abnormal cristae, findings common to all hepatocerebral mtDNA depletion syndromes [Dimmock et al 2008b, Al-Hussaini et al 2014].
  • Mitochondrial DNA content in liver tissue of affected individuals is typically less than 20% of matched control mtDNA content. Liver typically shows a combined deficiency of electron transport chain (ETC) complexes I, III, and IV [Dimmock et al 2008b].

Establishing the Diagnosis

The diagnosis of DGUOK deficiency is established in a proband by the identification of biallelic pathogenic variants in DGUOK on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of mtDNA depletion syndromes is broad, children with the distinctive clinical and laboratory findings of neonatal multisystem disease are likely to be diagnosed using gene-targeted testing (see Option 1), whereas the phenotype of those with isolated hepatic disease may be indistinguishable from many inherited disorders with liver disease and thus is more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of neonatal multisystem disease due to DGUOK deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of DGUOK is performed first. If only one pathogenic variant is found, gene-targeted deletion/duplication analysis is performed next.
  • A multigene panel that includes DGUOK and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders with liver disease, molecular genetic testing approaches can include a combination of genomic testing (comprehensive genomic sequencing) or gene-targeted testing (multigene panel):

Table 1.

Molecular Genetic Testing Used in DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
DGUOK Sequence analysis 3~95% 4
Gene-targeted deletion/duplication analysis 5~5% 4

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

Deoxyguanosine kinase (DGUOK) deficiency presents in the majority of affected individuals as neonatal multisystem disease and in the minority of affected individuals later in infancy or childhood as isolated hepatic disease.

Affected sibs sharing the same pathogenic variants have exhibited multisystem disease and isolated hepatic disease with divergent long-term outcomes. Similarly, diverse long-term outcomes have been observed in affected individuals from unrelated families harboring the same pathogenic variants [Tadiboyina et al 2005].

Neonatal Multisystem Disease

Most affected infants have lactic acidosis and hypoglycemia in the first week of life. Within weeks of birth, all infants with this form of disease have hepatic disease and neurologic dysfunction.

Neurologic manifestations include hypotonia, psychomotor retardation, and typical rotary nystagmus developing into opsoclonus. Neurologic features, particularly profound hypotonia, significant psychomotor retardation, and nystagmus, are associated with poor long-term outcome [Dimmock et al 2008a].

Brain magnetic resonance imaging (MRI) is usually normal. However, subtentorial abnormal myelination and globus pallidus hyperintensity have been reported [Brahimi et al 2009].

Liver involvement includes jaundice, cholestasis, hepatomegaly, and elevated transaminases. Hepatic dysfunction progresses in the majority of children, causing neonatal- or infantile-onset liver failure with ascites, edema, and coagulopathy [Dimmock et al 2008b, Al-Hussaini et al 2014, Sezer et al 2015, McKiernan et al 2016].

The prognosis for neonatal multisystem disease is poor: most affected children die of liver failure before age four years [Sezer et al 2015].

Isolated Hepatic Disease

A minority of affected children initially presents in infancy or childhood with isolated hepatic disease manifesting as jaundice, cholestasis, hepatomegaly, and elevated transaminases. Compared to neonatal multisystem disease, this form is associated with a less severe and later-onset liver disease. The liver disease, occasionally induced by a viral illness, is typically progressive and can lead to liver failure. However, hepatic disease has undergone reversal in one individual with isolated liver disease [Mousson de Camaret et al 2007, Dimmock et al 2008b].

One individual with isolated liver disease subsequently developed hepatocellular carcinoma [Freisinger et al 2006, Grabhorn et al 2014].

Although neurologic manifestations are typically absent, long-term follow up suggests that individuals with isolated hepatic disease may subsequently develop mild hypotonia and some may also have renal involvement manifest as proteinuria and aminoaciduria [Dimmock et al 2008a].

Other less frequent manifestations. The following variable phenotypes have occasionally been reported:

Genotype-Phenotype Correlations

No clear genotype/phenotype correlation is evident among individuals with DGUOK pathogenic missense variants. Affected sibs with the same DGUOK missense variants have exhibited divergent long-term outcomes. Similarly, diverse long-term outcomes have been observed in affected individuals from unrelated families harboring the same missense variants. These findings suggest that in individuals with pathogenic missense variants, the genotype and/or family history may not be helpful in predicting long-term outcome.

In contrast, two null variants have been typically associated with multisystem disease and a more severe clinical phenotype [Dimmock et al 2008b].


No large population-based studies have evaluated the prevalence of mtDNA depletion in general or DGUOK deficiency specifically. DGUOK deficiency is one of the most common causes of hepatocerebral mtDNA depletion syndromes and is estimated to account for 15%-20% of all mtDNA depletion cases [Sezer et al 2015].

Differential Diagnosis

Multisystem Disease

The neonatal multisystem form of DGUOK deficiency needs to be differentiated from other mtDNA depletion syndromes, a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. Table 3 includes the currently known mtDNA depletion syndromes.

Mitochondrial DNA depletion syndromes occur as a result of defects in mtDNA maintenance caused by pathogenic variants in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG and TWNK [formerly C10orf2]).

Mitochondrial DNA depletion syndromes are phenotypically classified into hepatocerebral, encephalomyopathic, neurogastrointestinal, and myopathic forms [El-Hattab & Scaglia 2013].

Table 3.

Mitochondrial DNA Depletion Syndromes

PhenotypeGeneMitochondrial DNA Depletion Syndrome #, TypeReference 1
cerebral 2
DGUOK 3, hepatocerebral type
POLG 4A, Alpers type POLG-Related Disorders
MPV17 6, hepatocerebral type MPV17-Related Hepatocerebral Mitochondrial DNA Depletion Syndrome
TWNK (C10orf2)7, hepatocerebral typeOMIM 271245
myopathic 2
SUCLA2 5, encephalomyopathic type w/methylmalonic aciduria SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria
FBXL4 13, encephalomyopathic type FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion Syndrome
SUCLG1 9, encephalomyopathic type w/methylmalonic aciduria SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria
RRM2B 8A, encephalomyopathic type w/renal tubulopathy RRM2B-Related Mitochondrial Disease
OPA1 14, encephalocardiomyopathic typeOMIM 616896
intestinal 2
TYMP 1, MNGIE type Mitochondrial Neurogastrointestinal Encephalopathy Disease
POLG 4B, MNGIE type POLG-Related Disorders
RRM2B 8B, MNGIE type RRM2B-Related Mitochondrial Disease
Myopathic 2 TK2 2, myopathic type TK2-Related Mitochondrial DNA Depletion Syndrome, Myopathic Form
AGK 10, cardiomyopathic type (Sengers syndrome)OMIM 212350
MGME1 11, myopathic typeOMIM 615084
SLC25A4 12B, cardiomyopathic typeOMIM 615418

See hyperlinked GeneReview or OMIM phenotype entry for more information.


Within each phenotypic category, mtDNA depletion syndromes are ordered by relative prevalence.

Isolated Hepatic Disease

The differential diagnosis of the isolated hepatic form of DGUOK deficiency involves other genetic and non-genetic age-specific causes of cholestatic liver diseases, including the following.

Genetic causes

Non-genetic causes

  • Extrahepatic biliary atresia
  • Choledochal cyst
  • Hypothyroidism
  • Total parenteral nutrition (TPN) cholestasis
  • Neonatal hemochromatosis


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DGUOK deficiency, the following evaluations are recommended.

For both neonatal multisystem diseases and isolated hepatic disease

  • Evaluation of hepatic status by a physician familiar with the care of children with liver failure. Initial testing should include measurement of serum concentrations of ALT, AST, GGT, bilirubin, albumin, and coagulation profile.
  • Hepatic sonography and AFP to screen for hepatocellular carcinoma. AFP is a sensitive, but not specific, marker used to differentiate hepatocellular carcinoma from nonmalignant liver disease. Although the value of a highly elevated serum concentration of AFP in the detection of hepatocellular carcinoma in DGUOK deficiency is not known, the possibility of hepatocellular carcinoma should be considered in individuals with a solid tumor detected by abdominal ultrasound examination and a highly increased serum AFP concentration [Freisinger et al 2006].
  • Nutritional assessment by a dietician with experience in managing children with hepatic failure
  • Consultation with a clinical geneticist and/or genetic counselor

Additional evaluation for neonatal multisystem diseases

  • Measurement of plasma lactate and fasting blood sugar
  • Comprehensive neurologic examination and developmental/cognitive assessment. Neuroimaging may be considered.

Additional evaluation for isolated hepatic disease. Urine analysis and evaluation for urine amino acids to evaluate for renal involvement

Treatment of Manifestations

Management requires a multidisciplinary team including specialists in hepatology, neurology, child development, nutrition, and clinical genetics.

Management of Neurologic Manifestations in Neonatal Multisystem Disease

Hypotonia may be significant. Therefore, ongoing monitoring of gross motor development and skills with the intervention of appropriate therapies is appropriate in these children.

Management of Liver Involvement in both Neonatal Multisystem Disease and Isolated Hepatic Disease

Management of liver disease should be guided by the results of initial evaluation in consultation with a hepatologist.

Children with cholestatic liver disease or renal disease are at significant risk of nutritional insufficiency; therefore, a dietician with experience in managing children with hepatic and renal dysfunctions should be involved in their care:

  • Formulas with an enriched medium-chain-triglyceride content may provide better nutritional support for infants with cholestasis than formulas with predominantly long-chain triglycerides [Feranchak & Sokol 2007].
  • Cornstarch may reduce symptomatic hypoglycemia in individuals with isolated hepatic disease.
  • Fractional meals and enteral nutrition during the night can result in good nutritional control [Dimmock et al 2008b].

Affected individuals often develop life-threatening liver failure, but the benefits of liver transplantation are disputable because of the frequent severe neurologic involvement due to the underlying mitochondrial disease. A total of 14 individuals with DGUOK deficiency were reported to have undergone liver transplantation.

  • The one-year survival rate was 64%.
  • Five of the 14 survived longer than five years.
  • Eight of the 14 died within two years of transplantation from severe pulmonary hypertension (3/8), neurologic degeneration (2/8), procedure-related complications (2/8), and early postoperative multiorgan failure (1/8).
  • Although survival after liver transplantation for DGUOK deficiency is lower than survival after liver transplantation for other indications, a significant proportion of affected individuals survived more than five years despite initial neurologic abnormalities. Nevertheless, a decision to perform liver transplantation for individuals with DGUOK deficiency remains difficult because neurologic manifestations may occur and/or worsen after liver transplantation despite their absence before transplantation [Grabhorn et al 2014].

Prevention of Secondary Complications

Nutritional deficiencies such as essential fatty acid deficiency and fat-soluble vitamin deficiency need to be prevented. Specific management requires a dietician experienced in the management of individuals with liver disease. Affected individuals need to be supplemented with fat-soluble vitamins and essential fatty acids [Feranchak & Sokol 2007].

Because they have not been associated with clinical decompensation in persons with DGUOK deficiency, routine immunizations (including influenza vaccine) are recommended at this time for all individuals with DGUOK deficiency and their household contacts.


No clinical guidelines for surveillance are available. The following evaluations are suggested, with frequency varying according to the severity of the condition.

  • Neonatal multisystem disease:
    • Hepatic function
    • Nutritional status
    • Developmental and neurologic assessment
    • AFP and hepatic sonography to monitor for hepatocellular carcinoma.
  • Isolated hepatic disease
    • Hepatic function
    • Nutritional status
    • Evidence of renal disease (proteinuria and aminoaciduria)
    • AFP and hepatic sonography to monitor for hepatocellular carcinoma

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Deoxyguanosine kinase (DGUOK) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one DGUOK pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with DGUOK deficiency would be obligate heterozygotes (carriers) for a pathogenic variant in DGUOK. To date, however, fertility is unknown, as no affected individuals have reproduced.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a DGUOK pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the DGUOK pathogenic variants in the family.

Related Genetic Counseling Issues

Although penetrance of DGUOK deficiency is probably complete, age of onset and severity of the clinical symptoms vary, even in the same family.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the DGUOK pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for DGUOK deficiency are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Liver Foundation
    Phone: 800-465-4837 (HelpLine)
  • Canadian Liver Foundation
    Phone: 800-563-5483
    Email: clf@liver.ca
  • Childhood Liver Disease Research Network (ChiLDReN)
    Phone: 720-777-2598
    Email: joan.hines@childrenscolorado.org
  • Children's Liver Disease Foundation
    United Kingdom
    Phone: +44 (0) 121 212 3839
    Email: info@childliverdisease.org
  • United Mitochondrial Disease Foundation
    Phone: 888-317-UMDF (8633)
    Email: info@umdf.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Deoxyguanosine Kinase Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
DGUOK 2p13​.1 Deoxyguanosine kinase, mitochondrial DGUOK database DGUOK DGUOK

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Deoxyguanosine Kinase Deficiency (View All in OMIM)


Gene structure. The gene is approximately 33 kb in size and consists of seven coding exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. There are no common pathogenic variants or mutation hot spots [Dimmock et al 2008b].

Normal gene product. Deoxyguanosine kinase (DGUOK) is a mitochondrial protein that has a molecular weight of 28 kd with 277 amino acids.

Abnormal gene product. Missense, nonsense, and splice site variants result in a reduction or absence of DGUOK enzyme activity, which causes an imbalance of the mitochondrial deoxynucleotide pools. Because the mitochondria depend heavily on the salvage pathway for the supply of deoxynucleotides, DGUOK deficiency results in mitochondrial DNA depletion [Ashley et al 2007].


Literature Cited

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  • Sezer T, Ozçay F, Balci O, Alehan F. Novel deoxyguanosine kinase gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome. J Child Neurol. 2015;30:124–8. [PubMed: 24423689]
  • Tadiboyina VT, Rupar A, Atkison P, Feigenbaum A, Kronick J, Wang J, Hegele RA. Novel mutation in DGUOK in hepatocerebral mitochondrial DNA depletion syndrome associated with cystathioninuria. Am J Med Genet A. 2005;135:289–91. [PubMed: 15887277]
  • Vilarinho S, Sari S, Yilmaz G, Stiegler AL, Boggon TJ, Jain D, Akyol G, Dalgic B, Günel M, Lifton RP. Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension. Hepatology. 2016;63:1977–86. [PMC free article: PMC4874872] [PubMed: 26874653]

Chapter Notes

Author History

David Dimmock, MD; Medical College of Wisconsin (2009-2016)
Ayman W El-Hattab, MD, FAAP, FACMG (2016-present)
Fernando Scaglia, MD, FAAP, FACMG (2009-present)
Lee-Jun Wong, PhD (2009-present)

Revision History

  • 22 December 2016 (bp) Comprehensive update posted live
  • 18 June 2009 (et) Review posted live
  • 10 February 2009 (fs) Original submission
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Bookshelf ID: NBK7040PMID: 20301766


Tests in GTR by Gene

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