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Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated

, MD, FAAP, FACMG, , MD, PhD, FACMG, and , PhD, MBA, FACMG.

Author Information

Initial Posting: .

Estimated reading time: 15 minutes

Summary

Clinical characteristics.

The int22h1/int22h2-mediated Xq28 duplication syndrome is a recently recognized X-linked intellectual disability syndrome characterized in males by cognitive impairment, behavioral and psychiatric problems, recurrent infections and atopic diseases, obesity, and distinctive facial features. Females heterozygous for this duplication exhibit a milder phenotype (with learning difficulties and distinctive facies) or are clinically unaffected. To date 26 individuals (14 males and 12 females) with this recurrent duplication have been described.

Diagnosis/testing.

The diagnosis of the int22h1/int22h2-mediated Xq28 duplication is established by detection of a 0.5-Mb duplication (hemizygous in males and heterozygous in females) at chromosome Xq28 extending from 154.1 Mb to 154.6 Mb in the reference genome (NCBI Build GRCh37/hg19).

Management.

Treatment of manifestations: Early intervention with speech and physical therapy for young children with developmental delay; special education programs for school-aged children with intellectual disability. Recurrent bacterial infections are treated with standard antibiotics; recurrent ear infections are treated in the standard manner. Nutritional counseling and regular exercise for obese individuals. Standard management for behavioral and psychiatric problems.

Surveillance: The following monitoring is recommended: assessment of developmental progress and cognitive abilities; screening for behavioral and psychiatric problems; and routine audiologic and ophthalmologic evaluations.

Evaluation of relatives at risk: Clinically asymptomatic children who have the familial duplication should be assessed and monitored for developmental delay with the goal of early initiation of therapies and support if needed.

Genetic counseling.

The int22h1/int22h2-mediated Xq28 duplication is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be hemizygous for this Xq28 duplication. All mothers (tested to date) of individuals with this Xq28 duplication were found to be heterozygous for the duplication. When mothers are heterozygous for this Xq28 duplication, the chance of transmission in each pregnancy is 50%: sons who inherit the duplication will be affected; daughters who inherit the duplication will be heterozygotes and may have a milder phenotype or may be clinically unaffected. Prenatal testing using genomic testing that will detect this Xq28 duplication is possible when the mother is known to be heterozygous for the duplication.

Diagnosis

Suggestive Findings

The int22h1/int22h2-mediated Xq28 duplication syndrome should be suspected in males with the following clinical findings:

  • Cognitive impairment
  • Behavioral and psychiatric problems: aggressiveness, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, sleep disturbance, anxiety, and psychotic disorders
  • Recurrent respiratory infections and atopic diseases
  • Obesity
  • Distinctive facial features: tall forehead, upper eyelid fullness, wide nasal bridge, and thick vermilion of the lower lip (see Figure 1A-E)
Figure 1.

Figure 1.

Facial features of males (A-E) and females (F-K) with int22h1/int22h2-mediated Xq28 duplication A and B are brothers ages 11 and 3 years, respectively.

The int22h1/int22h2-mediated Xq28 duplication syndrome should be suspected in females with the following clinical findings:

  • Learning difficulties
  • Distinctive facial features: tall forehead, upper eyelid fullness, wide nasal bridge, and thick vermilion of the lower lip (see Figure 1F-K)

Establishing the Diagnosis

The diagnosis of the int22h1/int22h2-mediated Xq28 duplication is established by detection of a 0.5-Mb duplication (hemizygous in males and heterozygous in females) at chromosome Xq28 extending from 154.1 Mb to 154.6 Mb in the reference genome (NCBI Build GRCh37/hg19).

The duplicated segment extends from a low copy repeat (LCR) region located within intron 22 of F8 (known as intron 22 homologous region 1 [int22h1]) and another LCR region situated 0.5 Mb telomeric to the int22h1 region (known as intron 22 homologous region 2 [int22h2]). This duplication is mediated by nonallelic homologous recombination between the int22h1 and int22h2 LCR regions.

Note: A 0.8-Mb Xq28 duplication that overlaps with the int22h1/int22h2-mediated Xq28 duplication has been reported in individuals who shared some of the clinical findings of individuals with the int22h1/int22h2-mediated Xq28 duplication syndrome (see Genetically Related Disorders).

The duplicated region between int22h1 and int22h2 includes several genes. The cognitive impairment in individuals with the int22h1/int22h2-mediated Xq28 duplication syndrome is likely due to increased dosage of one or more of these genes; the most likely candidates are CLIC2 and RAB39B (see Molecular Genetics).

Genomic testing methods that determine the copy number of sequences can include chromosomal microarray (CMA) or targeted duplication analysis by quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), or other targeted quantitative methods. Although fluorescence in situ hybridization (FISH) using metaphase chromosomes is NOT reliable for detecting this duplication, it can be used to determine if the duplicated segment is inserted elsewhere in the genome (insertion translocation). Note: The int22h1/int22h2-mediated Xq28 duplication cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

Chromosomal microarray (CMA) using oligonucleotide arrays or SNP (single nucleotide polymorphism) genotyping arrays can detect the int22h1/int22h2-mediated Xq28 duplication. The ability to size the duplication depends on the type of microarray used and the density of probes in the Xq28 region.

Note: (1) Most individuals with the int22h1/int22h2-mediated Xq28 duplication are identified by CMA performed for the indication of developmental delay or intellectual disability. (2) Prior to 2011, CMA platforms did not include coverage for this region and thus could not detect this duplication. The earlier BAC (bacterial artificial chromosome)-based arrays could not detect this duplication.

Targeted duplication analysis. Quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA) or other targeted quantitative methods may be used to test relatives of a proband known to have the int22h1/int22h2-mediated Xq28 duplication.

Note: (1) Metaphase FISH is not a reliable method for detecting a duplication of this size; interphase FISH (iFISH) may be used if appropriate control studies are performed. (2) Targeted duplication testing is not appropriate for an individual in whom the int22h1/int22h2-mediated Xq28 duplication was not detected by CMA designed to target this region. (3) It is not possible to size the duplication routinely by use of targeted methods.

Table 1.

Genomic Testing Used in Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated

Duplication 1ISCA ID 2Region Location 3, 4MethodSensitivity
ProbandAt-risk family members
0.5-Mb duplication at Xq28 (hemizygous in males; heterozygous in females)PendingGRCh37/hg19 chrX: 154,124,111-154,564,398CMA 5100% 6100% 6
Targeted duplication analysis 7NA 7100% 6
1.

See Molecular Genetics for details of the duplication.

2.

Standardized clinical annotation and interpretation for genomic variants from the Clinical Genome Resource (ClinGen) project (formerly the International Standards for Cytogenomic Arrays (ISCA) Consortium).

3.

Genomic coordinates represent the minimum duplication size associated with the int22h1/int22h2-mediated Xq28 duplication as designated by ClinGen. Duplication coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the duplication as calculated from these genomic positions may differ from the expected duplication size due to the presence of segmental duplications near breakpoints.

4.

See Molecular Genetics for genes of interest included in this region.

5.

Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the Xq28 region. Note: The int22h1/int22h2-mediated Xq28 duplication may not have been detectable by older oligonucleotide or BAC platforms.

6.
7.

Not applicable. Targeted duplication analysis methods can include: quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA) and iFISH as well as other targeted quantitative methods. Targeted duplication analysis is not appropriate for an individual in whom the int22h1/int22h2-mediated Xq28 duplication was not detected by CMA designed to target this region.

Evaluating at-risk relatives. qPCR, iFISH or other quantitative methods of targeted duplication analysis can be used to identify the int22h1/int22h2-mediated Xq28 duplication in at-risk relatives of the proband. Testing of maternal samples is important in determining recurrence risk (see Genetic Counseling).

Clinical Characteristics

Clinical Description

The int22h1/int22h2-mediated Xq28 duplication syndrome is a recently recognized X-linked intellectual disability syndrome characterized in males by cognitive impairment, behavioral and psychiatric problems, recurrent infections, atopic diseases, obesity, and distinctive facial features. Females heterozygous for this duplication exhibit a milder phenotype (with learning difficulties and distinctive facies) or are clinically unaffected.

To date 26 individuals (14 males and 12 females) with this recurrent duplication have been described. The clinical description below is based on the clinical phenotype described in these 26 individuals (see Table 2) [El-Hattab et al 2011, Lannoy et al 2013, Vanmarsenille et al 2014, El-Hattab et al 2015].

Cognitive impairment. Cognitive impairment has been reported in all males with the int22h1/int22h2-mediated Xq28 duplication. Developmental delay is typically observed in early childhood. The majority of affected males require special education. Intellectual disability in the affected males is typically in the mild to moderate range.

Females heterozygous for this duplication have milder cognitive impairment (i.e., learning difficulties in 6 of 12 affected females) or no cognitive impairment.

Behavioral and psychiatric problems. Behavioral problems are common in affected males; they include aggressiveness, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, and sleep disturbance.

Only one heterozygous female was reported to have ADHD.

Additionally, two males and one female were reported to have psychotic disorders including mood disorders and schizophrenia (Table 2).

Recurrent infections and atopic diseases. Approximately 70% of males with the int22h1/int22h2-mediated Xq28 duplication have experienced recurrent infections including otitis media and pneumonia. Atopic diseases, including asthma, eczema, and allergic rhinitis, are also common in these males.

None of the heterozygous females were reported to have recurrent infections or atopic diseases (Table 2).

Growth abnormalities. Obesity was reported in four affected males and one female heterozygous for the Xq28 duplication.

Tall stature was observed in three affected males and microcephaly in one (Table 2).

Table 2.

Clinical Manifestations in 26 Individuals with the Int22h1/Int22h2-Mediated Xq28 Duplication Syndrome

ManifestationMales (n=14)Females (n=12)
Cognitive impairment14 (100%)6 (50%)
Behavioral problems9 (64%)1 (8%)
  • Aggressiveness
6 (43%)
  • ADHD
5 (36%)1 (8%)
  • Autism spectrum disorder
2 (14%
  • Sleep disturbance
2 (14%
  • Anxiety
2 (14%
  • Socialization difficulties
1 (7%)
  • Motor tics
1 (7%)
  • Self-mutilation
1 (7%)
Psychotic disorders2 (14%)1 (8%)
  • Depression/bipolar
1 (7%)1 (8%)
  • Schizophrenia
1 (7%)
Recurrent infections10 (71%)
  • Otitis media
8 (57%)
  • Pneumonia
4 (29%)
  • Upper respiratory tract infections
1 (7%)
Atopic diseases6 (43%)
  • Asthma
5 (36%)
  • Allergic rhinitis
4 (29%)
  • Eczema
1 (7%)
Growth abnormalities6 (43%)1 (8%)
  • Obesity
4 (29%)1 (8%)
  • Tall stature
3 (21%)
  • Microcephaly
1 (7%)

Characteristic facial features. The most common facial features in both males and females are listed in Diagnosis and represented in Figure 1.

Less common facial features are listed in Table 3 (pdf).

Other infrequent manifestations. Hand and foot anomalies have been infrequently observed in males with this duplication. Clinodactyly was reported twice; single palmar crease, fetal finger pads, rocker bottom feet, pes valgus, pes planus, metatarsus adductus, sandal gap, 2-3 toe syndactyly, short second toe, and short heel cords were each reported once in a male with this duplication.

Hearing loss was reported in one affected boy.

Strabismus, myopia, and astigmatism were each reported once in a male with this duplication.

Patent ductus arteriosus (PDA), atrial septal defect (ASD), esophageal atresia with tracheoesophageal fistula, Pierre Robin sequence with cleft palate, cryptorchidism, phimosis, hip dysplasia, kyphoscoliosis, and polyhydramnios were each reported once in an affected male.

Hemihyperplasia, hypothyroidism, and kyphoscoliosis were each reported once in a heterozygous female.

X-chromosome inactivation in heterozygous females. X-chromosome inactivation analyses were reported to be skewed in nine of 12 females heterozygous for the int22h1/int22h2-mediated Xq28 duplication; however, skewing of X-chromosome inactivation was inconsistent; that is, it was observed with the normal X chromosome and the X chromosome with the duplication. Additionally, no clear correlation between the X-chromosome inactivation pattern and the cognitive phenotypes was evident: random and skewed patterns occurred in both cognitively normal and cognitively impaired females [El-Hattab et al 2015].

Penetrance

Int22h1/int22h2-mediated Xq28 duplication syndrome is completely penetrant for cognitive impairment in males.

Cognitive impairment is incompletely penetrant in females heterozygous for this duplication with only 50% reported to have learning difficulties [El-Hattab et al 2011, Lannoy et al 2013, Vanmarsenille et al 2014, El-Hattab et al 2015].

Prevalence

Int22h1/int22h2-mediated Xq28 duplication has been reported in 26 individuals (14 males and 12 females) to date [El-Hattab et al 2011, Lannoy et al 2013, Vanmarsenille et al 2014, El-Hattab et al 2015].

The prevalence of this duplication is not known, but has been estimated at 1:1000 among males with intellectual disability [Vanmarsenille et al 2014]; this may, however, be an overestimate.

Differential Diagnosis

MECP2 duplication syndrome is a severe neurodevelopmental disorder characterized by infantile hypotonia, delayed psychomotor development leading to severe intellectual disability, poor speech development, progressive spasticity, recurrent respiratory infections, seizures, autistic behaviors, and gastrointestinal dysfunction. Inheritance is X-linked with complete penetrance in males.

Occasionally females have been described with a MECP2 duplication and related clinical findings, often associated with concomitant X-chromosomal abnormalities that prevent inactivation of the duplicated region.

This syndrome is caused by duplications in chromosome Xq28 that include MECP2 (153.3 Mb) and range from 0.3 to 4 Mb. In contrast, the int22h1/int22h2-mediated Xq28 duplication syndrome is caused by 0.5-Mb duplication in Xq28 located telomeric to the MECP2 locus and extending from 154.1 to 154.6 Mb. Cognitive impairment and recurrent infections are common in both syndromes. However, infantile hypotonia, spasticity, and seizures have not been observed in int22h1/int22h2-mediated Xq28 duplication syndrome.

Other. Differential diagnosis also includes different forms of syndromic X-linked intellectual disability and nonsyndromic X-linked intellectual disability; see OMIM Phenotypic Series: Mental retardation, X-linked syndromic and Mental retardation, X-linked nonsyndromic to view genes associated with these phenotypes in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with the int22h1/int22h2-mediated Xq28 duplication syndrome, the following evaluations are recommended:

  • Review of medical history for behavioral and psychiatric problems, recurrent infections, and atopic diseases
  • Comprehensive physical examination with emphasis on growth parameters, hands and feet, and possible kyphoscoliosis
  • Neuropsychological evaluation to assess level of cognitive functioning and for any behavioral problems
  • Psychiatric evaluation if psychiatric illness is suspected
  • Echocardiogram
  • Audiologic evaluation
  • Ophthalmologic examination
  • Spine x-ray and orthopedic evaluation if kyphoscoliosis is present
  • Nutritional evaluation and counseling if obesity is present
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Early intervention with speech and physical therapy is recommended for young children with developmental delay. Special education programs are subsequently recommended for school-aged children with intellectual disability.

Recurrent bacterial infections are treated with standard antibiotics. Children with recurrent ear infections should be referred to ENT to assess need for tympanostomy tubes.

Nutritional counseling and regular exercise are needed when obesity is an issue.

Standard management is recommended for the following:

  • Behavioral and psychiatric problems
  • Kyphoscoliosis
  • Cardiac malformations
  • Hearing impairment
  • Eye problems

Surveillance

The following routine monitoring is recommended:

  • Assessment of developmental progress and cognitive abilities
  • Screening for behavioral and psychiatric problems
  • Audiology evaluation
  • Ophthalmologic evaluation

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic children who are relatives of an affected individual by genomic testing for the int22h1/int22h2-mediated Xq28 duplication. Clinically asymptomatic children who have the familial duplication should be assessed and monitored for developmental delay with the goal of early initiation of therapies and support if needed.

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 EU Clinical Trials Register 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

The int22h1/int22h2-mediated Xq28 duplication is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

  • The father of an affected male will not have the disorder nor will he be hemizygous for the Xq28 duplication; therefore, he does not require further evaluation/testing.
  • All mothers (tested to date) of individuals with the int22h1/int22h2-mediated Xq28 duplication were found to be heterozygous for the duplication.
  • In a family with more than one affected individual, the mother of an affected individual is an obligate heterozygote.
  • In a family with one affected individual (i.e., a simplex case), the mother may be heterozygous for the int22h1/int22h2-mediated Xq28 duplication or the affected male may have a de novo duplication, in which case the mother is not heterozygous; however, de novo int22h1/int22h2-mediated Xq28 duplications have not been reported to date.
  • Testing of maternal samples is important in determining recurrence risk. Evaluation of the mother by genomic testing that will detect the int22h1/int22h2-mediated Xq28 duplication present in the proband is recommended.

Sibs of a proband. The risk to sibs depends on the genetic status of the mother:

  • If the mother of the proband has the Xq28 duplication, the chance of transmission in each pregnancy is 50%.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the int22h1/int22h2-mediated Xq28 duplication 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. However, all mothers (tested to date) of probands with the int22h1/int22h2-mediated Xq28 duplication were found to be heterozygous for the duplication.

Offspring of a male proband. No affected male has been reported to reproduce.

Offspring of a female proband. Women with the int22h1/int22h2-mediated Xq28 duplication have a 50% chance of transmitting the duplication to each child:

Other family members. The risk to other family members depends on the genetic status of the proband's mother. If the mother has the int22h1/int22h2-mediated Xq28 duplication, her family members may also have the duplication.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the int22h1/int22h2-mediated Xq28 duplication syndrome.

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 Testing

Pregnancies known to be at increased risk for the int22h1/int22h2-mediated Xq28 duplication. Once the int22h1/int22h2-mediated Xq28 duplication has been identified in an affected family member, prenatal testing and preimplantation genetic testing for a pregnancy at increased risk are possible options.

Pregnancies not known to be at increased risk for int22h1/int22h2-mediated Xq28 duplication. Chromosomal microarray (CMA) performed in a pregnancy not known to be at increased risk may detect this duplication.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

  • Chromosome Disorder Outreach (CDO)
    PO Box 724
    Boca Raton FL 33429-0724
    Phone: 561-395-4252 (Family Helpline)
    Email: info@chromodisorder.org
  • Unique: The Rare Chromosome Disorder Support Group
    G1 The Stables
    Station Road West
    Oxted Surrey RH8 9EE
    United Kingdom
    Phone: +44 (0) 1883 723356
    Email: info@rarechromo.org; rarechromo@aol.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated: Genes and Databases

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 Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated (View All in OMIM)

300138CHLORIDE INTRACELLULAR CHANNEL 2; CLIC2
300774RAS-ASSOCIATED PROTEIN RAB39B; RAB39B
300815CHROMOSOME Xq28 DUPLICATION SYNDROME

Molecular Pathogenesis

The int22h1/int22h2-mediated Xq28 duplication breakpoints are localized to the directly oriented LCRs int22h1 (located within intron 22 of F8) and int22h2 (situated 0.5 Mb telomerically to int22h1). The duplication is mediated by nonallelic homologous recombination between int22h1and int22h2 [El-Hattab et al 2011]. A third homologous region, int22h3, is located 0.6 Mb telomerically to int22h1. No duplications using the int22h3, which is in opposite orientation to int22h1, have been observed.

Genomic inversions between int22h1 and either int22h2 or int22h3 are known to disrupt F8 in nearly half of individuals with severe hemophilia A [Bagnall et al 2005]. However, int22h1/int22h2-mediated Xq28 duplication does not result in hemophilia A because a complete copy of F8 is preserved after formation of this duplication [El-Hattab et al 2011].

The 0.5-Mb duplicated region between int22h1 and int22h2 includes several genes. The cognitive impairment in individuals with the int22h1/int22h2- mediated Xq28 duplication syndrome is likely due to increased dosage of one or more of these genes; the most likely candidates are RAB39B and CLIC2 (see following) [El-Hattab et al 2015].

Genes of interest in this region

  • CLIC2 encodes chloride intracellular channel 2 (CLIC2) protein that functions as an intrinsic stabilizer of ryanodine receptors (RyR); therefore, it can modulate calcium signaling through the regulation of RyR channel activity [Meng et al 2009]. A missense pathogenic variant in CLIC2 was reported in two brothers with cognitive impairment, seizures, and cardiac anomalies [Takano et al 2012].
  • RAB39B encodes a member of the Rab protein family, which are small GTPases involved in intracellular signaling proteins that coordinate vesicle trafficking during a variety of cellular processes, including neuronal development and signaling [Ng & Tang 2008, Stenmark 2009].
    Loss of-function pathogenic variants in RAB39B were identified in families with X-linked intellectual disability [Giannandrea et al 2010].
    RAB39B overexpression was found in two individuals with the int22h1/int22h2-mediated Xq28 duplication. Overexpression of Rab39b in mouse primary hippocampal neurons results in decreased neuronal branching and synapse number, suggesting that the increased dosage of RAB39B disturbs neuronal development [Vanmarsenille et al 2014].

References

Literature Cited

  • Andersen EF, Baldwin EE, Ellingwood S, Smith R, Lamb AN. Xq28 duplication overlapping the int22h-1/int22h-2 region and including RAB39B and CLIC2 in a family with intellectual and developmental disability. Am J Med Genet A. 2014;164A:1795–801. [PubMed: 24700761]
  • Bagnall RD, Giannelli F, Green PM. Polymorphism and hemophilia A causing inversions in distal Xq28: a complex picture. J Thromb Haemost. 2005;3:2598–9. [PubMed: 16241967]
  • El-Hattab AW, Fang P, Jin W, Hughes JR, Gibson JB, Patel GS, Grange DK, Manwaring LP, Patel A, Stankiewicz P, Cheung SW. Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions. J Med Genet. 2011;48:840–50. [PubMed: 21984752]
  • El-Hattab AW, Schaaf CP, Fang P, Roeder E, Kimonis VE, Church JA, Patel A, Cheung SW. Clinical characterization of int22h1/int22h2-mediated Xq28 duplication/deletion: new cases and literature review. BMC Med Genet. 2015;16:12. [PMC free article: PMC4422130] [PubMed: 25927380]
  • Giannandrea M, Bianchi V, Mignogna ML, Sirri A, Carrabino S, D'Elia E, Vecellio M, Russo S, Cogliati F, Larizza L, Ropers HH, Tzschach A, Kalscheuer V, Oehl-Jaschkowitz B, Skinner C, Schwartz CE, Gecz J, Van Esch H, Raynaud M, Chelly J, de Brouwer AP, Toniolo D, D'Adamo P. Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am J Hum Genet. 2010;86:185–95. [PMC free article: PMC2820185] [PubMed: 20159109]
  • Lannoy N, Grisart B, Eeckhoudt S, Verellen-Dumoulin C, Lambert C, Vikkula M, Hermans C. Intron 22 homologous regions are implicated in exons 1-22 duplications of the F8 gene. Eur J Hum Genet. 2013;21:970–6. [PMC free article: PMC3746252] [PubMed: 23299923]
  • Meng X, Wang G, Viero C, Wang Q, Mi W, Su XD, Wagenknecht T, Williams AJ, Liu Z, Yin CC. CLIC2-RyR1 interaction and structural characterization by cryo-electron microscopy. J Mol Biol. 2009;387:320–34. [PMC free article: PMC2667806] [PubMed: 19356589]
  • Ng EL, Tang BL. Rab GTPases and their roles in brain neurons and glia. Brain Res Rev. 2008;58:236–46. [PubMed: 18485483]
  • Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 2009;10:513–25. [PubMed: 19603039]
  • Takano K, Liu D, Tarpey P, Gallant E, Lam A, Witham S, Alexov E, Chaubey A, Stevenson RE, Schwartz CE, Board PG, Dulhunty AF. An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity. Hum Mol Genet. 2012;21:4497–507. [PMC free article: PMC3459470] [PubMed: 22814392]
  • Vanmarsenille L, Giannandrea M, Fieremans N, Verbeeck J, Belet S, Raynaud M, Vogels A, Männik K, Õunap K, Jacqueline V, Briault S, Van Esch H, D'Adamo P, Froyen G. Increased dosage of RAB39B affects neuronal development and could explain the cognitive impairment in male patients with distal Xq28 copy number gains. Hum Mutat. 2014;35:377–83. [PubMed: 24357492]

Chapter Notes

Revision History

  • 10 March 2016 (bp) Review posted live
  • 31 July 2015 (aweh) Original submission
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