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Alpha-Thalassemia X-Linked Intellectual Disability Syndrome

Synonyms: ATRX Syndrome; Alpha Thalassemia/Mental Retardation, X-Linked
, MD, FACMG
Clinical Genetics and Cytogenetics
Greenwood Genetic Center
Greenwood, South Carolina

Initial Posting: ; Last Update: November 6, 2014.

Summary

Clinical characteristics.

Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is characterized by distinctive craniofacial features, genital anomalies, severe developmental delays, hypotonia, intellectual disability, and mild-to-moderate anemia secondary to alpha-thalassemia. Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short nose, tented vermilion of the upper lip, and thick or everted vermilion of the lower lip with coarsening of the facial features over time. Although all affected individuals have a normal 46,XY karyotype, genital anomalies range from hypospadias and undescended testicles to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Global developmental delays are evident in infancy and some affected individuals never walk independently or develop significant speech.

Diagnosis/testing.

The diagnosis of ATRX syndrome is established in individuals with somatic abnormalities, intellectual disability, hypotonia, abnormal hemoglobin H production, and a family history consistent with X-linked inheritance. ATRX is the only gene in which mutation causes ATRX syndrome.

Management.

Treatment of manifestations: Calorie-dense formula and/or gavage feeding as needed for adequate nutrition; anticholinergics, botulinum toxin type A injection of the salivary glands, and/or surgical redirection of the submandibular ducts for excessive drooling; early intervention programs and special education.

Prevention of secondary complications: Antibiotic prophylaxis and vaccination to prevent pneumococcal and meningococcal infection in those with asplenia.

Surveillance: Regular assessment of growth in infancy and childhood; regular monitoring of developmental progress.

Other: Anemia rarely requires treatment.

Genetic counseling.

ATRX syndrome is inherited in an X-linked manner. The mother of a proband may be a carrier or the affected individual may have a de novo mutation. Carrier women have a 50% chance in each pregnancy of transmitting the ATRX pathogenic variant; offspring with a 46,XY karyotype who inherit the ATRX pathogenic variant will be affected; offspring with a 46,XX karyotype who inherit the pathogenic variant are unaffected female carriers. Affected individuals do not reproduce. Carrier testing for at-risk females and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.

Diagnosis

Diagnosis of alpha-thalassemia X-linked intellectual disability (ATRX) syndrome should be suspected in individuals with the following:

  • Characteristic craniofacial features, including telecanthus or widely spaced eyes, short nose, tented vermilion of the upper lip, and thick or everted vermilion of the lower lip with coarsening of the facial features over time
  • Microcephaly
  • Genital anomalies, including hypospadias and undescended testes, ambiguous genitalia, or normal external female genitalia in a 46,XY individual
  • Skeletal anomalies, including short stature, brachydactyly, tapering fingers, clinodactyly, digital contractures, overlapping digits, pes planus, varus and valgus foot deformations, pectus carinatum, kyphosis, scoliosis, and dimpling over the lower spine
  • Laboratory findings of alpha-thalassemia
  • Intellectual disability, typically in the severe to profound range

Because the phenotypic findings (with the exception of alpha-thalassemia) overlap with those of other syndromes, clinical diagnosis should be confirmed by molecular genetic testing.

Testing

Affected individuals. Hematologic studies show evidence of alpha-thalassemia in approximately 85% of affected individuals with a 46,XY karyotype who have an ATRX pathogenic variant [Gibbons et al 2008].

  • Red blood cell indices. Although microcytic hypochromic anemia may be seen in some affected individuals, many have red cell indices in the normal range [Gibbons et al 1995a].
  • HbH inclusions (β-globin tetramers) in erythrocytes can be demonstrated following incubation of fresh blood smears with 1% brilliant cresyl blue (BCB). The proportion of cells with HbH inclusions ranges from 0.01% to 30% [Gibbons et al 1995b].
    Note: (1) HbH inclusions may be demonstrated readily in some individuals, found only in an occasional erythrocyte in some, or observed only after repeated testing in others. (2) The absence of HbH inclusions in 10%-20% of affected individuals and the rarity of inclusions (≤1% of erythrocytes) in an additional 40% of affected individuals diminish the utility of this testing in most clinical settings.
  • Hemoglobin electrophoresis can also demonstrate HbH; however, the test is not highly sensitive and may fail to identify many cases. Rare cases of ATRX syndrome have been identified through the detection of HgH on newborn screening for hemoglobinopathies.

Female carriers. HbH inclusions are found in about 25% of female carriers [Gibbons et al 1995b].

The diagnosis of ATRX syndrome is established in a proband by molecular genetic testing (see Table 1).

One genetic testing strategy is molecular genetic testing of ATRX.

  • Sequencing of the ATRX zinc finger domain (also designated the PHD and ADD domain) and helicase domain detects more than 80% of pathogenic variants (exons 7, 8, 9, and 17-20 inclusively).
  • A second level of molecular testing includes full-gene sequencing or cDNA sequencing to detect exonic and splice mutations outside the zinc finger and helicase domains.
  • Duplication/deletion analysis may be required to identify whole-exon and whole-gene deletions or duplications and to delineate smaller deletions and duplications not readily resolved by sequencing.
  • Although staining of erythrocytes with BCB to identify HbH inclusions has been a helpful and inexpensive adjunct to diagnosis in the past, its utility is diminished by the fact that in 10%-20% of affected individuals, erythrocytes do not have these inclusions and in 40% of affected individuals, no more than 1% of erythrocytes have these inclusions. Nonetheless, the test may be useful in supporting the diagnosis in individuals with clinical findings of ATRX syndrome in whom molecular genetic testing does not identify a pathogenic variant.

An alternative genetic testing strategy is use of a multi-gene panel that includes ATRX and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Genomic testing. If single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of ATRX syndrome, genomic testing may be considered. Such testing may include whole exome sequencing (WES), whole genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

Notes regarding WES and WGS: (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations cannot be detected; (4) deletions/duplications larger than 8-10 nucleotides are not detected effectively [Biesecker & Green 2014].

Notes regarding WmitoSeq: (1) Pathogenic mtDNA variants present at low levels of heteroplasmy in blood may not be detected in DNA extracted from blood and may require DNA extracted from skeletal muscle; (2) mtDNA deletions/duplications may not be detected effectively.

Gene. ATRX is the only gene known to be associated with ATRX syndrome.

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Alpha-Thalassemia X-Linked Intellectual Disability Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
Affected Males 2Carrier Females
ATRXSequence analysis of select exons 3, 485% 5See footnote 6
Sequence analysis / mutation scanning 795% 5See footnote 6
Deletion/duplication analysis 8, 9<5% 5Unknown
X-chromosome inactivation studyNA 1095% of carrier females 11
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Approximately 25% of individuals tested on the basis of suggestive clinical findings have the diagnosis confirmed by gene testing [Badens et al 2006a].

3.

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.

4.

Sequence analysis of exon 7, exon 8, proximal area of exon 9, and the helicase domains (exons 17-20) detects approximately 90% of known ATRX pathogenic variants [Villard & Fontes 2002, Badens et al 2006a, Argentaro et al 2007].

5.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

6.

Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

7.

Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

8.

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.

9.

Only a few deletions and duplications in affected males and carrier females have been identified [Gibbons et al 2008, Lugtenberg et al 2009].

10.

Not applicable

11.

Greater than 95% of carrier females have marked skewing of X-chromosome inactivation (>90:10). However, non-random X-chromosome inactivation is not unique to ATRX syndrome; thus, the finding of skewed X-chromosome inactivation is not diagnostic and must be used in the context of clinical findings.

Clinical Characteristics

Clinical Description

A more or less distinctive phenotype has emerged from the study of individuals with alpha-thalassemia X-linked intellectual disability (ATRX) syndrome.

Craniofacial, genital, and developmental manifestations are prominent among the most severely affected individuals [Gibbons et al 1995a, Badens et al 2006a, Stevenson et al 2012]. As clinical experience with the condition has increased and additional individuals/families have been evaluated using molecular genetic testing, the range of phenotypic variability has broadened, particularly on the mild end of the spectrum. Findings by Guerrini et al [2000] and Yntema et al [2002] confirm this. Both describe families within which affected males have mild, moderate, or profound intellectual disability. Adults in the family described by Yntema et al [2002] appeared to have nonsyndromic XLID, although childhood photographs showed evidence of facial hypotonia. Basehore et al [2014] reported 25 affected males in five families with a p.Arg37Ter mutation who had variable but overall milder phenotypes.

A recognizable pattern of craniofacial findings includes small head circumference, upsweep of the frontal hair, telecanthus or widely spaced eyes, short triangular nose with high insertion of the columella, tented vermilion of the upper lip, thick or everted vermilion of the lower lip, and open mouth. Irregular anatomy of the pinnae, widely spaced teeth, and protruding tongue are supplemental findings, the latter two adding to a coarseness of the facial appearance, particularly after the first few years of life.

The external genitalia are usually abnormal. The anomalies are often minor, including first-degree hypospadias, undescended testes, and underdevelopment of the scrotum. More severe defects are second- and third-degree hypospadias, small penis, and ambiguous genitalia. Although all individuals with ATRX syndrome have a normal 46,XY karyotype, occasionally gonadal dysgenesis results in inadequate testosterone production and ambiguous genitalia or even normal-appearing female external genitalia. Although the spectrum of possible genital anomalies in ATRX syndrome is broad, the type of genital anomaly appears to be consistent within a family.

Stature is typically short (>2 SD below the mean in 67% of individuals using standard growth charts; syndrome-specific growth charts are not available). Short stature may be accompanied by minor skeletal anomalies (brachydactyly, clinodactyly, tapered digits, joint contractures, pectus carinatum, kyphosis, scoliosis, dimples over the lower spine, varus and valgus foot deformation, and pes planus).

Major malformations are not common, but ocular coloboma, cleft palate, cardiac defects, inguinal hernia, heterotaxy, and asplenia [Leahy et al 2005] have been reported.

The severe developmental impairment and intellectual disability are the most important clinical manifestations. From the outset, developmental milestones are globally and markedly delayed. Speech and ambulation occur late in childhood. Some affected individuals never walk independently or develop significant speech.

Hypotonia is a hallmark of the condition, contributing to the facial manifestations, drooling, and developmental delays. Seizures occur in approximately one third of individuals [Gibbons et al 1995a].

The majority of affected individuals have gastrointestinal symptoms that contribute significantly to morbidity. Approximately three fourths have gastroesophageal reflux and one third have chronic constipation. Gastric pseudo-obstruction resulting from abnormal suspension of the stomach and constipation resulting from colon hypoganglionosis have been observed [Martucciello et al 2006]. Aspiration, presumably related to gastroesophageal reflux, has been a fatal complication in some.

Although the neurobehavioral phenotype has not been extensively delineated, most individuals appear affable, but some are emotionally labile with tantrums and bouts of prolonged crying or laughing.

Alpha-thalassemia. A microcytic, hypochromic anemia characteristic of alpha-thalassemia may be seen, but many individuals with ATRX syndrome have normal red cell indices and normal hematocrit/hemoglobin. Pathogenic variants in ATRX apparently downregulate α-globin gene expression in those individuals with HbH inclusions.

Genotype-Phenotype Correlations

Badens et al [2006a] found that pathogenic variants that affect the ATRX zinc finger domain produce severe psychomotor impairment and urogenital anomalies, whereas pathogenic variants in the helicase domains cause milder phenotypes. A nonsense mutation in exon 2 (p.Arg37Ter) appears to be a common pathogenic variant that results in an overall milder phenotype [Guerrini et al 2000, Abidi et al 2005, Basehore et al 2014].

Heterozygous females rarely show clinical manifestations.

  • Badens et al [2006b] reported a girl conceived by in vitro fertilization (IVF) who had craniofacial features, growth retardation, and developmental impairment typical of ATRX syndrome. Leukocyte studies showed marked skewing of X-chromosome inactivation with her pathogenic variant-bearing X chromosome being the active X chromosome. The role of IVF in this unique case of female expression is not known.
  • Wada et al [2005] reported moderate intellectual disability without other phenotypic features of ATRX syndrome in a female carrier with random X-chromosome inactivation.

Penetrance

Penetrance is presumed to be 100% in males as ATRX mutation has not been reported in normal males.

Nomenclature

"Alpha-thalassemia X-linked intellectual disability syndrome" and "ATRX syndrome" are the preferred designations for this disorder.

Carpenter-Waziri syndrome, Holmes-Gang syndrome, Chudley-Lowry syndrome and XLID-arch fingerprints-hypotonia syndrome are allelic, each reported in a single family, and clinically similar to ATRX syndrome [Stevenson et al 1997, Abidi et al 1999, Stevenson et al 2000, Abidi et al 2005]; they are now considered to be in the phenotypic spectrum of ATRX syndrome and thus no compelling reason remains to retain their names.

Such is not the case for Juberg-Marsidi syndrome and Smith-Fineman-Myers syndrome (see Genetically Related Disorders).

Prevalence

The prevalence is not known. More than 200 affected individuals are known to the laboratories conducting molecular genetic testing; substantial under-ascertainment, especially of those with milder phenotypes, is probable.

No racial or ethnic concentration of individuals has been reported.

Differential Diagnosis

Coffin-Lowry syndrome (CLS) is usually characterized by severe to profound intellectual disability in males and normal intelligence to profound intellectual disability in heterozygous females. The facial appearance is characteristic in the affected older male child or adult. The hands are short, soft, and fleshy, often with remarkably hyperextensible tapering fingers. Short stature, microcephaly, and dental anomalies are common. Childhood-onset stimulus-induced drop attacks (SIDAs) in which unexpected tactile or auditory stimuli or excitement triggers a brief collapse but no loss of consciousness are present in approximately 20% of individuals. Progressive kyphoscoliosis and early mortality are seen. Pathogenic variants in RPS6KA3 are causative. Inheritance is X linked.

MECP2 duplication syndrome is characterized by severe intellectual disability, spasticity, infantile hypotonia, absent or limited speech, seizures, and recurrent respiratory infections [Friez et al 2006]. In addition to the core features, autistic behaviors and gastrointestinal dysfunction have been observed in several affected boys. Half of affected males die by early adulthood. Marked skewing of X-chromosome inactivation occurs in most carrier females. The face is not as characteristically hypotonic as in ATRX syndrome, nor does microcephaly occur as commonly. Duplications of MECP2 ranging from 0.3 to 4 Mb are found in all affected males. Inheritance is X-linked.

Alpha-thalassemia. Hemoglobin H (HbH) disease, one of the two clinically significant forms of alpha-thalassemia, is characterized by microcytic hypochromic hemolytic anemia, hepatosplenomegaly, mild jaundice, and sometimes thalassemia-like bone changes; it results from reduced production of the α chains of adult hemoglobin (designated Hb α2β2). In individuals with developmental delay who are of Mediterranean, Southeast Asian, or African American origin, it is appropriate to determine the α-globin genotype. Individuals with ATRX syndrome have a normal α-globin genotype (αα/αα), whereas those with HbH disease have deletion or dysfunction of three of four α-globin alleles. Intellectual disability is not a component of alpha-thalassemia involving α-globin production.

Alpha-thalassemia mental retardation chromosome 16 (ATR-16) (OMIM 141750) is the association of alpha-thalassemia and intellectual disability in individuals with a contiguous gene deletion involving the distal short arm of chromosome 16. Such deletions produce alpha-thalassemia by deleting the two genes in cis configuration at 16p13 that encode α-globin chains. Because the chromosomal deletions and rearrangements giving rise to ATR-16 are large and variable, no specific clinical phenotype is observed in ATR-16; this is in contrast to ATRX syndrome, in which the phenotype is more predictable.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with alpha-thalassemia X-linked intellectual disability (ATRX) syndrome, the following evaluations are recommended:

  • Review of medical history for developmental progress and seizures
  • Assessment of growth in infants and children
  • Physical examination including assessment of facial features, muscle tone, and deep tendon reflexes
  • Assessment of cognitive and adaptive functions by neuropsychological testing
  • Auscultation of the heart for evidence of structural defect
  • Examination of the genitalia for cryptorchidism and other anomalies
  • Assessment of feeding in early childhood for swallowing difficulties, gastroesophageal reflux, and/ or recurrent vomiting
  • Ophthalmologic evaluation for strabismus, visual acuity problems, or structural eye defects if indicated by clinical assessment
  • Medical genetics consultation

Treatment of Manifestations

The following treatments are recommended:

  • Calorie-dense formula and/or gavage feeding to compensate for poor nutritional intake
  • If food refusal is an issue, evaluation for gastrointestinal causes such as peptic ulcer disease
  • If drooling is a serious problem, treatment with anticholinergics, botulinum toxin type A injection of the salivary glands and/or surgical redirecting of the submandibular ducts
  • Treatment in the usual manner for gastroesophageal reflux, recurrent respiratory and urinary tract infections, seizures, severe behavior problems, anomalies (e.g., cleft palate, cardiac malformations, cryptorchidism, ambiguous genitalia, hypospadias)
  • Early intervention programs and special education for developmental delays

Prevention of Secondary Complications

Antibiotic prophylaxis and vaccination to prevent pneumococcal and meningococcal infection are reasonable precautions in the rare patient with asplenia [Leahy et al 2005].

Surveillance

Growth should be followed regularly in infancy and childhood and plotted on age-appropriate growth charts. (Syndrome-specific growth charts are not available.)

Developmental progress should be monitored throughout infancy and childhood.

Evaluation of Relatives at Risk

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

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.

Other

Anemia, if present, is mild and rarely requires treatment.

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

Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

  • In a family with more than one affected individual, the mother of an affected individual is an obligate carrier of an ATRX pathogenic variant.
  • In families with only one affected individual, the mother may be a carrier or the affected individual may have ATRX syndrome as a result of de novo mutation. No data on the frequency of de novo mutation in this condition are available.

Sibs of a proband

  • The risk to sibs of a proband depends on the carrier status of the mother.
  • If the mother of the proband has a pathogenic variant, the chance of transmitting it is 50% in each pregnancy. Sibs with a 46,XY karyotype who inherit the pathogenic variant will be affected; sibs with a 46,XX karyotype who inherit the pathogenic variant are female carriers and will not be affected.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the ATRX pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism. Maternal mosaicism (somatic and germline) for a pathogenic variant of ATRX has resulted in recurrent ATRX syndrome in two brothers [Shimbo et al 2014].

Offspring of a proband. No affected individual has reproduced.

Other family members of a proband. The proband's maternal aunts and their offspring may be at risk of being carriers or being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the ATRX pathogenic variant has been identified 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, or are at risk of being carriers.

Assisted reproduction technologies (ART). Donor eggs may be utilized by carrier females to avoid the risk of transmitting an ATRX pathogenic variant. Although experience with ART in ATRX syndrome is limited, one female conceived by IVF had total inactivation of her normal X chromosome and the physical and psychomotor findings typical of ATRX syndrome in males [Badens et al 2006b].

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

If the ATRX pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

High-risk pregnancies. For pregnancies in which the mother has been identified as being heterozygous for the ATRX pathogenic variant identified in the family, the usual procedure is to determine fetal sex on cells obtained from amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation). If the fetus has a 46,XY karyotype, DNA can be analyzed to determine if the ATRX pathogenic variant identified in the family is present.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Indeterminate-risk pregnancies. Germline mosaicism has been documented in ATRX syndrome [Bachoo & Gibbons 1999, Shimbo et al 2014]; thus, the mother of a proband who does not demonstrate the ATRX pathogenic variant in her leukocytes is still at risk of having a second affected child. Prenatal diagnosis as described for high-risk pregnancies should be offered for all XY fetuses.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the ATRX pathogenic variant has 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.

  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 202-387-1968
    Fax: 202-387-2193
    Email: sis@aaidd.org
  • Medline Plus

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.

Alpha-Thalassemia X-Linked Intellectual Disability Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
ATRXXp11​.21-q22.3Transcriptional regulator ATRXATRX @ LOVDATRX

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 Alpha-Thalassemia X-Linked Intellectual Disability Syndrome (View All in OMIM)

300032ATR-X GENE; ATRX
301040ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED; ATRX

Gene structure. The gene extends over 350 kb and includes 35 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Although pathogenic variants have been distributed throughout ATRX, more than 90% of those reported are in regions encoding the zinc finger and helicase domains [Villard et al 1999b, Villard & Fontes 2002, Borgione et al 2003, Badens et al 2006a, Argentaro et al 2007, Thienpont et al 2007]. Missense mutations appear more commonly than do frameshift and nonsense mutations. Deletions, insertions, intragenic duplications, and missense, nonsense, and splice mutations have been found (for more information, see Table A).

Table 2.

ATRX Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.109C>Tp.Arg37TerNM_000489​.4
NP_000480​.3

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.

Normal gene product. Zinc finger domain functions as a transcription factor; the helicase domains function in the transcription process opening double-stranded DNA. In combination with other chromatin-associated proteins, the ATRX protein appears to play a role in chromatin remodeling, possibly silencing gene expression during development [Xue et al 2003, Ausió et al 2003, Tang et al 2004a, Tang et al 2004b, Kernohan et al 2010].

Abnormal gene product. The mutant ATRX protein downregulates the α-globin locus, resulting in thalassemia, and probably suppresses expression of other genes by disturbances in transcription and chromatin structure, leading to malformations and intellectual disability [Tang et al 2004a, Tang et al 2004b, Argentaro et al 2007, Nan et al 2007, Ritchie et al 2008, Kernohan et al 2010].

References

Literature Cited

  1. Abidi F, Schwartz CE, Carpenter NJ, Villard L, Fontés M, Curtis M. Carpenter-Waziri syndrome results from a mutation in XNP. Am J Med Genet. 1999;85:249–51. [PubMed: 10398237]
  2. Abidi FE, Cardoso C, Lossi AM, Lowry RB, Depetris D, Mattéi MG, Lubs HA, Stevenson RE, Fontes M, Chudley AE, Schwartz CE. Mutation in the 5' alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome. Eur J Hum Genet. 2005;13:176–83. [PubMed: 15508018]
  3. Argentaro A, Yang JC, Chapman L, Kowalczyk MS, Gibbons RJ, Higgs DR, Neuhaus D, Rhodes D. Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX. Proc Natl Acad Sci U S A. 2007;104:11939–44. [PMC free article: PMC1924575] [PubMed: 17609377]
  4. Ausió J, Levin DB, De Amorim GV, Bakker S, Macleod PM. Syndromes of disordered chromatin remodeling. Clin Genet. 2003;64:83–95. [PubMed: 12859401]
  5. Bachoo S, Gibbons RJ. Germline and gonosomal mosaicism in the ATR-X syndrome. Eur J Hum Genet. 1999;7:933–6. [PubMed: 10602370]
  6. Badens C, Lacoste C, Philip N, Martini N, Courrier S, Giuliano F, Verloes A, Munnich A, Leheup B, Burglen L, Odent S, Van Esch H, Levy N. Mutations in PHD-like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome. Clin Genet. 2006a;70:57–62. [PubMed: 16813605]
  7. Badens C, Martini N, Courrier S, DesPortes V, Touraine R, Levy N, Edery P. ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern. Am J Med Genet A. 2006b;140:2212–5. [PubMed: 16955409]
  8. Basehore MJ, Michaelson-Cohen R, Levy-Lahad E, Sismani C, Bird LM, Friez MJ, Walsh T, Abidi F, Holloway L, Skinner C, McGee S, Alexandrou A, Syrrou M, Patsalis PC, Raymond G, Wang T, Schwartz CE, King MC, Stevenson RE. Alpha-thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation - c.109C>T (p.R37X). Clin Genet. 2014 May 7. [PubMed: 24805811]
  9. Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;371:1170. [PubMed: 25229935]
  10. Borgione E, Sturnio M, Spalletta A, Angela Lo Giudice M, Castiglia L, Galesi O, Ragusa A, Fichera M. Mutational analysis of the ATRX gene by DGGE: a powerful diagnostic approach for the ATRX syndrome. Hum Mutat. 2003;21:529–34. [PubMed: 12673795]
  11. Friez MJ, Jones JR, Clarkson K, Lubs H, Abuelo D, Bier JA, Pai S, Simensen R, Williams C, Giampietro PF, Schwartz CE, Stevenson RE. Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics. 2006;118:e1687-95. [PubMed: 17088400]
  12. Friez MJ, Brooks SS, Abidi F, Schwartz CE, Stevenson RE. Juberg-Marsidi syndrome and Brooks syndreome are allelic X-linked intellectual disability syndrome due to a HUWE1 mutation. Berlin, Germany: 15th International Workshop on Fragile X and other Early-Onset Cognitive Disorders. 2011.
  13. Gibbons RJ, Brueton L, Buckle VJ, Burn J, Clayton-Smith J, Davison BC, Gardner RJ, Homfray T, Kearney L, Kingston HM, Newbury-Ecob R, Porteous MEP, Wilkie AOM, Higgs DR. Clinical and hematologic aspects of the X-linked alpha-thalassemia/mental retardation syndrome (ATR-X). Am J Med Genet. 1995a;55:288–99. [PubMed: 7726225]
  14. Gibbons RJ, Picketts DJ, Villard L, Higgs DR. Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell. 1995b;80:837–45. [PubMed: 7697714]
  15. Gibbons RJ, Wada T, Fisher CA, Malik N, Mitson MJ, Steensma DP, Fryer A, Goudie DR, Krantz ID, Traeger-Synodinos J. Mutations in the chromatin-associated protein ATRX. Hum Mutat. 2008;29:796–802. [PubMed: 18409179]
  16. Guerrini R, Shanahan JL, Carrozzo R, Bonanni P, Higgs DR, Gibbons RJ. A nonsense mutation of the ATRX gene causing mild mental retardation and epilepsy. Ann Neurol. 2000;47:117–21. [PubMed: 10632111]
  17. Kernohan KD, Jiang Y, Tremblay DC, Bonvissuto AC, Eubanks JH, Mann MR, Bérubé NG. ATRX partners with cohesin and MeCP2 and contributes to developmental silencing of imprinted genes in the brain. Dev Cell. 2010;18:191–202. [PubMed: 20159591]
  18. Leahy RT, Philip RK, Gibbons RJ, Fisher C, Suri M, Reardon W. Asplenia in ATR-X syndrome: a second report. Am J Med Genet A. 2005;139:37–9. [PubMed: 16222662]
  19. Lossi AM, Millán JM, Villard L, Orellana C, Cardoso C, Prieto F, Fontés M, Martínez F. Mutation of the XNP/ATR-X gene in a family with severe mental retardation, spastic paraplegia and skewed pattern of X inactivation: demonstration that the mutation is involved in the inactivation bias. Am J Hum Genet. 1999;65:558–62. [PMC free article: PMC1377954] [PubMed: 10417298]
  20. Lugtenberg D, de Brouwer AP, Oudakker AR, Pfundt R, Hamel BC, van Bokhoven H, Bongers EM. Xq13.2q21.1 duplication encompassing the ATRX gene in a man with mental retardation, minor facial and genital anomalies, short stature and broad thorax. Am J Med Genet A. 2009;149A:760–6. [PubMed: 19291773]
  21. Martucciello G, Lombardi L, Savasta S, Gibbons RJ. Gastrointestinal phenotype of ATR-X syndrome. Am J Med Genet A. 2006;140:1172–6. [PubMed: 16688741]
  22. Nan X, Hou J, Maclean A, Nasir J, Lafuente MJ, Shu X, Kriaucionis S, Bird A. Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation. Proc Natl Acad Sci U S A. 2007;104:2709–14. [PMC free article: PMC1796997] [PubMed: 17296936]
  23. Ritchie K, Seah C, Moulin J, Isaac C, Dick F, Bérubé NG. Loss of ATRX leads to chromosome cohesion and congression defects. J Cell Biol. 2008;180:315–24. [PMC free article: PMC2213576] [PubMed: 18227278]
  24. Shimbo H, Ninomiya S, Kurosawa K, Wada T. A case report of two brothers with ATR-X syndrome due to low maternal frequency of somatic mosaicism for an intragenic deletion in the ATRX. J Hum Genet. 2014;59:408–410. [PubMed: 24898829]
  25. Stevenson RE, Häne B, Arena JF, May M, Lawrence L, Lubs HA, Schwartz CE. Arch fingerprints, hypotonia, and areflexia associated with X linked mental retardation. J Med Genet. 1997;34:465–9. [PMC free article: PMC1050968] [PubMed: 9192265]
  26. Stevenson RE. Splitting and lumping in the nosology of XLMR. Am J Med Genet. 2000;97:174–82. [PubMed: 11449485]
  27. Stevenson RE, Abidi F, Schwartz CE, Lubs HA, Holmes LB. Holmes-Gang syndrome is allelic with XLMR-hypotonic face syndrome. Am J Med Genet. 2000;94:383–5. [PubMed: 11050622]
  28. Stevenson RE, Schwartz CE, Rogers RC. Atlas of X-Linked Intellectual Disability Syndromes. 2 ed. Oxford, UK: Oxford University Press; 2012:17-19.
  29. Tang J, Wu S, Liu H, Stratt R, Barak OG, Shiekhattar R, Picketts DJ, Yang X. A novel transcription regulatory complex containing death domain-associated protein and the ATR-X syndrome protein. J Biol Chem. 2004a;279:20369–77. [PubMed: 14990586]
  30. Tang P, Park DJ, Marshall Graves JA, Harley VR. ATRX and sex differentiation. Trends Endocrinol Metab. 2004b;15:339–44. [PubMed: 15350606]
  31. Thienpont B, de Ravel T, Van Esch H, Van Schoubroeck D, Moerman P, Vermeesch JR, Fryns JP, Froyen G, Lacoste C, Badens C, Devriendt K. Partial duplications of the ATRX gene cause the ATR-X syndrome. Eur J Hum Genet. 2007;15:1094–7. [PubMed: 17579672]
  32. Villard L, Ades LC, Gecz J, Fontes M. Identification of a mutation in the XNP/ATR-X gene in a Smith-Fineman-Myers family: are ATR-X and SFM allelic syndromes? Strasbourg, France: 9th International Workshop on Fragile X Syndrome and X-Linked Mental Retardation. 1999a.
  33. Villard L, Bonino MC, Abidi F, Ragusa A, Belougne J, Lossi AM, Seaver L, Bonnefont JP, Romano C, Fichera M, Lacombe D, Hanauer A, Philip N, Schwartz C, Fontés M. Evaluation of a mutation screening strategy for sporadic cases of ATR-X syndrome. J Med Genet. 1999b;36:183–6. [PMC free article: PMC1734331] [PubMed: 10204841]
  34. Villard L, Fontes M. Alpha-thalassemia/mental retardation syndrome, X-Linked (ATR-X, MIM #301040, ATR-X/XNP/XH2 gene MIM #300032). Eur J Hum Genet. 2002;10:223–5. [PubMed: 12032728]
  35. Wada T, Sugie H, Fukushima Y, Saitoh S. Non-skewed X-inactivation may cause mental retardation in a female carrier of X-linked alpha-thalassemia/mental retardation syndrome (ATR-X): X-inactivation study of nine female carriers of ATR-X. Am J Med Genet A. 2005;138:18–20. [PubMed: 16100724]
  36. Xue Y, Gibbons R, Yan Z, Yang D, McDowell TL, Sechi S, Qin J, Zhou S, Higgs D, Wang W. The ATRX syndrome protein forms a chromatin-remodeling complex with Daxx and localizes in promyelocytic leukemia nuclear bodies. Proc Natl Acad Sci U S A. 2003;100:10635–40. [PMC free article: PMC196856] [PubMed: 12953102]
  37. Yntema HG, Poppelaars FA, Derksen E, Oudakker AR, van Roosmalen T, Jacobs A, Obbema H, Brunner HG, Hamel BC, van Bokhoven H. Expanding phenotype of XNP mutations: mild to moderate mental retardation. Am J Med Genet. 2002;110:243–7. [PubMed: 12116232]

Suggested Reading

  1. Juberg RC, Marsidi I. A new form of X-linked mental retardation with growth retardation, deafness, and microgenitalism. Am J Hum Genet. 1980;32:714–22. [PMC free article: PMC1686104] [PubMed: 6107045]
  2. McPherson EW, Clemens MM, Gibbons RJ, Higgs DR. X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: a new kindred with severe genital anomalies and mild hematologic expression. Am J Med Genet. 1995;55:302–6. [PubMed: 7726227]
  3. Smith RD, Fineman RM, Myers GG. Short stature, psychomotor retardation, and unusual facial appearance in two brothers. Am J Med Genet. 1980;7:5–9. [PubMed: 7211953]
  4. Stevenson RE, Schwartz CE. Clinical and molecular contributions to the understanding of X-linked mental retardation. Cytogenet Genome Res. 2002;99:265–75. [PubMed: 12900574]
  5. Villard L, Gecz J, Mattei JF, Fontes M, Saugier-Veber P, Munnich A, Lyonnet S. XNP mutation in a large family with Juberg-Marsidi syndrome. Nat Genet. 1996;12:359–60. [PubMed: 8630485]
  6. Villard L, Lossi AM, Cardoso C, Proud V, Chiaroni P, Colleaux L, Schwartz C, Fontes M. Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase. Genomics. 1997;43:149–55. [PubMed: 9244431]

Chapter Notes

Author Notes

Web: Greenwood Genetic Center

Dr. Stevenson's work focuses on the clinical and laboratory delineation of intellectual disability and birth defects.

Revision History

  • 6 November 2014 (me) Comprehensive update posted live
  • 3 June 2010 (me) Comprehensive update posted live
  • 13 August 2009 (cd) Revision: deletion/duplication analysis no longer available clinically
  • 15 October 2007 (me) Comprehensive update posted to live Web site
  • 27 October 2006 (cd) Revision: mutation scanning clinically available
  • 24 March 2006 (cd) Revision: sequence analysis of all 35 exons and associated splice junctions of ATRX clinically available
  • 14 June 2005 (me) Comprehensive update posted to live Web site
  • 15 April 2003 (me) Comprehensive update posted to live Web site
  • 19 June 2000 (me) Review posted to live Web site
  • 29 November 1999 (rs) Original submission
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