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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Thrombocytopenia Absent Radius Syndrome

Synonyms: Radial Aplasia Amegakaryocytic Thrombocytopenia, Radial Aplasia Thrombocytopenia Syndrome, TAR Syndrome
, PhD
Director, Clinical Genetics
Spectrum Health
Grand Rapids, Michigan

Initial Posting: ; Last Update: May 29, 2014.

Summary

Disease 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 primarily clinical: the combination of thrombocytopenia and absent radius with presence of thumbs suggests the diagnosis. In addition, individuals with TAR syndrome almost always have a minimally deleted 200-kb region at chromosome band 1q21.1 (distinct from the region involved in the 1q21.1 deletion/duplication syndrome). Thus, identification of the 200-kb minimally deleted region confirms the diagnosis of TAR syndrome in individuals with bilateral absence of the radius and presence of thumbs. This deletion involves multiple genes, including RBM8A. Recently, the majority of individuals with the 200-kb deletion were found to have a pathogenic variant in the remaining RBM8A allele. Individuals with a clinical diagnosis of TAR syndrome in whom the 1q21.1 deletion was not found had biallelic intragenic mutations of RBM8A.

Management. Treatment of manifestations: Platelet transfusion for thrombocytopenia as needed; 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 typically have one R8BM8A hypomorphic mutation along with a null mutation, usually a minimally deleted 200-kb region at chromosome band 1q21.1. About 50%-75% of probands have inherited the 200-kb minimally deleted region from an unaffected parent; the deletion occurs de novo in about 25%-50% of probands. 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 mutation/deletion is de novo), each sib has 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

Clinical Diagnosis

The diagnosis of thrombocytopenia absent radius (TAR) syndrome is established by the combination of:

  • Bilateral absence of the radii with the presence of both thumbs. In addition, upper limb manifestations may include ulnar and/or humeral anomalies. Lower limb anomalies may include hip and/or patellar dislocation and anomalies of one or more of the long bones.
  • Thrombocytopenia is present in almost all, although it is generally transient. Onset ranges from before birth to adulthood, but in most it is manifest during the first weeks of life.

Testing

Platelet counts are determined as part of a complete blood count (CBC). Individuals with TAR syndrome usually have platelet counts below 50 platelets/nL. Normal range is 150-400 platelets/nL.

Molecular Genetic Testing

Locus/gene. RBM8A is the only gene in which biallelic mutations are known to cause TAR syndrome. One allele is typically inactivated by a minimally deleted region of 200 kb at chromosome band 1q21.1 (including RBM8A), which is distinct from the region involved in the 1q21.1 deletion/duplication syndrome (see Molecular Genetics) [Klopocki et al 2007, Mefford et al 2008]. The second R8BM8A allele has a pathogenic variant that is a hypomorphic allele (partial loss of gene function) in the noncoding region.

See Molecular Genetics for information on the discovery of RBM8A hypomorphic alleles and how they explain some of the previous observations of apparently unusual inheritance patterns of TAR syndrome.

Table 1. Summary of Molecular Genetic Testing Used in TAR Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
RBM8ADeletion/duplication analysis 2~95% 3
Sequence analysis 4~3% 5
Targeted mutation analysis 6, 7100% for the targeted mutation(s)

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

3. Detects a 200-kb minimally deleted region at 1q21.1 that includes RBM8A. 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.

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

5. Heterozygous RBM8A hypomorphic mutations identified in 51/53 affected individuals with the 200-kb deletion and biallelic RBM8A pathogenic variants in 2/53 affected individuals who do not have the 200 kb deletion [Albers et al 2012]. Sequencing analysis requires inclusion of 5’ UTR and intronic gene regions.

6. The two known hypomorphic mutant alleles are c.-21G>A and c.67+32G>C (see Molecular Genetics and Table 2).

7. Pathogenic variants included in a panel may vary by laboratory.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis is suspected on clinical grounds, initially based on bilateral absence of the radius and presence of thumbs. Newborns should be evaluated for thrombocytopenia; if platelet count is normal, it should be repeated whenever evidence of increased bleeding tendency (bruising, petechiae) occurs.

Deletion/duplication analysis should be performed first for identification of the 200-kb minimally deleted region at chromosome band 1q21.1. Presence of this deletion is sufficient to verify the diagnosis of TAR syndrome in individuals with bilateral absence of the radius and presence of thumbs. However, lack of identification of this deletion is not sufficient to rule out the diagnosis. Sequence analysis of the coding and noncoding regions of RBM8A should follow if no deletion is identified, or to identify the second RBM8A pathogenic variant for confirmation of the diagnosis and/or genetic counseling purposes.

Clinical Description

Natural History

Individuals with thrombocytopenia absent radius (TAR) syndrome almost always have bilateral absence of the radius. The thumbs are always present. Thumbs in 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].

Thrombocytopenia may be congenital or 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.

In addition, some individuals with TAR syndrome have been reported to have leukemoid reactions, 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.

Most have height on or below the 50th centile.

Other anomalies can also occur, and affect the skeletal, cardiac, gastrointestinal, and genitourinary systems.

Limb anomalies can affect both upper and lower limbs, although upper limb involvement tends to be more severe than lower limb involvement. The upper limbs may 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 of tetraphocomelia.

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

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 in rare cases, Mayer-Rokitansky-Kuster-Hauser syndrome (agenesis of uterus, cervix, and upper part of the vagina) [Griesinger et al 2005, Ahmad & Pope 2008].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Penetrance

Penetrance appears to be complete in individuals who have two 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 (HOS) 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 (RBS) is characterized by prenatal growth retardation (ranging from mild to severe), craniofacial findings (including microcephaly and 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. Craniofacial abnormalities include cleft lip and/or cleft palate, premaxillary protrusion, micrognathia, microbrachycephaly, malar hypoplasia, downslanting palpebral fissures, widely spaced eyes , exophthalmos resulting from shallow orbits, corneal clouding, hypoplastic nasal alae, beaked nose, and ear malformations. Intellectual disability is reported in the majority of affected individuals.
  • Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk of malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ears (and decreased hearing), heart, gastrointestinal system, and central nervous system; hypogonadism; and developmental delay. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. By age 40-50 years, the estimated cumulative incidence of bone marrow failure is 90%, the incidence of hematologic malignancies (primarily acute myeloid leukemia) 10%-30%, and of nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract) 25%-30%.
  • 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 anomaly-radial aplasia (Okihiro syndrome, acro-renal-ocular syndrome, IVIC syndrome) consists of 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 is characterized by the triad of imperforate anus (82%), dysplastic ears (overfolded superior helices and preauricular tags) (88%) frequently associated with sensorineural and/or conductive hearing impairment (65%), and thumb malformations (89%) (triphalangeal thumbs, duplication of the thumb (preaxial polydactyly), and rarely hypoplasia of the thumbs). 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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 initial diagnosis is based on radial aplasia with presence of thumbs
  • Orthopedic evaluation of both upper and lower limbs
  • Echocardiography to assess for cardiac anomalies
  • Evaluation of renal structure and function
  • Medical genetics consultation

Treatment of Manifestations

The treatment of thrombocytopenia is platelet support. 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].

Prevention of Primary Manifestations

Avoidance of cow’s milk lessens the severity of gastroenteritis and 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 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

  • Parents of individuals with TAR syndrome are typically unaffected. However, parent-to-child transmission [Ward et al 1986] and the presence of affected individuals in multiple generations have been reported [Schnur et al 1987].
  • Approximately 50%-75% of probands have inherited the 200-kb minimally deleted region at 1q21.1 from an unaffected parent. The deletion occurs de novo in about 25%-50% of probands [Klopocki et al 2007, Albers et al 2012].
  • Recommendations for the evaluation of parents of a proband include radiographs of the limbs (as minor limb involvement in some has been reported) and molecular genetic testing for the 200-kb minimally deleted region at 1q21.1 and/or the RBM8A pathogenic variant(s) identified in the 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 mutation/deletion is de novo), each sib has of an affected individual has a 50% chance of being an asymptomatic carrier, and a 50% chance of being unaffected and not a carrier.
  • When both parents are carriers, once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • The offspring of an individual with TAR syndrome are obligate heterozygotes (carriers) for a pathogenic variant in RBM8A.
  • If an individual with TAR syndrome has children with a carrier of a pathogenic variant in RBM8A, their offspring have a 50% chance of being affected and a 50% chance of being carriers. This may account for the reports of parent-to-child transmission [Ward et al 1986].

Other family members. The risk to other family members depends on the status of the proband's parents.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the 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

Pregnancies known to be at increased risk for TAR syndrome (both parents are known carriers of a pathogenic variant, one parent is a known carrier and the status of other parent is unknown, one parent has TAR syndrome, or one parent has a sib with TAR syndrome and their parental genetic status is unknown):

  • 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.

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 two RBM8A pathogenic variants or one pathogenic variant in RBM8A and the 200-kb minimally deleted region at 1q21.1 confirms the diagnosis of TAR syndrome [Houeijeh et al 2011].

Preimplantation genetic diagnosis (PGD) may be available for families in which the pathogenic variants have been identified.

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
  • Madisons Foundation
    PO Box 241956
    Los Angeles CA 90024
    Phone: 310-264-0826
    Fax: 310-264-4766
    Email: getinfo@madisonsfoundation.org
  • 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
  • NCI Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
    National Cancer Institute
    Phone: 800-518-8474
    Email: lisaleathwood@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

Gene SymbolChromosomal LocusProtein NameHGMD
Not applicable1q21​.1Not applicable
RBM8A1q21​.1RNA-binding protein 8ARBM8A

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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

Molecular Genetic Pathogenesis

With one exception, all individuals with TAR syndrome are compound heterozygotes for an RBM8A null allele and a RBM8A hypomorphic allele [Albers et al 2012]. The null alleles are inactivated either by the minimal 200-kb deletion of 1q21.1 or by an intragenic inactivating mutation in RBM8A. The hypomorphic alleles are in noncoding regions of RBM8A; the mechanism by which they reduce RBM8A transcription and protein expression is unknown. The finding that individuals with TAR syndrome have significantly reduced amounts of the protein encoded by RBM8A (compared to parents and controls) supports the assertion that RBM8A is the gene in which mutation is causative [Albers et al 2012].

Klopocki et al [2007] defined the minimal 200-kb deletion as a common defect in individuals with TAR syndrome and, because some unaffected parents were carriers, proposed that this deletion is necessary but not sufficient for a diagnosis of TAR syndrome. They hypothesized that one or more as-yet unidentified modifiers are thought to be necessary for the expression of the TAR syndrome phenotype. In a tour-de-force effort to identify the modifier, Albers et al [2012] performed exome sequencing of five affected individuals, which led to the identification of single-nucleotide variants (SNV, sometimes referred to as SNP [single nucleotide polymorphisms]) in noncoding regions of RBM8A. Multiple lines of evidence support the role of the RBM8A noncoding SNVs as hypomorphic alleles, which in combination with an inactivating RBM8A allele (e.g., minimal 200-kb deletion, frameshift, or nonsense mutation) result in the TAR syndrome phenotype. Data presented by Albers et al [2012] define the cause of TAR syndrome as biallelic RBM8AI pathogenic variants that reduce but do not completely abolish RBM8A function.

Compound heterozygosity for a null allele and a hypomorphic allele of RBM8A may elucidate unexplained inheritance patterns previously reported in TAR syndrome.

  • 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 the cases [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%, it would not be unusual for an individual with TAR syndrome to 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)

Gene structure. The 200-kb minimally deleted region at 1q21.1 observed in individuals with TAR syndrome encompasses at least 12 known genes including HFE2, TXNIP, POLR3GL, ANKRD34A, LIX1L, RBM8A, GNRHR2, PEX11B, ITGA10, ANKRD35, PIAS3, and NUDT1 [Klopocki et al 2007]. The BAC RP11-698N18 maps completely within the 200-kb minimally deleted region [Klopocki et al 2007]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

RBM8A transcript reference sequence NM_005105.3 has six exons. Previously, it was thought that two genes (RBM8A and RBM8B) encode the protein; it is now known that the RBM8B locus is a pseudogene [Faurholm et al 2001]. Two alternative start codons result in two forms of the protein, and this gene also uses multiple polyadenylation sites [provided by RefSeq, 7-08]

Pathogenic allelic variants. The minimally deleted segment is a 200-kb region at 1q21.1 encompassing RBM8A and the genes described above [Klopocki et al 2007]. However, the most frequently observed deleted allele (28/30 individuals with TAR syndrome) has a larger 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. However, in some instances 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].

The hypomorphic alleles in the 5’ UTR and in intron 1 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 the pathogenic variant in the 5’ UTR and 12 had the intron 1 pathogenic variant c.67+32G>C [Albers et al 2012].

Table 2. RBM8A Pathogenic Allelic Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide Change & Description 1Genome Coordinates 1 (GRCh37/hg19 assembly)
Hypomorphic allelesNM_005105​.3: c.-21G>A (in 5’ UTR) (rs139428292)G/A, Chr1:145507646
c.67+32G>C (intron 1)G/C, Chr1:145507765
Inactivating alleles4-bp insertion in exon 4AGCG, Chr1:145508476
Nonsense mutation in exon 6C-T, Chr1:145509173

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Albers et al [2012]

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

  1. Ahmad R, Pope S. Association of Mayer-Rokitansky-Küster-Hauser syndrome with Thrombocytopenia Absent Radii syndrome: a rare presentation. Eur J Obstet Gynecol Reprod Biol. 2008;139:257–8. [PubMed: 17537565]
  2. 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]
  3. Bot-Robin V, Vaast P, Deruelle P. Exacerbation of thrombocytopenia in a pregnant woman with thrombocytopenia-absent radius syndrome. Int J Gynaecol Obstet. 2011;114:77–8. [PubMed: 21530967]
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Suggested Reading

  1. 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]
  2. Rivers A, Slayton WB. Congenital cytopenias and bone marrow failure syndromes. Semin Perinatol. 2009;33:20–8. [PubMed: 19167578]

Chapter Notes

Revision History

  • 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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