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Thrombocytopenia Absent Radius Syndrome

Synonym: TAR Syndrome

, PhD.

Author Information

Initial Posting: ; Last Update: December 8, 2016.

Summary

Clinical characteristics.

Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia (<50 platelets/nL) that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.

Diagnosis/testing.

The diagnosis of TAR syndrome is established in a proband with bilateral absent radii, present thumbs, and thrombocytopenia. Identification of a heterozygous null allele (most often a minimally deleted 200-kb region at chromosome band 1q21.1) in trans with a heterozygous RBM8A hypomorphic allele on molecular genetic testing confirms the diagnosis.

Management.

Treatment of manifestations: Platelet transfusion for thrombocytopenia as needed; central venous catheter as an alternative to repeated venipuncture; orthopedic intervention as needed to maximize function of limbs.

Prevention of primary manifestations: Avoidance of cow’s milk to reduce the severity of gastroenteritis and to avoid exacerbations of thrombocytopenia.

Prevention of secondary complications: To reduce the risks of alloimmunization and infection, avoid platelet transfusion in older individuals whose platelet counts exceed a particular threshold (10/nL).

Surveillance: Platelet count whenever evidence of increased bleeding tendency (bruising, petechiae) occurs.

Genetic counseling.

TAR syndrome is inherited in an autosomal recessive manner and results from compound heterozygosity of RBM8A pathogenic variants. Affected individuals have one R8BM8A null allele, typically a 200-kb minimally deleted region at chromosome band 1q21.1, and one R8BM8A hypomorphic allele. About 50%-75% of probands have inherited the deletion (null allele) from an unaffected parent; the deletion occurs de novo in about 25%-50% of probands. If both parents carry one variant allele, 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. If only one parent is a carrier of a pathogenic variant (and the other variant/deletion is de novo), each sib of an affected individual has a 50% chance of being an asymptomatic carrier, and a 50% chance of being unaffected and not a carrier. Prenatal diagnosis for pregnancies at increased risk for TAR syndrome is possible using (a) molecular genetic testing if the genetic alterations are identified in the family and/or (b) ultrasound examination to evaluate the limbs.

Diagnosis

Suggestive Findings

Thrombocytopenia absent radius (TAR) syndrome should be suspected in individuals with absent radii and presence of thumbs in combination with thrombocytopenia.

Establishing the Diagnosis

The diagnosis of TAR syndrome is established in a proband with both of the following features:

  • Bilateral absence of the radii with the presence of both thumbs
  • Thrombocytopenia; usually <50 platelets/nL (normal range: 150-400 platelets/nL)

The diagnosis is confirmed by identification of a null heterozygous allele (most often a minimally deleted 200-kb region at chromosome band 1q21.1, but can be a heterozygous RBM8A pathogenic variant detected by molecular genetic testing) in trans with a heterozygous RBM8A hypomorphic allele that can be identified by molecular genetic testing (see Table 1).

Molecular Genetic Testing

Single-gene testing. Gene-targeted deletion/duplication analysis of RBM8A is performed first, followed by sequence analysis of RBM8A if no deletion is found. Although the diagnosis of TAR syndrome can be established by identification of a heterozygous minimally deleted 200-kb region at chromosome band 1q21.1, sequence analysis of RBM8A can be done subsequently in individuals with the deletion to confirm the presence of a second pathogenic variant (hypomorphic allele) and allow family studies. Homozygous RBM8A null alleles (e.g., deletions) are thought to be lethal (see Abnormal Gene Product).

A multigene panel that includes RBM8A 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.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes RBM8A) fails to confirm a diagnosis in an individual with features of TAR syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Thrombocytopenia Absent Radius Syndrome

Gene 1Test MethodProportion of Probands with Pathogenic Variant(s) 2 Detectable by This Method
RBM8AGene-targeted deletion/duplication analysis 395% 4
Sequence analysis 5~95% 6
1.
2.

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

3.

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

4.

Both a 200-kb and a more common 500-kb TAR syndrome-associated deletion have been described. Because the deletion often extends beyond the 200-kb minimally deleted region [Klopocki et al 2007], a test that can approximate the extent of the deletion is optimal.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.

6.

Sequence analysis requires inclusion of 5' UTR and intronic gene regions. A heterozygous RBM8A hypomorphic allele was identified in 51/53 affected individuals with the 200-kb deletion. Biallelic RBM8A pathogenic variants (1 null allele and 1 hypomorphic allele) were identified in two individuals who (out of the 55 individuals included in the study) did not have the 200-kb deletion. Two individuals (an affected mother and daughter) had a deletion identified, but did not have a hypomorphic allele identified [Albers et al 2012].

Clinical Characteristics

Clinical Description

Limb anomalies can affect both upper and lower limbs, although upper limb involvement tends to be more severe than lower limb involvement. Individuals with thrombocytopenia absent radius (TAR) syndrome almost always have bilateral absence of the radius. The thumbs are always present. The thumbs in individuals with TAR syndrome are of near-normal size, but are somewhat wider and flatter than usual. They are also held in flexion against the palm, and tend to have limited function, particularly in terms of grasp and pinch activities [Goldfarb et al 2007].

The upper limbs may also have hypoplasia or absence of the ulnae, humeri, and shoulder girdles. Fingers may show syndactyly, and fifth finger clinodactyly is common.

Lower limbs are affected in almost half of those with TAR syndrome; hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, and absence of the patella are common findings. The most severe limb involvement is tetraphocomelia.

Thrombocytopenia may be congenital or may develop within the first few weeks to months of life. In one review, it was noted that thrombocytopenia developed during the first week of life in only 59% [Hedberg & Lipton 1988]. In general, thrombocytopenic episodes decrease with age, with most children with TAR syndrome having normal platelet counts by school age. However, cow's milk allergy is common, and can be associated with exacerbation of thrombocytopenia.

Cardiac anomalies affect 15%-22% [Hedberg & Lipton 1988, Greenhalgh et al 2002] and usually include septal defects rather than complex cardiac malformations.

Gastrointestinal involvement includes cow's milk allergy and gastroenteritis. Both tend to improve with age.

Genitourinary anomalies include renal anomalies (both structural and functional) and rarely, Mayer-Rokitansky-Kuster-Hauser syndrome (agenesis of uterus, cervix, and upper part of the vagina) [Griesinger et al 2005, Ahmad & Pope 2008].

Leukemoid reactions have been reported in some individuals with TAR syndrome, with white blood cell counts exceeding 35,000 cells/mm3. These leukemoid reactions are generally transient [Klopocki et al 2007].

Cognitive development is usually normal in individuals with TAR syndrome.

Growth. Most have height on or below the 50th centile.

Other skeletal manifestations, including rib and cervical vertebral anomalies (e.g., cervical rib, fused cervical vertebrae), tend to be relatively rare.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Penetrance

Penetrance appears to be complete in individuals who have biallelic RBM8A pathogenic variants.

Prevalence

The prevalence of TAR syndrome is estimated at 1:200,000-1:100,000.

Differential Diagnosis

The following conditions, which include radial aplasia as a component manifestation, can show some overlap with TAR syndrome:

  • Holt-Oram syndrome, an autosomal dominant disorder resulting from pathogenic variants in TBX5, is characterized by (1) upper-extremity malformations involving radial, thenar, or carpal bones; a personal and/or family history of congenital heart malformation, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD), especially those occurring in the muscular trabeculated septum; and/or cardiac conduction disease. The thumb is often absent or hypoplastic in this condition.
  • Roberts syndrome, an autosomal recessive disorder resulting from pathogenic variants in ESCO2, is characterized by mild to severe prenatal growth retardation, microcephaly, cleft lip and/or palate, and limb malformations (including bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening). Other limb malformations include oligodactyly with thumb aplasia or hypoplasia, syndactyly, clinodactyly, and elbow and knee flexion contractures. Additional craniofacial abnormalities include downslanting palpebral fissures, widely spaced eyes, exophthalmos resulting from shallow orbits, corneal clouding, hypoplastic nasal alae, beaked nose, malar hypoplasia, ear malformations, and micrognathia. Intellectual disability is reported in the majority of affected individuals.
  • Fanconi anemia (FA) is characterized by bone marrow failure, an increased risk of malignancy, and specific physical features including: short stature, abnormal skin pigmentation, and malformations of the thumbs and forearms. Additional anomalies of the skeletal system, eyes, ears, heart, gastrointestinal system, kidneys and genitourinary tract, and central nervous system can also occur. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. FA can be inherited in an autosomal recessive manner (>15 genes reported), an autosomal dominant manner (RAD51-related FA), or an X-linked manner (FANCB-related FA).
  • Thalidomide embryopathy occurs secondarily to maternal ingestion of thalidomide. Affected children can have a pattern of limb, cardiac, craniofacial, and genitourinary anomalies.
  • VACTERL association is an acronym that stands for the cardinal manifestations of vertebral, anal, cardiac, tracheo-esophageal fistula, renal anomalies, and limb anomalies. The limb anomalies tend to affect the thumb and radius, although the thumb is often absent in this condition. Thrombocytopenia does not occur as a manifestation of VACTERL.
  • Duane-radial ray syndrome (Okihiro syndrome, acro-renal-ocular syndrome) is characterized by the combination of Duane anomaly (inability to abduct the eye) and radial anomalies of varying severity, ranging from thenar hypoplasia to radial aplasia. In addition, renal and skeletal anomalies and hearing loss and/or ear anomalies often occur. See SALL4-Related Disorders.
  • Townes-Brocks syndrome, an autosomal dominant disorder resulting from pathogenic variants in SALL1, is characterized by the triad of imperforate anus, dysplastic ears, and thumb malformations (triphalangeal thumbs, duplication of the thumb, and rarely thumb hypoplasia). Hematologic abnormalities do not occur in Townes-Brocks syndrome.
  • Rapadilino syndrome is an acronym of sorts for the cardinal manifestations of radial defects, absent/hypoplastic patellae (and high/cleft palate), diarrhea (and joint dislocations), little size, and a long/slender nose (and normal intelligence). The radial defects include absent or hypoplastic radii and absent or hypoplastic thumbs (thus distinguishing it from TAR syndrome). See Baller-Gerold Syndrome and Rothmund-Thomson Syndrome.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with thrombocytopenia absent radius (TAR) syndrome, the following evaluations are recommended:

  • Platelet count if this has not been completed
  • Orthopedic evaluation of both upper and lower limbs
  • Echocardiography to assess for cardiac anomalies
  • Evaluation of renal structure and function
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The treatment for thrombocytopenia is platelet transfusion as needed. Bone marrow transplantation is generally not indicated, given the transient nature of the thrombocytopenia.

The use of central venous catheters as an alternative to venipuncture has been suggested to reduce the pain associated with repeated procedures [Coccia et al 2012].

Orthopedic intervention is indicated to maximize function of limbs, with such intervention including prostheses, orthoses, adaptive devices, and surgery [McLaurin et al 1999, Al Kaissi et al 2015].

Prevention of Primary Manifestations

Avoidance of cow's milk lessens the severity of gastroenteritis and reduces exacerbations of thrombocytopenia (in older children).

Prevention of Secondary Complications

Frequent transfusion with platelets can lead to alloimmunization and increased risk of infection. It is therefore recommended that platelet transfusion in older individuals not be done until platelet counts fall below a particular threshold (10/nL). Note: The threshold for platelet transfusion in newborns is unknown.

Surveillance

Platelet count is indicated whenever evidence of increased bleeding tendency (bruising, petechiae) occurs.

Agents/Circumstances to Avoid

Avoid cow's milk to reduce the severity of gastroenteritis and associated thrombocytopenia (in older children).

Evaluation of Relatives at Risk

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

Pregnancy Management

Fewer than ten pregnancies have been reported in women with TAR syndrome. Almost all develop thrombocytopenia during pregnancy. In one, corticosteroids appeared to be fairly successful in treating the thrombocytopenia [Bot-Robin et al 2011]. In one pregnant woman with TAR syndrome, exacerbation of her thrombocytopenia preceded the development of preeclampsia.

Other considerations during pregnancy include potential difficulties with administration of regional anesthetics (given potential difficulties with vascular access) and difficulties accessing the airway for general anesthesia [Wax et al 2009].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu 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, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Thrombocytopenia absent radius (TAR) syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of inheriting the 200-kb minimally deleted region at 1q21.1 and/or an RBM8A pathogenic variant depends on the genetic status of the parents:

  • If both parents carry one allele, 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.
  • If only one parent is a carrier of a pathogenic variant (and the other variant/deletion is de novo), each sib of an affected individual has a 50% chance of being an asymptomatic carrier, and a 50% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

Other family members. The risk to other family members depends on the status of the proband's parents. If the parent of a proband is a carrier of a pathogenic variant in RBM8A, each sib of that parent is at increased risk of being a carrier of the RBM8A pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the RBM8A pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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 affected, are carriers of the 200-kb minimally deleted region at 1q21.1 or an RBM8A pathogenic variant, 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 Diagnosis

Once the RBM8A pathogenic variants (null allele and hypomorphic allele) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

For pregnancies known to be at increased risk for TAR syndrome – that is, either (a) both parents are known carriers of a TAR-associated variant in RBM8 (i.e., 1 parent carries a null allele, 1 parent carries a hypomorphic allele); or (b) one parent is a known carrier and the status of other parent is unknown; or (c) one parent has TAR syndrome; or (d) one parent with unknown genetic status has a sib with TAR syndrome:

  • Molecular genetic testing. If the pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers testing for pathogenic variants in RBM8A and the 200-kb minimally deleted region at 1q21.1.
  • Fetal ultrasound examination. Ultrasound evaluation of fetal limbs and heart can be used either alone or in conjunction with molecular genetic testing.

For pregnancies not known to be at increased risk for TAR syndrome

  • Fetal ultrasound examination. In a pregnancy not known to be at increased risk for TAR syndrome in which radial anomalies are identified on routine ultrasound evaluation, the fetus with TAR syndrome may be misdiagnosed as having Holt-Oram, Roberts, or other syndromes. The detection of a heterozygous 200-kb minimally deleted region at 1q21.1 [Houeijeh et al 2011] or other heterozygous RBM8A null allele in trans with a hypomorphic allele confirms the diagnosis of TAR syndrome in a fetus with typical radial anomalies.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

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.

  • Genetic and Rare Diseases Information Center (GARD)
    PO Box 8126
    Gaithersburg MD 20898-8126
    Phone: 888-205-2311 (toll-free); 888-205-3223 (toll-free TTY); 301-519-3194
    Fax: 301-251-4911
    Email: GARDinfo@nih.gov
  • National Library of Medicine Genetics Home Reference
  • National Organization for Rare Disorders (NORD)
    55 Kenosia Avenue
    PO Box 1968
    Danbury CT 06813-1968
    Phone: 800-999-6673 (toll-free); 203-744-0100; 203-797-9590 (TDD)
    Fax: 203-798-2291
    Email: RN@rarediseases.org; genetic_counselor@rarediseases.org; orphan@rarediseases.org
  • Medline Plus
  • Reach: The Association for Children with Hand or Arm Deficiency
    PO Box 54
    Helston Cornwall TR13 8WD
    United Kingdom
    Phone: +44 0845 1306 225
    Fax: +44 0845 1300 262
    Email: reach@reach.org.uk
  • National Cancer Institute Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
    Phone: 800-518-8474
    Email: NCI.IBMFS@westat.com

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.

Thrombocytopenia Absent Radius Syndrome: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
Not applicable1q21​.1Not applicable
RBM8A1q21​.1RNA-binding protein 8ARBM8ARBM8A

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 Thrombocytopenia Absent Radius Syndrome (View All in OMIM)

274000THROMBOCYTOPENIA-ABSENT RADIUS SYNDROME; TAR
605313RNA-BINDING MOTIF PROTEIN 8A; RBM8A

Gene Structure

RBM8A transcript reference sequence NM_005105.3 has six exons. Two alternative start codons result in two forms of the protein, and this gene also uses multiple polyadenylation sites (provided by RefSeq, 7-08). Note that the closely related pseudogene, RBM8B, has been described [Faurholm et al 2001]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic Variants

Deletions. The minimally deleted segment is a 200-kb region at 1q21.1 encompassing RBM8A as well as at least 12 known genes [Klopocki et al 2007]. However, the most frequently observed deleted allele (28/30 individuals with TAR syndrome) is a 500-kb deletion extending toward the telomere that spans an additional five genes [Klopocki et al 2007]. Both the 200-kb and 500-kb TAR syndrome-associated deletions are typically distinct and separate from the region of the 1q21.1 deletion/duplication syndrome (see Genetically Related Disorders). Larger rearrangements involving these regions have been reported [Brunetti-Pierri et al 2008, Mefford et al 2008]. An atypical TAR syndrome region deletion has also been described [Brunetti-Pierri et al 2008]. Note that homozygosity for two null alleles is thought to be lethal (see Abnormal Gene Product).

Hypomorphic alleles. The hypomorphic c.-21G>A and c.67+32G>C alleles have allele frequencies of 3.05% and 0.41%, respectively [Albers et al 2012]. Of the 51 individuals with TAR syndrome who were compound heterozygotes for the 200-bp deletion and a hypomorphic allele, 39 had c.-21G>A and 12 had c.67+32G>C [Albers et al 2012]. Note that individuals homozygous for these hypomorphic alleles do not have features of TAR syndrome.

Inheritance pattern. The inheritance pattern of TAR syndrome is unusual since RBM8A null alleles, typically a large deletion, are rare and the hypomorphic alleles are common in the population. The following observations were unexplained until the molecular mechanism of disease was determined:

  • A paucity of affected sibs. Greenhalgh et al [2002] reported that 20% of sibs were similarly affected while an unpublished survey found that 6% of sibs were similarly affected. This may partially be explained by the 200-kb minimally deleted region of 1q21.1 occurring as a de novo event in a substantial proportion (25%-50%) of individuals [Albers et al 2012].
  • Consanguinity of the parents of an affected child (rare reports). This phenomenon is now explicable, in that TAR syndrome is caused by compound heterozygosity for two different alterations, one inactivating and one hypomorphic.
  • Apparent parent-to-child transmission reported. Given that the frequency of one of the hypomorphic alleles is approximately 3%, an individual with TAR syndrome may have a reproductive partner who is a carrier of a hypomorphic allele.
  • Affected second- and third-degree relatives reported (with few or no manifestations in intervening relatives; see preceding bullet)

Table 2.

RBM8A Pathogenic Variants Discussed in This GeneReview

Variant ClassificationNucleotide Change
(Predicted Protein Change)
Reference Sequences
Hypomorphic allelesc.-21G>A 1NM_005105​.4
NP_005096​.1
c.67+32G>C
Inactivating allelesc.207_208insAGCG
c.487C>T
(p.Arg163Ter)

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Normal Gene Product

RBM8A encodes RNA-binding protein 8A, a protein with a conserved RNA-binding motif. The protein is found predominantly in the nucleus, although it is also present in the cytoplasm. It is preferentially associated with mRNAs produced by splicing, including both nuclear mRNAs and newly exported cytoplasmic mRNAs. It is thought that the protein remains associated with spliced mRNAs as a tag to indicate where introns had been present, thus coupling pre- and post-mRNA splicing events. RNA-binding protein 8A is involved with mRNA and snRNA biogenesis, based on its role as a component of the exon junction complex (adapted from NCBI, Gene ID: 9939; 6-15-12).

Abnormal Gene Product

TAR syndrome is the result of an insufficiency of RNA-binding protein 8A in certain tissues [Albers et al 2012]. The consequences of insufficiency are not fully understood, but thought to be related to tissue-specific and developmental stage-specific factors. Experiments in model animal systems indicate that a complete deficiency of RNA-binding protein 8A is not viable.

References

Literature Cited

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  • Albers CA, Paul DS, Schulze H, Freson K, Stephens JC, Smethurst PA, Jolley JD, Cvejic A, Kostadima M, Bertone P, Breuning MH, Debili N, Deloukas P, Favier R, Fiedler J, Hobbs CM, Huang N, Hurles ME, Kiddle G, Krapels I, Nurden P, Ruivenkamp CA, Sambrook JG, Smith K, Stemple DL, Strauss G, Thys C, van Geet C, Newbury-Ecob R, Ouwehand WH, Ghevaert C. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet. 2012;44:435–9. [PMC free article: PMC3428915] [PubMed: 22366785]
  • Al Kaissi A, Girsch W, Kenis V, Melchenko I, Ben Ghachem M, Pospischill R, Klaushofer K, Grill F, Ganger R. Reconstruction of limb deformities in patients with thrombocytopenia-absent radius syndrome. Orthop Surg. 2015;7:50–6. [PubMed: 25708036]
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  • Coccia P, Ruggiero A, Mastrangelo S, Attina G, Scalzone M, Pittiruti M, Zampino G, Maurizi P, Riccardi R. Management of children with thrombocytopenia-absent radius syndrome: an institutional experience. J Paediatr Child Health. 2012;48:166–9. [PubMed: 21771154]
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  • Griesinger G, Dafopoulos K, Schultze-Mosgau A, Schroder A, Felberbaum R, Diedrich K. Mayer-Rokitansky-Kuster-Hauser syndrome associated with thrombocytopenia-absent radius syndrome. Fertil Steril. 2005;83:452–4. [PubMed: 15705390]
  • Hedberg VA, Lipton JM. Thrombocytopenia with absent radii. A review of 100 cases. Am J Pediatr Hematol Oncol. 1988;10:51–64. [PubMed: 3056062]
  • Houeijeh A, Andrieux J, Saugier-Veber P, David A, Goldenberg A, Bonneau D, Fouassier M, Journel H, Martinovic J, Escande F, Devisme L, Bisiaux S, Chaffiotte C, Maux M, Kerckaert JP, Holder-Espinasse M, Mouvrier-Hanu S. Thrombocytopenia-absent radius (TAR) syndrome: a clinical genetic series of 14 further cases. Impact of the associated 1q21.1 deletion on the genetic counseling. Eur J Med Genet. 2011;54:e471–7. [PubMed: 21635976]
  • Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM, Habenicht R, König R, Seemanova E, Megarbane A, Ropers HH, Ullmann R, Horn D, Mundlos S. Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet. 2007;80:232–40. [PMC free article: PMC1785342] [PubMed: 17236129]
  • McLaurin TM, Bukrey CD, Lovett RJ, Mochel DM. Management of thrombocytopenia-absent radius (TAR) syndrome. J Pediatr Orthop. 1999;19:289–96. [PubMed: 10344309]
  • Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Räber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008;359:1685–99. [PMC free article: PMC2703742] [PubMed: 18784092]
  • Schnur RE, Eunpu D, Zackai E. Thrombocytopenia with absent radius in a boy and his uncle. Am J Med Genet. 1987;28:117–23. [PubMed: 3314504]
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Suggested Reading

  • Geddis AE. Congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii. Hematol Oncol Clin North Am. 2009;23:321–31. [PMC free article: PMC2757092] [PubMed: 19327586]
  • Rivers A, Slayton WB. Congenital cytopenias and bone marrow failure syndromes. Semin Perinatol. 2009;33:20–8. [PubMed: 19167578]

Chapter Notes

Revision History

  • 8 December 2016 (sw) Comprehensive update posted live
  • 29 May 2014 (me) Comprehensive update posted live
  • 28 June 2012 (cd) Revision: Albers et al [2012] documents a role for RBM8A mutations in TAR syndrome; testing for RBM8A mutations available clinically
  • 2 February 2012 (me) Comprehensive update posted live
  • 8 December 2009 (me) Review posted live
  • 26 August 2009 (hvt) Original submission
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