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FOR THE TESTED INDIVIDUAL – This information is intended to assist your physician or other qualified health care professional as part of their comprehensive assessment of the best approach to managing your genetic test results. It is not specific advice for your care and it does not replace consultation with a qualified health care professional. You should not alter your medical care based on this report without speaking to, and receiving guidance from, your physician based on your specific case.
FOR THE CLINICIAN – This information was prepared on the date indicated on the file and may have been updated subsequently. Please check UpToDate (UpToDate.com) for the latest version of this and other gene test interpretation monographs. UpToDate subscribers can access these monographs by entering the gene name or the phrase "Gene test interpretation" into the UpToDate search box. Your use of this information is subject to the terms set forth at https://www.uptodate.com/legal/license and any other terms in any applicable license agreement. This information is no substitute for individual patient assessment based on the healthcare provider's evaluation of each patient that includes personal and family history, findings from the physical examination, laboratory and other testing, and other factors unique to the patient. The information should be used as a tool to help the clinician reach diagnostic and treatment decisions, bearing in mind that individual and unique circumstances may lead to decisions other than those presented. The opinions expressed are those of the monograph's authors and editors.
Supported by an unrestricted educational grant from AncestryHealth®.
- V Reid Sutton, MD
- Linyan Meng, PhD, FACMG
- Section Editors:
- Louise Wilkins-Haug, MD, PhD
- Anne Slavotinek, MBBS, PhD
- Deputy Editors:
- Jennifer S Tirnauer, MD
- Elizabeth TePas, MD, MS
INTRODUCTION — This monograph discusses implications of genetic test results for the HEXA gene, which encodes the alpha subunit of beta-hexosaminidase A, the enzyme that is deficient in Tay-Sachs disease (TSD).
It does not discuss indications for testing and is not intended to replace clinical judgment in decisions to test or care of the tested individual. These subjects are discussed separately . (See 'Resources' below.)
How to read the report — The table summarizes major considerations for the clinician reviewing the genetic test results (table 1). These include the importance of obtaining a hard copy or digital report rather than a verbal statement, confirming which person was tested, and determining whether the test evaluated a targeted panel of common variants or the entire HEXA gene.
Testing used to guide clinical care should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. If not done initially and results are to be used in clinical decision-making, testing should be repeated in a CLIA-certified laboratory. Decision-making may be affected by positive results (expected or unexpected) or negative results in an individual at risk for carrying a disease variant. (See 'Epidemiology and inheritance' below.)
HEXA gene — HEXA encodes the alpha subunit of beta-hexosaminidase A (also called hexosaminidase A), an enzyme in lysosomes that breaks down gangliosides (glycolipids derived from neuronal membranes).
When enzyme activity is deficient, gangliosides accumulate inside neuronal lysosomes, causing neuronal cell death and progressive neurodegeneration. Tay-Sachs disease (TSD) is the resulting disease.
Absence (or near absence) of enzyme activity is required to damage neurons; neurons that have approximately half-normal activity are unaffected. Thus, TSD is autosomal recessive, requiring HEXA disease variant(s) on both paternally and maternally inherited genes (homozygosity or compound heterozygosity) (table 3).
Evaluation of HEXA can be done with either enzyme testing or DNA analysis.
●Enzyme assay – Enzyme testing generally has higher sensitivity than targeted sequence analysis. Enzyme testing is most often done on serum. Pregnancy elevates enzyme levels; testing in individuals who are pregnant or taking oral contraceptives should be done on peripheral blood leukocytes .
When enzyme testing is performed, it is important to be aware of HEXA variants that cause pseudodeficiency, a laboratory artifact with absent enzymatic activity in a standard assay but no clinical consequences. Two major pseudodeficiency variants have been well-characterized (c.739C>T and c.745C>T) . Individuals with reduced enzyme activity should be checked for these to determine whether the reduced activity is due to a pathogenic variant or a benign pseudodeficiency allele.
•Individuals heterozygous for a pseudodeficiency allele have reduced enzyme activity in vitro but are not carriers for TSD.
•Individuals with compound heterozygosity for a HEXA disease variant and a pseudodeficiency variant have severely deficient enzyme activity but are not affected with TSD; they are carriers.
Rarely, serum enzyme tests may yield inconclusive results that should be clarified with enzyme testing in leukocytes and/or DNA analysis.
●DNA analysis – Many pathogenic variants in HEXA have been described. Testing depends on the genetic background of the tested individual.
Three common pathogenic variants are seen in individuals of Eastern European (Ashkenazi) Jewish ancestry :
•c.1274_1277dupTATC (frameshift mutation that introduces premature stop codon)
•c.805G>A (replacement of glycine with serine at position 269)
•c.1421+1G>C (intronic variant causing abnormal splicing)
Variants in individuals of non-Ashkenazi backgrounds are spread throughout the HEXA gene.
In some cases, the clinical impact of a variant may be uncertain (variant of uncertain significance [VUS]), and enzyme testing may be required (table 4).
The hexosaminidase A enzyme is formed from an alpha and a beta subunit; the beta subunit is encoded by the HEXB gene. Sandhoff disease is a related disorder caused by disease variants in HEXB, which cause deficiency of two enzymes, hexosaminidase A and hexosaminidase B (formed from two beta subunits). These and other related disorders are summarized in the tables listing hereditary ataxias (table 5) and lysosomal storage disorders (table 6).
Epidemiology and inheritance — Tay-Sachs disease (TSD) is an autosomal recessive disorder (figure 1) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in the HEXA gene .
Certain populations are known to have a higher carrier frequency for HEXA disease variants [5,6].
●Individuals of Ashkenazi Jewish background (Central and Eastern European Jews, most Jews in the United States) have a carrier frequency of approximately 1 in 30. With effective carrier screening, most families are aware of the familial variant and which family members are carriers. Three common variants are listed above. (See 'HEXA gene' above.)
●Certain other backgrounds have an increased carrier frequency, including French Canadian, Cajun from Louisiana, and Pennsylvania Dutch. A few common pathogenic variants have been detected in these populations.
Individuals in the general population can also carry pathogenic variants in HEXA; race and ethnicity cannot be used to exclude this risk. A negative family history also cannot be used to exclude HEXA variants; as with most autosomal recessive disorders, heterozygotes are unaffected and the family history is often unremarkable.
Clinical features and diagnosis — TSD is a neurodegenerative lysosomal storage disease and a form of hereditary ataxia.
The age of presentation varies but is typically in infancy. In the classical infantile presentation, motor development is normal during the first few months of life, with symptom onset at approximately five to six months of age.
Symptoms include incoordination, exaggerated startle response, loss of muscle tone, progressive neurologic deterioration, functional decline, and loss of previously-attained developmental milestones; the median survival is approximately four years .
The retinal cherry red spot (picture 1) typically develops between 3 and 12 months of age. It is caused by accumulated glycolipids in neuroretinal cells surrounding the macula. The spot is the normal color of the macula; pallor surrounding the macula creates the appearance. The cherry red spot is not specific for TSD; it can be seen in other neuronopathic lysosomal storage disorders. (See "Overview of the hereditary ataxias".)
Juvenile and adult-onset (also called late-onset) forms of TSD are less common. Typical ages of presentation are two to five years and adolescence to early adulthood, respectively. Adults with late-onset disease have a more variable course including psychosis and gait disturbance .
Following clinical assessment, diagnosis is made by serum testing for enzyme activity and/or genetic testing for HEXA variants. (See 'HEXA gene' above.)
●If enzyme activity is low or absent, it may be prudent to rule out pseudodeficiency using genetic testing.
●For a variant of uncertain significance (VUS), enzyme activity testing will help establish the pathogenicity.
●Individuals with abnormal clinical findings and negative HEXA testing will require additional evaluations for other conditions.
Most states in the United States do not perform newborn screening for TSD. (See "Newborn screening", section on 'Resources'.)
Management — Therapy for TSD primarily involves supportive care to reduce morbidities and preserve functional status.
●Pulmonary – Airway clearance therapies are used to reduce the risk of pneumonia. (See "Respiratory muscle weakness due to neuromuscular disease: Management".)
●Neurologic – Seizure management is often required. No specific medications or therapies are more effective in TSD than in idiopathic epilepsies. Physical therapy is used to maintain functional status. (See "Seizures and epilepsy in children: Initial treatment and monitoring".)
●Gastrointestinal – Constipation may occur and may be treated with standard approaches. (See "Chronic functional constipation and fecal incontinence in infants, children, and adolescents: Treatment".)
●Psychiatric – Individuals with late-onset TSD may require antipsychotics or antidepressants. (See "Unipolar major depression in adults: Choosing initial treatment".)
Various disease-modifying approaches have been investigated, including restoring enzyme activity (enzyme replacement or gene therapy) or reducing the accumulated substrate (inhibiting glucosylceramide synthesis with miglustat); none have demonstrated efficacy. Approaches under consideration include targeted substrate reduction and enzyme replacement ligated to chaperones that cross the blood-brain barrier.
Parents of a child with TSD should receive genetic counseling (risks of having another affected child) and implications for their relatives. (See 'Partner testing' below and 'Asymptomatic adult' below.)
PRECONCEPTION SCREENING AND TESTING — Identification of HEXA disease variants before conception is the primary means of avoiding Tay-Sachs disease (TSD).
According to the American College of Obstetricians and Gynecologists (ACOG), couples should be offered carrier screening for conditions for which they are at increased risk, or if they request screening .
Known familial variant — Individuals with a known pathogenic HEXA variant in the family can be tested for that variant to determine if they are carriers.
Ashkenazi Jewish ancestry — Individuals of Ashkenazi Jewish ancestry, including Jews from Eastern Europe (the ancestry of most American Jews), should have the opportunity to be screened prior to conception.
Screening can be done by genetic testing and/or enzyme testing. If genetic testing is used, assessment for the common Ashkenazi Jewish variants is generally adequate to identify or exclude carrier status. A negative screen using a panel of these variants can reduce residual risk to approximately 1 in 5800. Enzyme testing and full HEXA gene sequencing have slightly higher sensitivity than targeted mutation analysis. (See 'Epidemiology and inheritance' above.)
Non-Ashkenazi Jewish (or unknown) ancestry — Individuals from non-Ashkenazi Jewish backgrounds, including those of unknown ancestry, should have the opportunity to be screened prior to conception if they have any reason for concern about carrier status, including a genetic background with increased carrier frequency, possible TSD in the family, or other reasons. (See 'Epidemiology and inheritance' above.)
Screening can be done by enzyme testing followed by genetic testing if needed. Full-gene HEXA analysis or simultaneous enzyme and genetic testing can also be used. If enzyme testing shows reduced activity, pseudodeficiency is excluded by identification of a specific HEXA pseudodeficiency variant. (See 'HEXA gene' above.)
A negative screen by full HEXA gene sequencing can reduce residual risk to approximately 1 in 100,000. (See 'HEXA gene' above.)
Partner testing — Partner testing is appropriate for any couple in which one member tests positive for a pathogenic or likely pathogenic HEXA variant.
●The algorithm illustrates our approach (algorithm 1).
●The figure summarizes potential outcomes if the partner is also a carrier (figure 2).
If both partners are carriers, genetic counseling should be offered and information provided about assisted reproductive technologies (ART) and prenatal testing .
●ART may include use of donor gametes (egg or sperm) or in vitro fertilization (IVF) with preimplantation genetic testing (PGT) of embryos. (See "Preimplantation genetic testing".)
●Prenatal testing involves amniocentesis or chorionic villus sampling, results of which can be used to inform pregnancy options.
ASYMPTOMATIC ADULT — An asymptomatic adult who is heterozygous for a single pathogenic or likely pathogenic variant in HEXA is an unaffected carrier.
Their first-degree relatives typically have a 50 percent chance of also carrying the variant and should be informed of this, especially if they are considering childbearing (or may do so in the future).
Second-degree relatives (table 7) who may consider childbearing may also benefit from this information, although it is preferable to first-degree relatives initially, if possible, followed by cascade testing if needed. (See "Genetics: Glossary of terms", section on 'Cascade testing'.)
Testing of relatives at-risk of carrier status can be deferred to childbearing age to allow the most meaningful counseling and informed consent. (See 'Preconception screening and testing' above.)
Counseling coordinated among family members may be advantageous to ensure that all receive comprehensive information and appropriate testing, which may be limited to testing for the specific familial variant in at-risk relatives.
•Clinical geneticists – American College of Medical Genetics and Genomics (ACMG).
•Genetic counselors – National Society of Genetic Counselors (NSGC). Genetic testing laboratories may also provide virtual (online or telephone) access to a genetic counselor.
•Patient support – National Tay-Sachs & Allied Diseases Association (NTSAD).
•Tay Sachs disease (TSD)/hereditary ataxias – (See "Overview of the hereditary ataxias".)
•Preconception/prenatal screening – (See "Preconception and prenatal carrier screening for genetic disease more common in the Ashkenazi Jewish population and others with a family history of these disorders".)
- Supporting references are provided in the associated UpToDate topics, with selected citation(s) below.
- Nakagawa S, Kumin S, Chandra P, Nitowsky HM. Human hexosaminidase isozymes. Assay of platelet activity for heterozygote identification during pregnancy. Clin Chim Acta 1978; 88:249.
- Kaback MM, Desnick RJ.. GeneReviews®, Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A. (Eds), University of Washington, Seattle, Seattle (WA) 1993.
- Hoffman JD, Greger V, Strovel ET, et al. Next-generation DNA sequencing of HEXA: a step in the right direction for carrier screening. Mol Genet Genomic Med 2013; 1:260.
- Sutton VR. Tay-Sachs disease screening and counseling families at risk for metabolic disease. Obstet Gynecol Clin North Am 2002; 29:287.
- Monaghan KG, Feldman GL, Palomaki GE, et al. Technical standards and guidelines for reproductive screening in the Ashkenazi Jewish population. Genet Med 2008; 10:57.
- Bley AE, Giannikopoulos OA, Hayden D, et al. Natural history of infantile G(M2) gangliosidosis. Pediatrics 2011; 128:e1233.
- Masingue M, Dufour L, Lenglet T, et al. Natural History of Adult Patients with GM2 Gangliosidosis. Ann Neurol 2020; 87:609.
- Committee on Genetics. Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Obstet Gynecol 2017; 129:e41. Reaffirmed 2019.
|Section of the report||Action(s)||Concern(s)|
|Patient identification|| ||Individuals may inadvertently provide the wrong name on a test sample. Testing should be done by a laboratory that can ensure that the identification matches the tested individual.|
|Testing laboratory|| ||All actionable medical testing (eg, positive finding or negative finding in an individual suspected of having a genetic disorder) should be conducted in a CLIA-certified laboratory that has met appropriate quality standards for performing the specific test. Some direct-to-consumer testing is not performed in CLIA-certified laboratories and may lack appropriate quality controls.|
|Date of testing|| ||Germline variants do not change over time. However, as new data become available, the classification of variant pathogenicity may change, especially for variants classified as VUS. Repeat testing may be considered, as the technologies for exome sequencing may improve and may identify a variant missed on a prior test.|
|Gene(s) tested|| ||Not all genetic testing panels are comprehensive in the genes or variants in those genes they evaluate. New disease genes or clinically important variants in existing genes may be identified through further research.|
|Testing method|| ||Not all methods will identify all variants. In some cases such as HFE testing, only one or two variants are clinically relevant, and sequencing of the entire coding region of the gene is not required, whereas in other conditions, limited testing for one or two variants may miss clinically important findings. Gene panels may be especially useful when multiple genes could potentially be responsible for a clinical phenotype.|
|Classification of pathogenicity|| ||Interpretation of pathogenicity takes into account many data sources including laboratory research, research databases, population studies, and pedigree analyses. In some cases, pathogenicity is well established (eg, the variant that causes sickle cell disease); in others, it is more subjective and incomplete. Variants classified as VUS, likely benign, or benign generally are not actionable and should not impact medical interventions. Consulting a publicly curated database such as ClinVar or discussing the results with an expert in the specific disease, or referral to a clinical geneticist, genetic counselor, or disease expert may be helpful.|
* Indications for testing vary according to the individual's medical history, family history, and other factors such as desire for preconception counseling. In some cases, an individual who did not have a clinical indication for testing may have an unexpected finding from genetic testing that, if accurate, would indicate the need for an intervention, and such findings may be actionable regardless of the initial reasons for testing.
|Autosomal dominant||Pattern of inheritance that requires only one affected variant allele (a variant inherited from one parent or that arises de novo) to transmit the trait or risk of disease. Not sex-linked. First-degree relatives (siblings, children) have a 50% chance of sharing (or inheriting) the variant allele.|
|Autosomal recessive||Pattern of inheritance that generally requires both variants on both alleles (one from each parent) in order to transmit the trait or risk of disease. Not sex-linked. Individuals with one variant are sometimes called carriers.|
|Carrier||Individual who has a specific variant in one allele of the gene in their germline DNA (inherited from one parent or arising de novo). For recessive disorders, refers to a heterozygote who is generally (or mostly) unaffected. For dominant disorders, carriers are generally considered at risk for the disorder.|
|Expressivity||Differences in the severity of disease manifestations in individuals who share the same genotype (eg, cystic fibrosis is said to have variable expressivity because two individuals with the same genotype may have differences in the degree of pancreatic or lung dysfunction).|
|Genotyping||Determining the DNA sequence of a particular gene or portion of a gene in an individual. Can be done on DNA from sources such as nucleated epithelial cells from saliva, tumor cells from a biopsy, or WBCs from peripheral blood. Can be used to determine germline or somatic sequence, depending on the source of the cells.|
|Germline||Derived from the gametes (sperm or egg cells) and present in the early embryo; germline variants are typically present in all body cells and do not change. Germline variants can be passed down to subsequent generations.|
|Mutation||Term that may be used to describe changes in DNA or protein sequence compared with a reference sequence. The American College of Genetics and Genomics (ACMG) has expressed concern that this term can cause confusion or incorrect assumptions regarding pathogenicity, and the ACMG recommends that findings from genetic testing be described using the term "variant" with a qualifier regarding pathogenicity (or lack thereof).|
|Pathogenicity||Likelihood that a specific variant is capable of causing disease or conferring disease risk. Does not determine the likelihood that disease will occur (which depends on other factors such as disease penetrance). Refer to separate table in UpToDate for the categories.|
|Pedigree||Diagram of a family showing relationships among family members, sex of each family member, presence or absence of one or more genetic disorders, and often the age at which they manifested. Used in genetic counseling to identify possible inherited causes of disease and their inheritance patterns.|
|Penetrance||Likelihood that a person with a disease-associated variant will manifest one or more features of the disease. Many disease variants have incomplete or variable penetrance, meaning that not all individuals with the variant will manifest the associated disorder.|
|Somatic||Referring to tissues that are not within the germline. Variation that arises in somatic tissues is not passed from parent to offspring. Somatic mutations are common in cancer.|
|Variant||Change in the sequence of DNA compared with a reference sequence. Variants can be benign (associated with normal gene function), pathogenic (associated with altered gene function and/or clinical disease, also called mutations), or somewhere in between. The term polymorphism is often (but not exclusively) used for benign variants. Refer to a separate table in UpToDate that defines the categories.|
|VUS||Variant of uncertain significance (or unknown significance). Refers to a variant for which insufficient information is available to classify as benign or pathogenic.|
|Hexosaminidase A |
|Heterozygous for a PV or LPV||Approximately half-normal||Unaffected carrier|| |
|Homozygous or compound heterozygous for a PV or LPV||Absent or nearly absent||Tay-Sachs disease|| |
|Compound heterozygous for a PV or LPV plus a pseudodeficiency variant||Absent or nearly absent||Unaffected carrier|| |
|Heterozygous for a pseudodeficiency variant||Approximately half-normal||None|| |
|Pathogenic||Associated with disease risk|
|Likely pathogenic||>90% likelihood of disease risk association|
|Variant of uncertain significance (VUS)||Available data do not allow classification into one of the other categories|
|Likely benign||>90% likelihood that variant is not associated with disease risk|
|Benign||Not associated with disease risk|
- Population data (allele frequency; prevalence of variant in affected individuals versus controls)
- Computational data (predicted effect on protein sequence or function)
- Functional data (functional studies show or do not show deleterious effect)
- Segregation data (variant segregates with disorder in families)
Supported by an unrestricted educational grant from AncestryHealth®.
|Disorder||Gene locus and protein|
|Hyperammonemias and aminoacidurias|
|Ornithine transcarbamylase deficiency||Xp21.1||Ornithine transcarbamylase|
|Argininosuccinic aciduria||7cen-q11||Arginosuccinate lyase|
|Hyperornithemia-hyperammonemia- homocitrullinuria syndrome||13q14||Mitochondrial ornithine transporter|
|Hartnup disease||5p15.33||Neutral amino acid transporter|
|Isovaleric acidemia||15q14||Isovaleric acid CoA dehydrogenase|
|Disorders of pyruvate and lactate metabolism|
|Pyruvate dehydrogenase complex||Xp22.2 (most common)||E1-alpha subunit (most common)|
|Multiple carboxylase deficiency||21q22||Holocarboxylase synthetase|
|Tay-Sachs disease||15q23-q24||Alpha subunit of hexosaminidase A|
|Sandhoff disease||15q13||Beta subunit of hexosaminidase A and B|
|Niemann-Pick type A and B||11p15.4-p15.1||Acid sphingomyelinase|
|Niemann-Pick type C||18q11-q12||NPC1|
|Metachromatic leukodystrophy||22q13||Arylsulfatase A|
|Abetalipoproteinemia||4q22||Microsomal triglyceride transfer protein|
|Cerebrotendinous xanthomatosis||2q33||Mitochondrial sterol 27-hydroxylase|
|Ataxia with vitamin E deficiency||8q13||Alpha-tocopherol transfer protein|
|Lesch-Nyhan syndrome||Xq26||Hypoxanthine-guanine phosphoribosyl- transferase|
|Wilson disease||13q14||ATP7B (copper transporting ATPase)|
|Ceroid lipofuscinosis||Several variants||Multiple gene products|
|Refsum disease||10pter||Phytanoyl CoA hydroxylase|
|X-linked ataxia, ichthyosis, and tapetoretinal dystrophy||Xpter-p22||Arylsulfatase C|
|MPS I (Hurler, Hurler-Scheie, Scheie)|
|MPS II (Hunter)|
|MPS III (Sanfillippo)|
|MPS IV (Morquio)|
|MPS VI (Maroteaux-Lamy)|
|MPS VII (Sly)|
|MPS IX (Natowicz)|
|GM2 gangliosidosis type 1 (Tay-Sachs)|
|GM2 gangliosidosis type 2 (Sandhoff)|
|Mucolipidosis type I (Sialidosis)|
|Mucolipidosis type II (I-cell)*|
|Mucolipidosis type III (pseudo-Hurler)*|
|Mucolopidosis type IV (Sialolipidosis)|
- Absence of family history of disease in prior generations
- 25% affected status rate among siblings of the affected proband
* If one member of a couple is from a high-risk group based on their ancestry or positive family history, they should be tested first; in these individuals, targeted testing for PVs may be adequate.
- Known familial HEXA variant – Test for the familial variant.
- Known Ashkenazi (Eastern European) Jewish ancestry – Test for the three common Ashkenazi Jewish variants.
- All others◊ – Perform HEXA gene sequencing coupled with enzymatic testing (enzymatic testing can be done concurrently or if genetic testing is positive for a PV, LPV, or VUS).
Δ Reasons for concern may include a partner with a positive family history of TSD or strong desire for testing due to ancestry from a group with a high carrier frequency.
◊ Includes general population, other groups with high carrier frequency, and individuals of unknown ancestry.
|First degree||Second degree||Third degree|
Grandparents (parents' parents)Aunts and uncles (parents' siblings)
Grandchildren (children's children)Nieces and nephews (siblings' children)
Contributor DisclosuresV Reid Sutton, MDNothing to discloseLinyan Meng, PhD, FACMGEmployment: Baylor Genetics [Genetic testing reference lab]. Patent Holder: Modulation of UBE3A-ATS expression [Angelman syndrome therapy]. Grant/Research/Clinical Trial Support: National Institute of Health [Prenatal noninvasive diagnosis].Louise Wilkins-Haug, MD, PhDNothing to discloseAnne Slavotinek, MBBS, PhDGrant/Research/Clinical Trial Support: UCSF [P3EGS project]; National Human Genome Research Institute, National Institutes of Health [Clinical sequencing evidence generating research 2]; Retrophin [CTX, early-onset idiopathic bilateral cataracts (Natural history study testing for cerebrotendinous xanthomatosis)]. Consultant/Advisory Boards: American Board of Medical Genetics and Genomics [Director]; Roche [Alpha globin testing]. Employment: American Journal of Medical Genetics [Deputy Editor]. Other Financial Interest: Oxford University Press [Royalties from book].Jennifer S Tirnauer, MDNothing to discloseElizabeth TePas, MD, MSNothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.