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SOX2-Related Eye Disorders

, PhD and , MD, FRCP(EDIN).

Author Information

Initial Posting: ; Last Update: July 31, 2014.

Summary

Clinical characteristics.

SOX2-related eye disorders are characterized by anophthalmia and/or microphthalmia that is usually bilateral, severe, and apparent at birth or by prenatal ultrasound examination. Other common findings include brain malformations, esophageal atresia, cryptorchidism and/or micropenis in males, and hypogonadotropic hypogonadism and/or pituitary hypoplasia. Postnatal growth failure, delayed motor development, and learning disability are common.

Diagnosis/testing.

The diagnosis of SOX2-related eye disorders is established by clinical findings, cytogenetic or molecular analysis to detect deletions of 3q27 (which includes SOX2), and molecular genetic testing. Molecular genetic testing identifies a heterozygous SOX2 pathogenic variant in approximately 40% of individuals with bilateral anophthalmia/microphthalmia.

Management.

Treatment of manifestations: Use of optically clear expanders to stimulate growth of the orbit and periorbital tissues; special educational services for visually impaired infants and children; physiotherapy for motor impairment; special education for neurodevelopmental problems; use of melatonin for abnormal sleep patterns; antiepileptic drugs for seizure management.

Surveillance: Annual hearing test and annual neurodevelopmental assessment until age five years; measurement of height, weight, and head circumference every three to six months during childhood.

Genetic counseling.

SOX2-related eye disorders are inherited in an autosomal dominant manner, most often resulting from a de novo pathogenic variant. The risk to the sibs of a proband is usually small; however, if a parent of a proband has germline mosaicism, the risk to the sibs may be as high as 50%. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known. Fetal ultrasound examination reveals marked reduction in the size of the globes.

GeneReview Scope

SOX2-Related Eye Disorders: Included Phenotypes
  • SOX2 anophthalmia syndrome
  • Anophthalmia-esophageal atresia-genital abnormalities (AEG) syndrome

For synonyms and outdated names see Nomenclature.

Diagnosis

Suggestive Findings

Diagnosis of SOX2-related eye disorders should be suspected in individuals with:

  • Bilateral anophthalmia and/or microphthalmia
  • Unilateral anophthalmia or microphthalmia
  • Cryptorchidism and/or micropenis in males
  • Malformation and/or heterotopia of the mesial temporal structures of the brain, particularly the hippocampus
  • Tracheoesophageal fistula and/or esophageal atresia
  • Learning disability
  • Delayed motor development
  • Postnatal growth failure
  • Hypogonadotropic hypogonadism with or without pituitary hypoplasia

Establishing the Diagnosis

The diagnosis of SOX2-related eye disorders is established in a proband by genetic testing to detect deletions, chromosome translocation, or pathogenic variation involving SOX2.

Cytogenetic analysis includes chromosome analysis and copy number variant analyses including array comparative genomic hybridization (aCGH) and high-resolution detection of microdeletions known to occur in 15% of patients.

Molecular analysis (see Table 1) can include single-gene testing and use of a multigene panel.

  • Single-gene testing. Sequence analysis of SOX2 is often performed first, followed by deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes SOX2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here

Table 1.

Molecular Genetic Testing Used in SOX2-Related Eye Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
SOX2Sequence analysis 225%-30% 3
Deletion/duplication analysis 47%-10% 5
FISH 64% 3, 6
1.

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

2.

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

3.

Screening of >1000 individuals with severe eye malformations using a combination of scanning of the entire coding region for pathogenic variants, direct sequencing of the entire coding region, high-resolution copy number variant analyses, and FISH analysis for large-scale deletions detects SOX2 pathogenic variants in 25%-30% of individuals, including 40% of individuals with bilateral anophthalmia/microphthalmia and <3% of individuals with unilateral eye involvement [Gerth-Kahlert et al 2013, Chassaing et al 2014, Williamson & FitzPatrick 2014].

4.

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

5.

Detection frequency is 7%-10% for deletions in cases with severe microphthalmia or anophthalmia [Bakrania et al 2007, Gerth-Kahlert et al 2013, Schilter et al 2013]. No duplications have been identified.

6.

Large (partial- and whole-gene) deletions. Detection frequency is 4% [Bakrania et al 2007].

Clinical Characteristics

Clinical Description

A total of 114 individuals from 97 families with SOX2-related eye defects have been studied in detail to date [Williamson & FitzPatrick 2014].

Bilateral anophthalmia and/or microphthalmia. SOX2-related eye defects are usually bilateral, severe, and apparent at birth or on routine prenatal ultrasound examination. In the 114 individuals reported to date, 56 (49%) had bilateral anophthalmia, 19 (17%) had anophthalmia with contralateral microphthalmia, and 12 (10%) had bilateral microphthalmia. The remaining individuals have a wide spectrum of eye malformations including the following [Williamson & FitzPatrick 2014]:

  • Unilateral anopthalmia or microphthalmia and a normal eye
  • Unilateral microphthalmia with coloboma or iris defect in the contralateral eye
  • Coloboma
  • Optic nerve hypoplasia
  • Cataract
  • Retinal dysplasia
  • Anterior segment dysgenesis (including sclerocornea or microcornea)
  • Refractive error

Three individuals with loss-of-function pathogenic variants had bilateral structurally normal eyes. These individuals were: a monozygotic twin with tracheoesophageal fistula and unilateral reduced palpebral fissure (the other twin had anophthalmia-esophageal atresia-genital abnormalities [AEG] syndrome with unilateral anophthalmia) [Zenteno et al 2006]; a sibling fetus in a family with AEG syndrome, with brain anomalies and 11 rib pairs [Chassaing et al 2007]; and a mother (with heterozygosity or a high level of mosaicism of the pathogenic variant) with isolated hypogonadotropic hypogonadism who, following assisted conception, had two children with bilateral anophthalmia or unilateral microphthalmia with coloboma [Stark et al 2011].

The degree of visual impairment is usually severe and consistent with the degree of structural abnormality in the eye. In general, retina tissue that is present has some functional activity. For example, even in extreme microphthalmia, functional retinal tissue can give some light/dark perception with or without color perception.

Brain malformation. Twelve children had mesial temporal (hippocampal and parahippocampal) malformations evident on MRI. Two also had evidence of heterotopic grey matter in the mesial temporal region [Sisodiya et al 2006]. Pituitary hypoplasia and agenesis or dysgenesis of the corpus callosum have been reported in multiple individuals [Guichet et al 2004, Ragge et al 2005a, Zenteno et al 2005, Hever et al 2006, Kelberman et al 2006, Williamson et al 2006, Bakrania et al 2007, Kelberman et al 2008, Zhou et al 2008, Schneider et al 2009, Gonzalez-Rodriguez et al 2010, Gerth-Kahlert et al 2013, Chassaing et al 2014, Macchiaroli et al 2014].

Anterior pituitary hypoplasia. The majority of cases have some evidence of hypothalamo-pituitary axis dysfunction when detailed measurement of growth hormone and gonadotrophins are undertaken [Tziaferi et al 2008].

  • Postnatal growth failure. Birth weight in most infants is normal for gestational age. However, most children have a reduced growth velocity in the first years of life resulting in symmetric growth failure.
  • Hypogonadotropic hypogonadism. This feature is reported in 17 individuals, including one mother with normal eyes [Stark et al 2011] and one male with unilateral retinal detachment, micropenis, and cryptorchidism [Takagi et al 2014].
  • Genital abnormalities. Micropenis, hypospadias, and cryptorchidism were frequent abnormalities in male cases, whereas hypoplastic uterus and ovarian agenesis were rare features in female cases.

Delayed motor development was reported in the majority of cases; the age of achieving independent walking ranged from 12 months to four years, although some individuals never achieve independent ambulation.

Learning disability is highly variable and ranged from normal intelligence to severe learning disability, with the majority of those tested scoring between these extremes. The degree of learning disability is not predictable by mutation type or severity of the eye involvement.

Seizures were observed in 16 individuals; onset is variable, but common in early childhood. Information on the exact seizure type is limited, but most appeared to be grand mal tonic-clonic seizures, which appeared in early childhood and responded well to standard anticonvulsant medication.

Sensorineural hearing loss. Five children had apparently non-progressive moderate sensorineural hearing loss requiring hearing aids.

Esophageal atresia with or without tracheoesophageal fistula. Heterozygous pathogenic variants in SOX2 have been identified in eight unrelated individuals and monozygotic twins with AEG syndrome (OMIM 206900) [Kelberman et al 2006, Williamson et al 2006, Zenteno et al 2006, Bakrania et al 2007, Chassaing et al 2007, Chassaing et al 2014]. AEG syndrome does not appear to be a distinct entity, but rather part of the spectrum of SOX2-related eye disorders.

Genotype-Phenotype Correlations

Almost all SOX2 pathogenic variants reported to date appear to represent heterozygous loss of function; thus, it is difficult to draw genotype-phenotype correlations.

Penetrance appears to be complete for non-mosaic loss-of-function pathogenic variants. Variable expressivity is a feature observed with some pathogenic variants, such as the most common variant allele that alters the N-terminal region polyglycine repeat [Zenteno et al 2006, Gerth-Kahlert et al 2013], and the recurrent variant allele that alters a specific residue in the partner-binding domain [Mihelec et al 2009, Gerth-Kahlert et al 2013].

Penetrance

Penetrance appears to be complete for non-mosaic loss-of-function pathogenic variants.

Nomenclature

The condition has also been called SOX2 anophthalmia syndrome [Ragge et al 2005b].

Microphthalmia-anophthalmia-coloboma (MAC) was used as an umbrella term for the spectrum of severe eye malformations in some early publications describing SOX2-related eye disorders. This may be an inappropriate acronym as it implies that coloboma is an intrinsic part of all microphthalmia, which no longer appears to be the case.

Each of the hypothetic explanations for the embryonic origin of the small or missing eyes associated with SOX2 pathogenic variants predicts a different spectrum of clinical phenotypes.

  • If the primary defect were in the mechanism of optic fissure closure, the predicted order of severity would be iris coloboma, choroidal/retinal coloboma, microphthalmia with coloboma or orbital cyst, and anophthalmia.
  • If lens induction were impaired, the predicted clinical spectrum would be congenital cataract > microphthalmia > anophthalmia.
  • If the main effects of SOX2 were in retinal differentiation, the predicted clinical manifestations would be retinal dystrophy > microphthalmia.
  • It is also possible that complete failure of optic vesicle formation results in anophthalmia without optic nerve formation.

Thus, the term MAC has inadequate descriptive power to be useful. The particular spectrum associated with SOX2-related eye disorders is not yet clear because most affected individuals have very small or absent eyes, which are thus morphologically unclassifiable. Coloboma has been reported but is not a common feature.

Anophthalmia-esophageal atresia-genital abnormalities (AEG) syndrome was previously reported to be a distinct disorder, but is now known to be associated with heterozygous pathogenic loss-of-function variants in SOX2 in some individuals [Williamson et al 2006, Zenteno et al 2006]; thus, it appears that esophageal atresia with or without tracheoesophageal fistula is a feature of SOX2-related eye disorders and not a separate condition. This is consistent with the known expression of SOX2 in the endoderm and genital ridge during development of chick and mouse embryos.

Prevalence

Prevalence is approximately 1:250,000 (UK estimate) [Author, personal data].

Differential Diagnosis

SOX2 pathogenic variants account for 40% of bilateral anophthalmia, making it the most frequent known genetic cause of severe bilateral eye malformations. However, these disorders show marked etiologic heterogeneity.

OTX2 anophthalmia syndrome (OMIM 610125), caused by heterozygous pathogenic loss-of-function variants in OTX2, can present with almost identical ocular and brain features to SOX2 anophthalmia syndrome [Gerth-Kahlert et al 2013]. However, esophageal atresia and tracheoesophageal fistula have not been described in association with mutation of OTX2.

CHARGE syndrome should be considered in children with ocular malformations, growth deficiency, micropenis, and tracheaesophageal fistula. Sequence analysis of CHD7 in individuals with either typical CHARGE syndrome or a milder phenotype (i.e., fewer major characteristics) detects pathogenic variants in approximately 65%-70% of cases. In one individual with AEG syndrome in whom no SOX2 pathogenic variant was identified a heterozygous loss-of-function pathogenic variant in CHD7 has subsequently been identified [Williamson & FitzPatrick, unpublished].

One rather poorly defined condition that may resemble SOX2-related eye disorders is Lenz microphthalmia syndrome (LMS), characterized by unilateral or bilateral microphthalmia and/or anophthalmia with malformations of the ears, teeth, fingers, skeleton, or genitourinary system. Approximately 60% of affected males have mild-to-severe intellectual disability or developmental delay. Two loci on the X chromosome, MCOPS1 and MCOPS2, are known to be associated with LMS. The LMS-associated gene on MCOPS2 is BCOR. Inheritance is X-linked.

See Anophthalmia/Microphthalmia Overview for a more complete differential diagnosis. Pathogenic variants in CHX10, RAX, PAX6 (see Aniridia), and OTX2 can have overlapping phenotypes.

See Esophageal Atresia/Tracheoesophageal Fistula Overview for a more complete differential diagnosis.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a SOX2-related eye disorder, the following evaluations are recommended:

  • Examination by an experienced pediatric ophthalmologist
  • High-resolution cranial MRI for brain/pituitary malformations, optic nerve/chiasm/tract assessment
  • Endocrinologic evaluation to include corticosteroid, gonadotrphin, growth hormone, and thyroid function tests to assess pituitary function
  • Baseline neurodevelopmental assessment
  • Audiometry
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Visual impairment. The general management of visual impairment is not specific to anophthalmia or microphthalmia (see Anophthalmia/Microphthalmia Overview). Care includes:

  • Early referral to an experienced multidisciplinary team
  • Consideration of use of expanders to stimulate growth of the orbit and periorbital tissues. Because accurate assessment of visual function is necessary, optically clear expanders should be used.
  • Referral to special educational services for visually impaired infants

Other

  • Referral to endocrinologist for growth or hypogonadism concerns
  • Referral to physiotherapist if any evidence of motor impairment exists
  • Referral to special educational services for neurodevelopmental problems as needed
  • Consideration of use of melatonin for regulation of circadian rhythm if sleep pattern is abnormal
  • Parent/caregiver training in seizure management

Prevention of Secondary Complications

Many neonates can have an adequate MRI without general anesthesia using the "feed and wrap" method. In this case, assess morning cortisol levels prior to any subsequent anesthetic if this MRI reveals pituitary hypoplasia. If an anesthetic is required before adequate intracranial imaging is available, an endocrinologic evaluation is indicated.

Surveillance

The following measures are suggested:

  • Annual hearing test
  • Measurement of height, weight, and head circumference every three to six months during childhood
  • Neurodevelopmental assessment annually for the first five years of life

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 in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SOX2-related eye disorders are inherited in an autosomal dominant manner, most often resulting from a de novo pathogenic variant. Rarely, parental germline mosaicism can result in a "pseudo-autosomal recessive" pattern of inheritance [Faivre et al 2006, Schneider et al 2008, Zhou et al 2008, Schneider et al 2009].

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents.

Offspring of a proband. Each child of an individual with a SOX2-related eye disorder has a 50% chance of inheriting the SOX2 pathogenic variant.

Other family members of a proband. Because the majority of SOX2-related eye disorders occur as the result of a fully penetrant de novo pathogenic variant, unaffected family members other than parents of a proband are not at increased risk. Variable expressivity can result in relatively mild phenotypes in rare cases.

Related Genetic Counseling Issues

When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, the SOX2 pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the SOX2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for a SOX2-related eye disorder are possible. However, severity of disease and specific clinical findings are variable and cannot be accurately predicted by the family history or results of molecular genetic testing.

Fetal ultrasound examination/fetal MRI is also possible as the eye malformations in fetuses with SOX2-related eye disorders (bilateral anophthalmia or severe microphthalmia) are usually severe and can be detected during the second trimester of pregnancy using fetal ultrasound.

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.

  • International Children's Anophthalmia and Microphthalmia Network (ICAN)
    c/o Center for Developmental Medicine and Genetics
    5501 Old York Road
    Genetics, Levy 2 West
    Philadelphia PA 19141
    Phone: 800-580-4226 (toll-free)
    Email: ican@anophthalmia.org
  • The Micro and Anophthalmic Children’s Society
    Kemp House, 152 City Road
    Suite 472
    London EC1V 2NX
    United Kingdom
    Phone: 0800 169 8088
    Email: enquiries@macs.org.uk
  • American Epilepsy Society (AES)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jernigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org

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.

SOX2-Related Eye Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SOX23q26​.33Transcription factor SOX-2SOX2 @ The Human Genetics Unit Edinburgh U.K.SOX2SOX2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for SOX2-Related Eye Disorders (View All in OMIM)

184429SRY-BOX 2; SOX2
206900MICROPHTHALMIA, SYNDROMIC 3; MCOPS3

Gene structure. The coding region comprises one exon. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. The NHLBI Exome Sequencing Project Exome Variant Server http://evs.gs.washington.edu/EVS/(accessed 6-14) lists seven benign variants that do not alter the primary protein sequence, and seven variants that are likely benign or of unknown significance and that are predicted to substitute residues in the transactivation domain of SOX-2. There are no variants of these types known to affect the HMG domain or the partner-binding domain. The SOX genes are defined as having greater than 60% homology within the HMG domain to human SRY. Within the SOX family, SOX2 belongs to the SOXB subgroup with SOX1, SOX3, SOX14, and SOX21.

Pathogenic variants. All SOX2 pathogenic variants identified to date result in apparent loss of function. The most common variant types are nonsense and frameshift. Five alleles, predicted to frameshift the codons of an N-terminal region polyglycine repeat, account for almost one fifth of the pathogenic variants in individuals and families. The remaining known pathogenic variants are nonsynonymous, in-frame insertion, and whole-gene deletion alleles. Details of all the known pathogenic variants are available in an online SOX2 mutation database.

Normal gene product. Transcription factor SOX-2 is a 317-amino acid peptide. It has an HMG DNA-binding domain (amino acids 40-111), a partner-binding domain and a C-terminal transactivation domain. The N-terminal region is of unknown function and contains short polyglycine and polyalanine repeats.

SOX2 is expressed in mouse embryonic stem cells and has been shown to act as part of a transcriptional activator complex for several important developmental genes [Ambrosetti et al 2000, Tomioka et al 2002] including other genes known to be critical to eye development (e.g., PAX6 and MAF1) [Kamachi et al 2001, Muta et al 2002]. It is an early marker of neurulation in chick embryos and shows site- and stage-specific expression in the developing nervous system, genital ridge, and foregut in all vertebrates studied.

Abnormal gene product. As SOX2 is a single-exon gene, it is not subject to nonsense-mediated decay and it is possible that truncated peptide may be produced in affected individuals. If these abnormal peptides were stable, they could have a dominant-negative effect. However, with the increase in the number of variant alleles known, differences between the clinical features of those with whole-gene deletions and those with stop gain pathogenic variants are not evident, suggesting that there is no dominant-negative effect.

Two thirds of the missense pathogenic variants that have been identified are within the highly conserved HMG DNA-binding domain. Functional studies on two of these variants, using a modified yeast one-hybrid system, confirm that these pathogenic variants severely diminish the activation of DC5 delta crystalline enhancer through loss of cooperative SOX2/PAX6 binding [Williamson et al 2006].

References

Literature Cited

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Chapter Notes

Acknowledgments

Professor Veronica van Heyningen for continued helpful collaboration

MACS family support organization for their interest and support

Revision History

  • 31 July 2014 (me) Comprehensive update posted live
  • 25 August 2009 (me) Comprehensive update posted live
  • 7 March 2008 (cd) Revision: FISH analysis available clinically
  • 5 December 2007 (cd) Revision: deletion/duplication analysis available clinically
  • 23 February 2006 (me) Review posted live
  • 14 April 2005 (drf) Original submission
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