Coverage Policy Manual
Policy #: 2013040
Category: Laboratory
Initiated: November 2013
Last Review: December 2023
  Genetic Test: Alpha and Beta Thalassemia
Description:
Alpha thalassemia represents a group of clinical syndromes of varying severity characterized by hemolytic anemia and ineffective hematopoiesis. Genetic defects in any or all of four alpha globin genes are causative of these syndromes. Rates of variants in the alpha thalassemia gene vary across ethnic groups and are highest in individuals from Southeast Asia, Africa, and the Mediterranean region.
 
Alpha-thalassemia is a common genetic disorder, affecting approximately 5% of the world's population (Vichinsky, 2010). The frequency of variants is highly dependent on ethnicity, with the highest rates seen in Asians, and much lower rates in Northern Europeans. The carrier rate is estimated to be 1 in 20 in Southeast Asians, 1 in 30 for Africans, and between 1 in 30 and 1 in 50 for individuals of Mediterranean ancestry. By contrast, for individuals of northern European ancestry, the carrier rate is less than 1 in 1000.
 
Hemoglobin, which is the major oxygen carrying protein molecule of red blood cells, consists of two alpha globin chains and two beta globin chains. Alpha-thalassemia refers to a group of syndromes that arise from deficient production of alpha globin chains. Deficient alpha globin production leads to an excess of beta globin chains, which results in anemia by a number of mechanisms (Muncie, 2009):
 
    • Ineffective erythropoiesis in the bone marrow.
    • Production of nonfunctional hemoglobin molecules.
    • Shortened survival of red blood cells due to intravascular hemolysis and increased uptake of the abnormal red blood cells (RBCs) by the liver and spleen.
 
The physiologic basis of alpha thalassemia is a genetic defect in the genes coding for alpha globin production. Each individual carries four genes that code for alpha globin (2 copies each of HBA1 and HBA2, located on chromosome 16), with the wild genotype (normal) being aa/aa. Genetic variants may occur in any or all of these four alpha globin genes. The number of genetic variants determines the phenotype and severity of the alpha thalassemia syndromes. The different syndromes are classified as follows:
    • Silent carrier (alpha-thalassemia minima). This arises from one of four abnormal alpha genes (aa/a-) and is a silent carrier state. A small amount of abnormal hemoglobin can be detected in the peripheral blood, and there may be mild hypochromia and microcytosis present, but there is no anemia or other clinical manifestations.
    • Thalassemia trait (alpha-thalassemia minor). This is also called alpha-thalassemia trait and arises from the loss of two alpha globin genes, resulting on one of two genotypes (aa/--, or a-/a-). There is a mild anemia present, and red blood cells are hypochromic and microcytic. Clinical symptoms are usually absent and, in most cases, the hemoglobin electrophoresis is normal.
    • Hemoglobin H disease (HgH, alpha-thalassemia intermedia). This syndrome results from three abnormal alpha globin genes (a-/--), resulting in a moderate to severe anemia. In HbH disease, there is an imbalance in α- and β-globin gene chain synthesis, resulting in the precipitation of excess β chains into the characteristic hemoglobin H, or β-tetramer. This condition has marked phenotypic variability, but most individuals have mild disease and live a normal life without medical intervention (Galanello, 2011).
 
A minority of individuals may develop clinical symptoms of chronic hemolytic anemia. These include neonatal jaundice, hepatosplenomegaly, hyperbilirubinemia, leg ulcers, and premature development of biliary tract disease. Splenomegaly can lead to the need for splenectomy, and transfusion support may be required by the third to fourth decade of life. It has been estimated that approximately 25% of patients with HgH disease will require transfusion support during their lifetime (Vichinsky, 2010). In addition, increased iron deposition can lead to premature damage to the liver and heart. Inappropriate iron therapy and oxidant drugs should be avoided in patients with HbH disease.
 
There is an association between genotype and phenotype among patients with HbH disease. Individuals with a nondeletion variant typically have an earlier presentation, more severe anemia, jaundice, and bone changes, and more frequently require transfusions (Origa, 2016).
    • Hemoglobin Bart syndrome (alpha thalassemia major). This syndrome results from variants in all four alpha globin genes (--/--), resulting in absent production of alpha globin chains. This condition causes hydrops fetalis, which often leads to intrauterine death, or death shortly after birth. There are also increased complications of pregnancy for a woman carrying a fetus with hydrops fetalis. These include hypertension, preeclampsia, antepartum hemorrhage, renal failure, premature labor, and abruption placenta (Vichinsky, 2010).
 
Genetic testing
A number of different types of genetic abnormalities are associated with alpha-thalassemia. More than one hundred different genetic variants have been described. Deletion of one or more of the alpha globin chains is the most common genetic defect. This is the type of genetic defect found in approximately 90% of cases (Mayo Medical Laboratories, 2013). Large genetic rearrangements can also occur from defects in crossover and/or recombination of genetic material during reproduction. Single nucleotide variants in one or more of the alpha genes can occur that impair transcription and/or translation of the alpha globin chains.
 
Testing is commercially available through several genetic labs. Targeted variant analysis for known α-globin gene variants can be performed by polymerase chain reaction (PCR). PCR can also be used to identify large deletions or duplications. Newer testing methods have been developed to facilitate identification of α-thalassemia variants, such as multiplex amplification methods and real-time PCR analysis (Fallah, 2010; Lacerra, 2007; Grimholt, 2014). In patients with suspected α-thalassemia and a negative PCR test for genetic deletions, direct sequence analysis of the α-globin locus is generally performed to detect single nucleotide variants (Origa, 2016).
 
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Genetic testing for alpha thalassemia is available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
 
Coding
There is a Tier 1 molecular pathology CPT code for testing for common deletions or variants:
 
81257 - HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (e.g., Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, and Constant Spring)
 
There is also a Tier 2 molecular pathology CPT code which includes relevant testing:
 
Code 81404 includes:
HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia), duplication/deletion analysis
Policy/
Coverage:
Effective January 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Preconception (carrier) testing is considered a contract exclusion in some member benefit certificates of coverage.
 
For members with benefit certificates without a contract exclusion, genetic testing for alpha- or beta- thalassemia meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following situations:
 
    • Testing for alpha-thalassemia in prospective parents when both parents have evidence of possible alpha-thalassemia (including α-thalassemia minor, hemoglobin H disease [α-thalassemia intermedia], or α-thalassemia minima [silent carrier]) based on biochemical testing. (Biochemical testing consists of complete blood count [CBC], microscopic examination of the peripheral blood smear, and hemoglobin electrophoresis. In silent carriers and in α-thalassemia trait, the hemoglobin electrophoresis will most likely be normal. However, there should be evidence of possible α-thalassemia minor on the CBC and peripheral smear.) OR
 
    • Testing for beta-thalassemia in prospective parents when both parents have evidence of possible beta-thalassemia (including both transfusion-dependent or non-transfusion-dependent subtypes). OR
 
    • Testing to confirm an alpha- or beta- thalassemia in individuals for whom other testing to diagnose the cause of microcytic anemia has been inconclusive.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Preconception (carrier) testing for alpha or beta thalassemia in prospective parents does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any other situation.
 
For members with contracts without primary coverage criteria, preconception (carrier) testing for alpha or beta thalassemia in prospective parents is considered investigational in any other situation. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Genetic testing to confirm a diagnosis of alpha or beta thalassemia does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any other situation.
 
For members with contracts without primary coverage criteria, genetic testing to confirm a diagnosis of alpha or beta thalassemia is considered investigational in any other situation. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Genetic testing of individuals with hemoglobin H disease (α-thalassemia intermedia) to determine prognosis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, genetic testing of individuals with hemoglobin H disease (α-thalassemia intermedia) to determine prognosis is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Genetic testing for alpha or beta thalassemia in other clinical situations (recognizing that prenatal testing is not addressed in this policy) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, genetic testing for alpha or beta thalassemia in other clinical situations (recognizing that prenatal testing is not addressed in this policy) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to January 2024
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing to confirm a diagnosis of alpha thalassemia does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, genetic testing to confirm a diagnosis of alpha thalassemia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Genetic testing for alpha thalassemia in other clinical situations (recognizing that prenatal testing is not addressed in this policy) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, genetic testing for alpha thalassemia in other clinical situations (recognizing that prenatal testing is not addressed in this policy) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Preconception (carrier) testing for alpha thalassemia in prospective parents is considered a contract exclusion. Services for genetic testing to determine the likelihood of passing an inheritable disease or congenital abnormality to an offspring are not covered in most member benefit certificates of coverage.
 
Rationale:
The published literature on genetic testing for alpha thalassemia consists primarily of reports describing the molecular genetics of testing, the types of mutations encountered, and genotype-phenotype correlations.
 
Analytic validity
No published literature was identified on the analytic validity of genetic screening. Some information on the analytic validity of testing was identified from genetic laboratory testing sites. For example, one site reports that “rare” polymorphisms can cause false-negative or false-positive results on gene sequence analysis (Mayo Medical Laboratories, 2013).
 
Clinical Validity
No published literature was identified on the clinical validity of genetic screening. Clinical validity is expected to be high when the causative mutation is a large deletion of one or more alpha globin gene, as PCR testing is generally considered highly accurate for this purpose. When a point mutation is present, the clinical validity is less certain.
 
Clinical Utility
There are several potential areas for clinical utility. Genetic testing can be used to determine the genetic abnormalities underlying a clinical diagnosis of alpha thalassemia. It can also be used define the genetics of alpha globin genes in relatives of patients with a clinical diagnosis of alpha thalassemia. Preconception (carrier) testing can be performed to determine the likelihood of an offspring with an alpha thalassemia syndrome. Prenatal (in utero) testing can also be performed to determine the presence and type of alpha thalassemia of a fetus. Prenatal testing will not be addressed in this policy.
 
The diagnosis of alpha thalassemia can be made without use of genetic testing. This is first done by analysis of the complete blood count (CBC) and peripheral blood smear, in conjunction with testing for other forms of anemia. Patients with a CBC demonstrating microcytic, hypochromic red blood cell (RBC) indices who are not found to have iron deficiency, have a high likelihood of thalassemia. On peripheral blood smear, the presence of inclusion bodies and target cells is consistent with the diagnosis of alpha thalassemia.
 
Hemoglobin electrophoresis can distinguish between the asymptomatic carrier states and alpha thalassemia intermedia (HgH disease) by identifying the types and amounts of abnormal hemoglobin present. In the carrier states, >95% of the Hb molecules are normal (HbA) with a small minority of HgBA2 present(1-3%) (Galanello, 2011). Alpha thalassemia intermedia is diagnosed by finding a substantial portion of HgbH (1-30%) on electrophoresis (Galanello, 2011). In alpha thalassemia major, the majority of the Hgb is abnormal, in the form of Hgb Bart (85-90%) (Galanello, 2011).
 
However, biochemical testing cannot always reliably distinguish between the asymptomatic carrier state and alpha thalassemia trait. Genetic testing can differentiate between the asymptomatic carrier state (alpha thalassemia minima) and alpha thalassemia trait (alpha thalassemia minor) by elucidating the number of abnormal genes present. This distinction is not important clinically since both the carrier state and alpha thalassemia trait are asymptomatic conditions that do not require medical care. Since the diagnosis of clinically relevant alpha thalassemia conditions can be done without genetic testing, there is little utility to genetic testing of a patient with a clinical diagnosis of thalassemia to determine the underlying genetic abnormalities.
 
Prognostic Testing in Patients With alpha-Thalassemia
Among patients with hemoglobin H disease, there is heterogeneity in the nature of the mutation (ie, deletional vs nondeletional), with variations across geographic areas and ethnic groups (Fucharoen, 2009). Patients with deletional mutations may have a less severe course of illness than those with nondeletional mutations (Fucharoen, 2009). In a cohort of 147 Thai pediatric patients with HbH disease, those with nondeletional mutations were more likely to have pallor after fever, hepatomegaly, splenomegaly, jaundice, short stature, need for transfusions, and gallstones (Laosombat, 2009).
 
The evidence suggests that different genetic mutations leading to alpha-thalassemia are associated with differences in prognosis. New treatments for some of the complications of HbH disease that result from ineffective erythropoiesis and iron overload and may differ for different genotypes are under development (Laosombat, 2009). However, no evidence was identified to indicate that patient management or outcomes would be changed by prognostic testing.
 
 
Summary
Mutations in the alpha thalassemia gene are common in certain ethnic groups. A variety of alpha thalassemia syndromes can occur, with severity determined by the number of abnormal genes present in an individual. The diagnosis of alpha thalassemia can be made clinically, and the thalassemia syndromes that have clinical implications (HgBH disease, Hg Bart’s) can be diagnosed biochemically without the need for genetic testing.
 
For patients with hemoglobin H disease, there may be a genotype-phenotype correlation for disease severity, but there is not currently evidence to indicate that patient management or outcomes would be altered through genetic testing.
 
2015 Update
A literature search conducted through October 2015 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search using the MEDLINE database through October 2017 did not reveal any new literature that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
One study assessing the analytic validity was identified. This 2016 study evaluated the reproducibility and accuracy of a PCR-based multicolor melting curve analysis method for detecting common nondeletional variants in the HBA2 gene from 700 whole blood samples (Huang, 2016). Reproducibility of the assay was high. In the clinical samples, there was 100% concordance between the 20 genotypes identified and the genotyping method. Petropoulou et al (2015) evaluated a PCR-based high-resolution melting curve analysis of duplicated areas of the HBA1 and HBA2 genes with novel non-deletion variants (Petropoulou, 2015). The study included 62 samples with previously identified novel variants and 18 normal controls; the melting curve analysis was able to distinguish at least 80% of novel homozygote samples detected by earlier generation tests.
 
Additionally, one study was identified assessing clinical validity. In 2016, Henderson et al reported on a retrospective study of genotype and phenotype correlations of the novel thalassemia and abnormal hemoglobin variants identified after adoption of routine DNA sequencing of α- and β-globin genes for all U.K. samples referred for evaluation of hemoglobinopathy for the preceding 10 years (Henderson, 2016). Of a total of approximately 12,000 samples, 15 novel α+-thal variants, 19 novel β-thal variants, and 11 novel β-globin variants were detected.
 
2018 Update
A literature search was conducted through November 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
American College of Obstetricians and Gynecologists
The American College of Obstetricians and Gynecologists published an opinion document in 2017 that includes multiple general recommendations about carrier screening of genetic conditions (ACOG, 2017). They are not summarized in this evidence review. Specific descriptions of genetic testing for α-thalassemia include the following: DNA-based genetic testing should be used to detect a-globin gene characteristics of suspected cases of thalassemia “if the mean corpuscular volume is below normal, iron deficiency anemia has been excluded, and the hemoglobin [Hb] electrophoresis is not consistent with b-thalassemia trait (ie, there is no elevation of Hb A2 or Hb F).”
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2019 Chinese study of over 15,000 samples that utilized both next-generation sequencing and PCR reported similar numbers of alpha thalassemia (n=19) and beta thalassemia (N=21) variants (Zhang, 2019).
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
There is an association between genotype and phenotype among patients with HbH disease. Individuals with a nondeletion variant typically have an earlier presentation, more severe anemia, jaundice, and bone changes, and more frequently require transfusions (Tamary, 2023).
 
A number of types of genetic abnormalities are associated with α-thalassemia. More than 100 genetic variants have been described. Deletion of 1 or more of the α-globin chains is the most common genetic defect. This type of genetic defect is found in approximately 90% of cases (Tamary, 2023). Large genetic rearrangements can also occur from defects in crossover and/or recombination of genetic material during reproduction. Single nucleotide variants in 1 or more of the α genes that impair transcription and/translation of the α-globin chains.
 
Testing is commercially available through several genetic labs. Targeted variant analysis for known α-globin gene variants can be performed by polymerase chain reaction (PCR) (Tamary, 2023). PCR can also be used to identify large deletions or duplications. Newer testing methods have been developed to facilitate identification of α-thalassemia variants, including chromosomal microarray analysis using oligonucleotide or SNP arrays, and next-generation sequencing (NGS) for analysis of deletion breakpoints.
Patients with deletional variants may have a less severe course of illness than those with nondeletional variants (Abolghasemi, 2022).
 
Unlike clinical diagnosis, for carrier testing, it is important to distinguish between α-thalassemia carrier (1 abnormal gene) and α-thalassemia trait (2 abnormal genes), and important to distinguish between the 2 variants of α-thalassemia trait, i.e., the αα/-- (cis variant) and the α-/α- (trans variant). This is important because only when both parents have the αα/-- cis variant is there a risk for a fetus with α-thalassemia major (Langlois, 2008). When both parents are α-thalassemia carriers (αα/--), there is a 1 in 4 likelihood that an offspring will have α-thalassemia major and hydrops fetalis. These parents may decide to pursue preimplantation genetic diagnosis in conjunction with in vitro fertilization to avoid a pregnancy with hydrops fetalis.
CPT/HCPCS:
81257HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; common deletions or variant (eg, Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, Constant Spring)
81258HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; known familial variant
81259HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; full gene sequence
81269HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; duplication/deletion variants
81361HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); common variant(s) (eg, HbS, HbC, HbE)
81362HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); known familial variant(s)
81363HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); duplication/deletion variant(s)
81364HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); full gene sequence
81404Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) ACADS (acyl-CoA dehydrogenase, C-2 to C-3 short chain) (eg, short chain acyl-CoA dehydrogenase deficiency), targeted sequence analysis (eg, exons 5 and 6) AQP2 (aquaporin 2 [collecting duct]) (eg, nephrogenic diabetes insipidus), full gene sequence ARX (aristaless related homeobox) (eg, X-linked lissencephaly with ambiguous genitalia, X-linked mental retardation), full gene sequence AVPR2 (arginine vasopressin receptor 2) (eg, nephrogenic diabetes insipidus), full gene sequence BBS10 (Bardet-Biedl syndrome 10) (eg, Bardet-Biedl syndrome), full gene sequence BTD (biotinidase) (eg, biotinidase deficiency), full gene sequence C10orf2 (chromosome 10 open reading frame 2) (eg, mitochondrial DNA depletion syndrome), full gene sequence CAV3 (caveolin 3) (eg, CAV3-related distal myopathy, limb-girdle muscular dystrophy type 1C), full gene sequence CD40LG (CD40 ligand) (eg, X-linked hyper IgM syndrome), full gene sequence CDKN2A (cyclin-dependent kinase inhibitor 2A) (eg, CDKN2A-related cutaneous malignant melanoma, familial atypical mole-malignant melanoma syndrome), full gene sequence CLRN1 (clarin 1) (eg, Usher syndrome, type 3), full gene sequence COX6B1 (cytochrome c oxidase subunit VIb polypeptide 1) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence CPT2 (carnitine palmitoyltransferase 2) (eg, carnitine palmitoyltransferase II deficiency), full gene sequence CRX (cone-rod homeobox) (eg, cone-rod dystrophy 2, Leber congenital amaurosis), full gene sequence CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1) (eg, primary congenital glaucoma), full gene sequence EGR2 (early growth response 2) (eg, Charcot-Marie-Tooth), full gene sequence EMD (emerin) (eg, Emery-Dreifuss muscular dystrophy), duplication/deletion analysis EPM2A (epilepsy, progressive myoclonus type 2A, Lafora disease [laforin]) (eg, progressive myoclonus epilepsy), full gene sequence FGF23 (fibroblast growth factor 23) (eg, hypophosphatemic rickets), full gene sequence FGFR2 (fibroblast growth factor receptor 2) (eg, craniosynostosis, Apert syndrome, Crouzon syndrome), targeted sequence analysis (eg, exons 8, 10) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), targeted sequence analysis (eg, exons 8, 11, 12, 13) FHL1 (four and a half LIM domains 1) (eg, Emery-Dreifuss muscular dystrophy), full gene sequence FKRP (fukutin related protein) (eg, congenital muscular dystrophy type 1C [MDC1C], limb-girdle muscular dystrophy [LGMD] type 2I), full gene sequence FOXG1 (forkhead box G1) (eg, Rett syndrome), full gene sequence FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), evaluation to detect abnormal (eg, deleted) alleles FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), characterization of haplotype(s) (ie, chromosome 4A and 4B haplotypes) GH1 (growth hormone 1) (eg, growth hormone deficiency), full gene sequence GP1BB (glycoprotein Ib [platelet], beta polypeptide) (eg, Bernard-Soulier syndrome type B), full gene sequence (For common deletion variants of alpha globin 1 and alpha globin 2 genes, use 81257) HNF1B (HNF1 homeobox B) (eg, maturity-onset diabetes of the young [MODY]), duplication/deletion analysis HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), full gene sequence HSD3B2 (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2) (eg, 3-beta-hydroxysteroid dehydrogenase type II deficiency), full gene sequence HSD11B2 (hydroxysteroid [11-beta] dehydrogenase 2) (eg, mineralocorticoid excess syndrome), full gene sequence HSPB1 (heat shock 27kDa protein 1) (eg, Charcot-Marie-Tooth disease), full gene sequence INS (insulin) (eg, diabetes mellitus), full gene sequence KCNJ1 (potassium inwardly-rectifying channel, subfamily J, member 1) (eg, Bartter syndrome), full gene sequence KCNJ10 (potassium inwardly-rectifying channel, subfamily J, member 10) (eg, SeSAME syndrome, EAST syndrome, sensorineural hearing loss), full gene sequence LITAF (lipopolysaccharide-induced TNF factor) (eg, Charcot-Marie-Tooth), full gene sequence MEFV (Mediterranean fever) (eg, familial Mediterranean fever), full gene sequence MEN1 (multiple endocrine neoplasia I) (eg, multiple endocrine neoplasia type 1, Wermer syndrome), duplication/deletion analysis MMACHC (methylmalonic aciduria [cobalamin deficiency] cblC type, with homocystinuria) (eg, methylmalonic acidemia and homocystinuria), full gene sequence MPV17 (MpV17 mitochondrial inner membrane protein) (eg, mitochondrial DNA depletion syndrome), duplication/deletion analysis NDP (Norrie disease [pseudoglioma]) (eg, Norrie disease), full gene sequence NDUFA1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 1, 7.5kDa) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFAF2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 2) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFS4 (NADH dehydrogenase [ubiquinone] Fe-S protein 4, 18kDa [NADH-coenzyme Q reductase]) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) (eg, spastic paraplegia), full gene sequence NLGN4X (neuroligin 4, X-linked) (eg, autism spectrum disorders), duplication/deletion analysis NPC2 (Niemann-Pick disease, type C2 [epididymal secretory protein E1]) (eg, Niemann-Pick disease type C2), full gene sequence NR0B1 (nuclear receptor subfamily 0, group B, member 1) (eg, congenital adrenal hypoplasia), full gene sequence PDX1 (pancreatic and duodenal homeobox 1) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence PHOX2B (paired-like homeobox 2b) (eg, congenital central hypoventilation syndrome), full gene sequence PLP1 (proteolipid protein 1) (eg, Pelizaeus-Merzbacher disease, spastic paraplegia), duplication/deletion analysis PQBP1 (polyglutamine binding protein 1) (eg, Renpenning syndrome), duplication/deletion analysis PRNP (prion protein) (eg, genetic prion disease), full gene sequence PROP1 (PROP paired-like homeobox 1) (eg, combined pituitary hormone deficiency), full gene sequence PRPH2 (peripherin 2 [retinal degeneration, slow]) (eg, retinitis pigmentosa), full gene sequence PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1) (eg, LEOPARD syndrome), targeted sequence analysis (eg, exons 7, 12, 14, 17) RET (ret proto-oncogene) (eg, multiple endocrine neoplasia, type 2B and familial medullary thyroid carcinoma), common variants (eg, M918T, 2647_2648delinsTT, A883F) RHO (rhodopsin) (eg, retinitis pigmentosa), full gene sequence RP1 (retinitis pigmentosa 1) (eg, retinitis pigmentosa), full gene sequence SCN1B (sodium channel, voltage-gated, type I, beta) (eg, Brugada syndrome), full gene sequence SCO2 (SCO cytochrome oxidase deficient homolog 2 [SCO1L]) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence SDHC (succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa) (eg, hereditary paraganglioma-pheochromocytoma syndrome), duplication/deletion analysis SDHD (succinate dehydrogenase complex, subunit D, integral membrane protein) (eg, hereditary paraganglioma), full gene sequence SGCG (sarcoglycan, gamma [35kDa dystrophin-associated glycoprotein]) (eg, limb-girdle muscular dystrophy), duplication/deletion analysis SH2D1A (SH2 domain containing 1A) (eg, X-linked lymphoproliferative syndrome), full gene sequence SLC16A2 (solute carrier family 16, member 2 [thyroid hormone transporter]) (eg, specific thyroid hormone
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American College of Obstetricians and Gynecologists, Committee on Genetics.(2018) Committee Opinion Number 691: Carrier Screening for Genetic Conditions. https://www.acog.org/Clinical-Guidance-andPublications/Committee-Opinions/Committee-on-Genetics/Carrier-Screening-for-Genetic-Conditions. Accessed January 22, 2018.

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Foglietta E, Bianco I, Maggio A et al.(2003) Rapid detection of six common Mediterranean and three non-Mediterranean alpha-thalassemia point mutations by reverse dot blot analysis. Am J Hematol 2003; 74(3):191-5.

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