Rare hemorrhagic disorder due to a constitutional thrombocytopenia
-Rare genetic disease
-Rare hematologic disease
Syndrome with limb reduction defects
-Rare bone disease
-Rare developmental defect during embryogenesis
The thrombocytopenia-absent radius syndrome (TAR) is characterized by reduction in the number of platelets and absence of the radius; preservation of the thumb distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such ... The thrombocytopenia-absent radius syndrome (TAR) is characterized by reduction in the number of platelets and absence of the radius; preservation of the thumb distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia (see 227650). Individuals with TAR have low numbers of megakaryocytes, platelet precursor cells that reside in bone marrow, and frequently present with bleeding episodes in the first year of life that diminish in frequency and severity with age. The severity of skeletal anomalies varies from absence of radii to virtual absence of upper limbs, with or without lower limb defects such as malformations of the hip and knee (summary by Albers et al., 2012).
Many skeletal dysplasias have been diagnosed prenatally after the birth of an affected sib. On the other hand, Donnenfeld et al. (1990) performed prenatal diagnosis in a primary (index) case of TAR syndrome. Ultrasound showed bilateral upper limb ... Many skeletal dysplasias have been diagnosed prenatally after the birth of an affected sib. On the other hand, Donnenfeld et al. (1990) performed prenatal diagnosis in a primary (index) case of TAR syndrome. Ultrasound showed bilateral upper limb phocomelia and asymmetric lower limb reduction deficiencies, and cordocentesis showed thrombocytopenia and anemia. Luthy et al. (1979) and Luthy et al. (1981) reported prenatal diagnosis of TAR by fetal radiography and ultrasound, respectively.
Shaw and Oliver (1959) described sibs with absent radii and thrombocytopenia. They suggested that this disorder is distinct from Fanconi pancytopenic syndrome (227650) because there was no hypoplasia of the erythron and the blood disorder was evident in ... Shaw and Oliver (1959) described sibs with absent radii and thrombocytopenia. They suggested that this disorder is distinct from Fanconi pancytopenic syndrome (227650) because there was no hypoplasia of the erythron and the blood disorder was evident in the first few months of life. The rare condition had been reported in sibs by Gross et al. (1956). In other reported cases congenital heart disease and renal malformations were found. Thrombocytopenia usually gives rise to symptoms early in life but is transient. Thus, the process is a more benign one than is Fanconi panmyelopathy, in which leukemia is a further complication. Other differences from Fanconi disease include the absence of particular change in the thumb, of pigmentary abnormalities, and of chromosomal breaks. In a family studied at the Johns Hopkins Hospital, Hall et al. (1969), who gave the name and acronym to this syndrome, described 4 affected sisters. One with tetralogy of Fallot had died. The oldest was alive at age 27 and had 2 normal children. The occurrence of hypoplastic radius and hypoplastic thrombocytopenia with trisomy 18 (Rabinowitz et al., 1967) is of interest although a relationship to the mendelizing syndrome is doubtful. Cow's milk intolerance is said to occur frequently in the TAR syndrome (Whitfield and Barr, 1976). Van Allen et al. (1982) showed that the radial artery is present (but with an abnormal course) in the TAR syndrome, suggesting that the radial aplasia is primary; in other forms of radial aplasia, abnormality of the blood supply appeared to be primary. Anyane-Yeboa et al. (1985) described an infant with the most severe expression in the limbs, tetraphocomelia, simulating thalidomide embryopathy. Pfeiffer and Haneke (1975) reported a similar case. The occurrence of cleft lip and palate in association with skeletal changes such as absent radius suggests Roberts syndrome (268300) or SC phocomelia (269000) rather than TAR syndrome. Clefting must be rare in TAR syndrome. Abnormalities in the legs are frequent (Ray et al., 1980; Schoenecker et al., 1984) and may be severe (e.g., Anyane-Yeboa et al., 1985). Feingold et al. (1980) pointed out the occurrence of nonpitting dorsal pedal edema in the newborn period and excessive perspiration. The patient reported by van Haeringen et al. (1989) showed, in addition to absent radii and intermittent thrombocytopenia, cleft of the soft palate, subcricoid stenosis, duodenal atresia, and sensitivity to x-rays. In addition to reviewing the manifestations of this syndrome, Hall (1987) announced the organization of a parent support group called TARSA (Thrombocytopenia Absent Radius Syndrome Association). Homans et al. (1988) found that megakaryocyte colony growth in vitro was virtually absent in optimally stimulated cultures of a patient's bone marrow progenitors, whereas erythroid and myeloid colony growth was preserved. Staining of the patient's bone marrow smears with antiserum against platelet membrane glycoproteins detected no immature, small megakaryocyte precursors. A high level of megakaryocyte colony stimulating activity, comparable to the levels present in sera from adults with aplastic anemia, was detected in the serum from the TAR infant. The elevated serum activity decreased by 6 months of age at which time partial platelet recovery had occurred. Ashinoff and Geronemus (1990) described a patient with the TAR syndrome and a very large port-wine stain involving the right half of the face, scalp, neck, and chest. Flashlamp-pumped pulsed dye laser (PDL) was considered the treatment of choice for port-wine stains. However, they observed no beneficial effect after 3 treatments and postulated that severe thrombocytopenia prevented the formation of platelet thrombi, thus inhibiting the action of the PDL. Among the children of second cousins of Mayan ancestry, Ceballos-Quintal et al. (1992) described a TAR-like syndrome. The sib described in detail had, in addition to the usual abnormalities of TAR syndrome, depressed nasal bridge, cataracts, glaucoma, megalocornea, and blue sclerae. Greenhalgh et al. (2002) reported the results of a clinical study of 34 patients with TAR syndrome. All patients had documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% intolerance to cow's milk, 23% renal anomalies, and 15% cardiac anomalies. Congenital anomalies also included facial capillary hemangiomata, intracranial vascular malformation, sensorineural hearing loss, and scoliosis. Menghsol et al. (2003) reported a patient with TAR syndrome who also had coarctation of the aorta and axial rotation of the kidney. He died at approximately 3 weeks of age from cardiorespiratory arrest due to pneumonia and sepsis. Postmortem examination showed left ventricular hypertrophy and subendocardial fibrosis in addition to coarctation of the aorta. Other findings included adducted thumbs, radial aplasia, hypoplasia of the cerebellar vermis, and axial malrotation of the kidney, which is thought to result from abnormal migration during fetal development. Skorka et al. (2005) reported a female infant with TAR syndrome and complete agenesis of the corpus callosum, hypoplasia of the cerebellum, and horseshoe kidney. She had cow's milk allergy, complex partial seizures with secondary generalization, and severe psychomotor retardation. She died at age 5 years of multiorgan failure following prolonged seizures. Skorka et al. (2005) concluded that cerebral dysgenesis is part of the TAR phenotype.
Given the unclear inheritance and frequently sporadic nature of TAR syndrome, Klopocki et al. (2007) searched for genomic aberrations in 30 patients with TAR syndrome and their families, using high-resolution microarray-based comparative genomic hybridization (rearray CGH). They identified ... Given the unclear inheritance and frequently sporadic nature of TAR syndrome, Klopocki et al. (2007) searched for genomic aberrations in 30 patients with TAR syndrome and their families, using high-resolution microarray-based comparative genomic hybridization (rearray CGH). They identified a common 200-kb deletion on the long arm of chromosome 1 in all the affected individuals and in 25 (32%) of 78 unaffected family members. The results indicated that TAR syndrome is associated with a microdeletion on 1q21.1 that is necessary but not sufficient to cause the phenotype. They postulated that the phenotype develops only in the presence of an additional modifier (mTAR). The TAR deletion does not overlap with the deletion on 1q21.1 identified in another syndrome of mental retardation and congenital anomalies (see 612474). Albers et al. (2012) reported that 51 of 55 cases of TAR syndrome had a 200-kb deletion on 1q21 while 2 had a truncation (605313.0004) or frameshift (605313.0003) (null) mutation in the RBM8A gene on 1 allele. Of these 53 cases, all had 1 of 2 low-frequency SNPs in regulatory regions of RBM8A on the other allele. The likelihood that this mode of inheritance happened by chance is less than 5 x 10(-228). Klopocki et al. (2007) had demonstrated that an inherited or de novo deletion on chromosome 1q21.1 is found in the majority of individuals with TAR syndrome, but the apparent autosomal recessive nature of this syndrome required the existence of an additional causative allele. To identify the additional causative allele, Albers et al. (2012) selected 5 individuals with TAR of European ancestry who had the 1q21.1 deletion and sequenced their exomes, but were unable to find TAR-associated coding mutations in any gene. However, 4 of the cases carried the minor allele of a low-frequency SNP in the 5-prime UTR of the RBM8A gene (dbSNP rs139428292; 605313.0001), while the remaining case carried a previously unknown SNP in the first intron of the same gene (605313.0002). Genotyping by Sanger sequencing of another 48 cases of European ancestry identified the 2 SNPs in 35 and 11 samples, respectively. A mother of non-European ancestry with TAR and her fetus, aborted on the grounds of prenatal diagnosis of TAR, both did not carry the 5-prime UTR or the intronic SNP, and Albers et al. (2012) suggested that in this instance there was a different causative allele. In the 25 trios where the deletion in the child was not a de novo event, Albers et al. (2012) confirmed that the deletion and the newly identified SNPs were inherited from different parents. The minor allele frequency of the 5-prime UTR and intronic SNPs were 3.05% and 0.42%, respectively, in 7,504 healthy individuals of the Cambridge BioResource, and the deletion was absent from 5,919 shared healthy controls of the Wellcome Trust Case Control Consortium. There were 2 TAR cases who did not carry the 1q21.1 deletion but were found to carry the 5-prime UTR SNP. Albers et al. (2012) identified a 4-bp frameshift insertion at the start of the fourth exon (605313.0003) in the first case and established that the noncoding SNP and insertion were on different chromosomes; in the second case, they identified a nonsense mutation in the last exon of RBM8A (605313.0004). Both mutations were absent from 458 exome samples of the 1000 Genomes Project and 416 samples from the Cohorte Lausannoise. Albers et al. (2012) concluded that in the vast majority of cases, compound inheritance of a rare null allele (containing a deletion, frameshift mutation, or encoded premature stop codon) and 1 of 2 low-frequency noncoding SNPs in RBM8A causes TAR syndrome. Albers et al. (2012) showed that the 2 regulatory SNPs result in diminished RBM8A transcription in vitro and that expression of Y14 (a subunit of the exon junction complex (EJC) encoded by the RBM8A gene) is reduced in platelets from individuals with TAR. Albers et al. (2012) concluded that their data implicated Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome. - Exclusion Studies Strippoli et al. (1998) screened the coding and promoter regions of the gene encoding the thrombopoietin receptor (TPOR; 159530) in 4 unrelated patients affected by TAR syndrome and found no mutations.
The diagnosis of thrombocytopenia absent radius (TAR) syndrome is established by the combination of:...
DiagnosisClinical 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 allele has a hypomorphic allele (partial loss of gene function) in the noncoding region of R8BM8A.In 51 of 53 affected individuals with the 200-kb contiguous gene deletion including RBM8A, the second RBM8A allele was found to have a hypomorphic mutation that diminished (but did not abolish) transcript and protein levels [Albers et al 2012]. Two hypomorphic mutations have been identified and both are in noncoding regions of RBM8A. (See Table 1 and Molecular Genetics). Two of 53 affected individuals without the 200-kb deletion had biallelic mutations within RBM8A: one was an inactivating mutation (nonsense or frameshift) and the second was a known hypomorphic mutation [Albers et al 2012]. 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 SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityRBM8ADeletion / duplication analysis 2200-kb minimally deleted region at 1q21.1 that includes RBM8A3, 4~95% ClinicalSequence analysisSequence variants in coding and noncoding regions 5~3% 6Targeted mutation analysis c.-21G>A, c.67+32G>C 7100% for the targeted mutations1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Testing that identifies deletions/duplications not readily 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. 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. See Molecular Genetics for a molecular description of the region.5. Noncoding regions where hypomorphic mutations have been identified include the 5’ UTR and intron one of RBM8A (see Molecular Genetics).6. Heterozygous RBM8A hypomorphic mutations identified in 51/53 affected individuals with the 200-kb deletion and biallelic RBM8A mutations 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.7. The two known hypomorphic mutant alleles (see Molecular Genetics).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 mutation for confirmation of the diagnosis and/or genetic counseling purposes.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with the 200-kb minimally deleted region at 1q21.1. Recurrent deletion or duplication of nearby DNA segments at 1q21.1 gives rise to the variable phenotypes associated with 1q21.1 deletion/duplication [Brunetti-Pierri et al 2008, Mefford et al 2008] (see 1q21.1 Microdeletion). Occasionally, these rearrangements may extend into the 200-kb minimally deleted TAR locus. See Molecular Genetics.No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in RBM8A.
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]....
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].
The following conditions, which include radial aplasia as a component manifestation, can show some overlap with TAR syndrome: ...
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) 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, ocular hypertelorism, 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, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; 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 to 48 years, the estimated cumulative incidence of bone marrow failure is 90%; the incidence of hematologic malignancies (primarily acute myeloid leukemia) 10%-33%; and of nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract) 28%-29%.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 triphalangeal thumb, anal anomalies (including imperforate anus), ear anomalies and/or preauricular tags, and occasional renal anomalies. 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with thrombocytopenia absent radius (TAR) syndrome, the following evaluations are recommended:...
Management Evaluations Following Initial DiagnosisTo establish the extent of disease 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 thumbsOrthopedic evaluation of both upper and lower limbsEchocardiography to assess for cardiac anomaliesEvaluation of renal structure and functionGenetics consultationTreatment of ManifestationsThe treatment of thrombocytopenia is platelet support. Bone marrow transplantation is generally not indicated, given the transient nature of the thrombocytopenia.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 ManifestationsAvoidance of cow’s milk lessens the severity of gastroenteritis and thrombocytopenia (in older children).Prevention of Secondary ComplicationsFrequent 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.SurveillancePlatelet count is indicated whenever evidence of increased bleeding tendency (bruising, petechiae) occurs.Agents/Circumstances to AvoidAvoid cow’s milk to reduce the severity of gastroenteritis and associated thrombocytopenia (in older children).Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementFewer 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 Clinical Trials.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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDNot applicable1q21.1Not applicable RBM8A1q21.1RNA-binding protein 8ARBM8AData 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) View in own window 274000THROMBOCYTOPENIA-ABSENT RADIUS SYNDROME; TAR 605313RNA-BINDING MOTIF PROTEIN 8A; RBM8AMolecular Genetic PathogenesisWith 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, as 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 mutations 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 rarely reported. 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 3.5%, 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).RBM8ANormal allelic variants. 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]. 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 thought that the RBM8B locus is a pseudogene. Two alternative start codons result in two forms of the protein, and this gene also uses multiple polyadenylation sites [provided by RefSeq, Jul 2008]Pathologic allelic variants. The minimally deleted segment is a 200-kb region at 1q21.1 encompassing RBM8B 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 mutation in the 5’ UTR and 12 had the intron 1 mutation c.67+32G>C [Albers et al 2012].Table 2. RBM8A Pathologic Allelic Variants Discussed in This GeneReviewView in own windowClass of Variant AlleleDNA Nucleotide Change & Description 1Genome Coordinates 1 (GRCh37/hg19 assembly)Hypomorphic allelesNM_005105.3: c.-21G>A 1 (in 5’ UTR) (rs139428292)G/A, Chr1:145507646c.67+32G>C (intron 1)G/C, Chr1:145507765Inactivating alleles4-bp insertion in exon 4AGCG, Chr1:145508476Nonsense mutation in exon 6C-T, Chr1:145509173See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 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.