Clinical Diagnosis

Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome may be suspected on the basis of characteristic craniofacial, genital, skeletal, and other somatic findings, and laboratory findings of alpha-thalassemia. Of greatest importance clinically is the failure to achieve developmental milestones on schedule. Cognitive function is usually profoundly impaired, although individuals with less severe intellectual disabilities have been reported.

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 mutation [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 only about 25% of female carriers [Gibbons et al 1995b].

Testing Strategy

Confirming the diagnosis in a proband

• Sequencing of the ATRX zinc finger domain (also designated the PHD and ADD domain) and helicase domain detects more than 80% of mutations (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 mutation.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Note: Female carriers are heterozygous for an ATRX mutation but rarely develop clinical findings.

Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

ATRX mutations have been found in several named X-linked mental retardation (XLMR) syndromes (Carpenter-Waziri syndrome, Holmes-Gang syndrome, Chudley-Lowry syndrome), XLMR with spastic paraplegia, XLMR with epilepsy, and nonsyndromic XLMR [Lossi et al 1999, Stevenson 2000, Yntema et al 2002]. These entities should be considered to be in the phenotypic spectrum of ATRX syndrome; there are no compelling reasons to maintain the syndromic names.

ATRX mutations have also been identified in families reported as having Juberg-Marsidi syndrome and Smith-Fineman-Myers syndrome [Villard et al 1999a]. Because ATRX mutations have not been reported in the original families with Juberg-Marsidi syndrome and Smith-Fineman-Myers syndrome, the relationship between ATRX syndrome and these two syndromes is unclear [Schwartz, personal communication 2010]

Natural History

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, Stevenson et al 2000b, Badens et al 2006a]. 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 XLMR, although childhood photographs showed evidence of facial hypotonia.

A recognizable pattern of craniofacial findings includes small head circumference, upsweep of the frontal hair, telecanthus or ocular hypertelorism, small triangular nose with retracted columella, tented upper lip, prominent or everted lower lip, and open mouth. Irregular anatomy of the pinnae, wide spacing of the teeth, and tongue protrusion 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, micropenis, 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.

Short stature is typical and 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). Stature is less than two standard deviations (SD) below the mean in two-thirds of individuals using standard growth charts; syndrome-specific growth charts are not available.

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 retardation. 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. The mutated ATRX gene apparently down-regulates α-globin gene expression in those individuals with HbH inclusions.

Genotype-Phenotype Correlations

Badens et al [2006a] found that mutations in the ATRX zinc finger domain produce severe psychomotor impairment and urogenital anomalies, whereas mutations in the helicase domains cause milder phenotypes.

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 mutation-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 mutations have not been reported in normal males.

Nomenclature

"Alpha-thalassemia X-linked mental retardation syndrome" and "ATRX syndrome" have been the two most widely accepted terms for this disorder; however, the preferred designation alpha-thalassemia X-linked intellectual disability in this GeneReview conforms to current terminology.

Carpenter-Waziri syndrome, Holmes-Gang syndrome, and Chudley-Lowry syndrome are allelic, each reported in a single family, and clinically similar to ATRX syndrome [Abidi et al 1999, Stevenson et al 2000a, 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; ATRX mutations have not been found in the original families with Juberg-Marsadid syndrome or Smith-Fineman-Myers syndrome; thus, allelism between these and ATRX syndrome cannot be considered proven.

Prevalence

The prevalence is not known. Over 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease 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
• 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

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

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.

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.
• In families with only one affected individual, the mother may be a carrier or the affected individual may have a de novo gene mutation. No data on the frequency of de novo gene mutations 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 disease-causing mutation, the chance of transmitting it is 50% in each pregnancy. Sibs with a 46,XY karyotype who inherit the mutation will be affected; sibs with a 46,XX karyotype who inherit the mutation are female carriers and will not be affected. Thus, with each pregnancy, a woman who is a carrier has a 25% chance of having an affected child.
• Germline mosaicism remains a possibility; thus, even if the disease-causing mutation has not been identified in leukocyte DNA from the mother, sibs of the proband are still at increased risk of inheriting the disease-causing mutation.

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 disease-causing mutation has been identified in the family.

Related Genetic Counseling Issues

Assisted reproduction technologies (ART). Donor eggs may be utilized by carrier females to avoid the risk of transmitting an ATRX mutation. 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].

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.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is possible for pregnancies at increased risk for ATRX syndrome.

High-risk pregnancies. For pregnancies in which the mother has been identified as being heterozygous for the disease-causing ATRX mutation 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 disease-causing ATRX mutation 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]; thus, the mother of a proband who does not demonstrate the ATRX mutation 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 disease-causing mutation has been identified.

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. 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]
9. Friez MJ, Jones JR, Clarkson K, Lubs H, Abuelo D, Bier JA, Pai S, Simensen R, Williams C, Giampietro PF, Schwartz CE, Stevenson RE (2006) Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics. 118:e1687-95. [PubMed: 17088400]
10. Gibbons RJ, Brueton L, Buckle VJ, Burn J, Clayton-Smith J, Davison BC, Gardner RJ, Homfray T, Kearney L, Kingston HM. et al. 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]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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]
16. 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]
17. 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]
18. 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]
19. 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]
20. 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]
21. Stevenson RE. Splitting and lumping in the nosology of XLMR. Am J Med Genet. 2000;97:174–82. [PubMed: 11449485]
22. Stevenson RE, Abidi F, Schwartz CE, Lubs HA, Holmes LB. Holmes-Gang syndrome is allelic with XLMR-hypotonic face syndrome. Am J Med Genet. 2000a;94:383–5. [PubMed: 11050622]
23. Stevenson RE, Schwartz CE, Schroer RJ (2000b) X-Linked Mental Retardation. Oxford Univ Press, pp 385-8.
24. 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]
25. Tang P, Park DJ, Marshall Graves JA, Harley VR. ATRX and sex differentiation. Trends Endocrinol Metab. 2004b;15:339–44. [PubMed: 15350606]
26. 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]
27. Villard L, Ades LC, Gecz J, Fontes M (1999a) Identification of a mutation in the XNP/ATR-X gene in a Smith-Fineman-Myers family: are ATR-X and SFM allelic syndromes? 9th Internaitonal Workshop on Fragile X Syndrome and X-Linked Mental Retardation. August 1999, Strasbourg.
28. 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]
29. 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]
30. 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]
31. 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]
32. 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]

Author Notes

Web: www.ggc.org

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

Revision History

• 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