Clinical characteristics.

The int22h1/int22h2-mediated Xq28 duplication syndrome is an X-linked intellectual disability syndrome characterized by variable degrees of cognitive impairment (typically more severe in males), a wide spectrum of neurobehavioral abnormalities, and variable facial dysmorphic features. Affected males also exhibit a peculiar combination of recurrent sinopulmonary infections and atopy, findings that have not been observed in affected females. All males reported to date with the syndrome have moderate-to-severe intellectual disability; in contrast, a minority of heterozygous females have been reported to have mild intellectual disability, while the majority have no discernible health or learning issues and are considered clinically unaffected.

Diagnosis/testing.

The diagnosis of int22h1/int22h2-mediated Xq28 duplication in a hemizygous male or a heterozygous female is established by detection of a 0.5-Mb duplication within the q28 region of the X chromosome extending between 154.1 Mb and 154.6 Mb in the reference genome (NCBI Build GRCh37/hg19).

Management.

Treatment of manifestations: Early intervention with speech and physical therapy for children with neurodevelopmental delays; enrollment in special education programs of school-aged children with intellectual disability; cognitive behavioral therapy and standard treatment with antidepressants and/or antipsychotics for individuals with mood and psychotic disorders; standard treatment per orthopedist for those with kyphoscoliosis; bacterial culture-driven antibiotic treatment of affected individuals who have recurrent infections; vaccinations against Strep pneumoniae, Haemophilus influenzae, and Neisseria meningitidis and annual influenza A vaccine; standard medical treatment of sleep issues, asthma, allergic rhinitis, eczema, hearing loss, and refractive error; standard surgical correction of congenital malformations (e.g., strabismus, hypospadias, cryptorchidism, heart defects, limb anomalies).

Surveillance: Measurement of growth parameters and assessment of neurodevelopmental progress, cognitive abilities, behavioral/psychiatric symptoms, and motor functioning at each visit; reassessment of special education needs annually in childhood and adolescence; routine follow up with orthopedist for those with contractures and/or kyphoscoliosis; pulmonary function testing as clinically indicated for those with severe asthma; at least annual audiologic and ophthalmologic evaluations.

Evaluation of relatives at risk: Clinically asymptomatic sibs of affected individuals who also have the duplication should be regularly assessed and carefully monitored for achievement of neurodevelopmental milestones with the goal of instituting early intervention if or when neurodevelopmental delays are noted.

Genetic counseling.

The int22h1/int22h2-mediated Xq28 duplication syndrome is inherited in an X-linked manner. Most affected individuals inherited the duplication from their heterozygous and often asymptomatic mother. However, individuals with de novo duplications have also been identified. Because offspring inherit one X chromosome from the mother, each child of a mother with an int22h1/int22h2-mediated Xq28 duplication has a 50% chance of inheriting the duplication. In other words, a female with an int22h1/int22h2-mediated Xq28 duplication has a 50% chance of passing the duplication to her offspring at each conception. Being hemizygous for X-linked genes, males who inherit the duplication are affected. In contrast, females who inherit the duplication will be heterozygous and thus, will either exhibit a milder phenotype or be clinically unaffected. Females in whom the X-inactivation pattern is skewed toward inactivation of the X chromosome bearing the duplication are more likely to be clinically unaffected. Once an int22h1/int22h2-mediated Xq28 duplication has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

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

• Mild-to-moderate intellectual disability, with or without mild-to-moderate neurodevelopmental delays
• Any of the following features presenting in infancy or childhood:
  • Characteristic neurobehavioral profile consisting of aggression and irritability, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, socialization deficits, and sleep disturbances – typically insomnia
  • Recurrent sinopulmonary infections (including otitis media) with existent atopic conditions (e.g., asthma, allergic rhinitis, eczema)
  • Obesity with or without tall stature
  • Nonspecific but consistent facial features (See Clinical Characteristics and Figure 1A-E.)

Figure 1.

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

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

• Mild learning disabilities
• Neurobehavioral manifestations resembling those of the inattentive-type childhood ADHD (impulsivity, inattention, and emotional lability)
• Mild-to-moderate socialization deficits
• Nonspecific but consistent facial features (See Clinical Characteristics and Figure 1F-K.)

Establishing the Diagnosis

The diagnosis of int22h1/int22h2-mediated Xq28 duplication syndrome is established in hemizygous males and heterozygous females by detection of a 0.5-Mb duplication of the subregion extending from 154.1 Mb to 154.6 Mb within the q28 region of the X chromosome in the reference genome (NCBI Build GRCh37/hg19).

More specifically, the duplicated segment extends from a low copy repeat (LCR) region within intron 22 of F8, also known as intron 22 homologous region 1 (int22h1), to another LCR region located about 0.5 Mb telomeric to the former region and known as intron 22 homologous region 2 (int22h2). This duplication is likely mediated by a nonallelic homologous recombination event between the int22h1 and int22h2 LCR regions.

However, it is worth noting that several reported individuals have duplications nested within or partially overlapping with the typical int22h1/int22h2-mediated 0.5-Mb Xq28 duplication (see Genotype-Phenotype Correlations and Genetically Related Disorders).

Molecular genetic testing for an individual with neurodevelopmental delays and/or intellectual disability typically begins with a chromosomal microarray analysis.

Chromosomal microarray (CMA) performed either with oligonucleotide arrays or SNP (single-nucleotide polymorphism) genotyping arrays is capable of detecting the presence of an int22h1/int22h2-mediated Xq28 duplication. However, the ability of the specific array used to size the detected duplication depends largely on the type and probe density of the array itself. The int22h1/int22h2-mediated Xq28 duplication cannot be identified through routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

Note: (1) Most individuals with an int22h1/int22h2-mediated Xq28 duplication can be identified with the current CMA performed routinely for a clinical indication of neurodevelopmental delay and/or intellectual disability. (2) Routine CMA platforms before 2011 did not include coverage for this region and thus, could not detect this duplication. Likewise, the earlier BAC (bacterial artificial chromosome)-based arrays were also incapable of detecting this duplication. (3) Metaphase FISH is not reliable for detecting a duplication of this size (i.e., ~0.5 Mb). However, interphase FISH (iFISH) may be used if appropriate control studies are performed. (4) FISH analysis can also be sought to determine whether the duplicated segment may have been inserted elsewhere in the genome (i.e., insertion translocation).

Targeted duplication analysis is not typically performed as a first-line test in the absence of a known family history of the condition (see Evaluation of Relatives at Risk). Targeted duplication analysis should not be sought for an individual in whom an int22h1/int22h2-mediated Xq28 duplication could not be detected by a CMA platform designed to cover this region. Moreover, targeted duplication analyses cannot be routinely used to size the detected duplication – unlike CMA, which may allow for size determination.

Clinical Description

The int22h1/int22h2-mediated Xq28 duplication syndrome is a relatively newly identified X-linked intellectual disability syndrome characterized by cognitive impairment, neurobehavioral abnormalities, and a peculiar combination of recurrent sinopulmonary infections (e.g., otitis media, sinusitis, recurrent upper respiratory tract infections) and atopic conditions (i.e., asthma, allergic rhinitis, and eczema) in affected males, who also often have obesity and exhibit nonspecific facial dysmorphic features (Table 2). Because affected males are hemizygous, they exhibit more severe manifestations than heterozygous females, who display a milder phenotype that predominantly consists of mild learning disabilities, inattentive-type childhood attention-deficit/hyperactivity disorder (ADHD)-like manifestations, and nonspecific facial dysmorphic features similar to those seen in affected males (Table 2). However, the majority of heterozygous females are clinically unaffected or have inconspicuous abnormalities.

To date, approximately 35 individuals (19 males and 16 females) with int22h1/int22h2-mediated Xq28 duplication syndrome have been identified and reported within the literature. The clinical features discussed below are based on the phenotypic manifestations of all 35 affected individuals identified to date (see Table 2) [El-Hattab et al 2011, Lannoy et al 2013, Vanmarsenille et al 2014, El-Hattab et al 2015, Ballout et al 2020].

Intellectual disability. All affected males who could be formally evaluated (i.e., excluding the two prenatally diagnosed cases and the newborn affected male) have been found to have intellectual disability. In contrast, only half of the heterozygous females identified to date with int22h1/int22h2-mediated Xq28 duplication syndrome have been found to have intellectual disability, which is consistent with the milder phenotype seen for the duplication in heterozygous females, compared with affected males, who are hemizygous. Moreover, while neurodevelopmental delays are typically noted early in childhood in affected males, they are often inconspicuous or identified later in heterozygous females. Additionally, the severity of intellectual disability (ID) associated with the syndrome differs between the sexes: while typically in the mild-to-moderate range in affected males, ID is occasionally mild in heterozygous females, or (more commonly) not apparent.

Neurobehavioral abnormalities. The neurobehavioral manifestations are more common and pervasive in affected males than in heterozygous females. The most common findings:

• ADHD, the predominant associated neurobehavioral manifestation in either sex
• Aggression and irritability, seen in nearly one third of males but only one female
• Autism spectrum disorder
• Anxiety, which affects both sexes equally
• Various socialization deficits

Psychiatric pathology also appears to be more prevalent in affected males than in females; two males and one female were reported to have a mood disorder, while another male has been reported to have schizophrenia, a psychotic disorder. No heterozygous females have been reported to date to have a psychotic disorder (see Table 2).

Sleep disturbances. While sleep disturbances appear to be equally prevalent in affected males and heterozygous affected females (16% and 13%, respectively), it has been recently noted that the "type" of insomnia experienced is different between the sexes. Both heterozygous females with sleep disturbances had difficulty falling asleep (i.e., sleep initiation), while all three affected males had difficulty remaining asleep (i.e., sleep maintenance) [Ballout et al 2020].

Recurrent sinopulmonary infections and atopic diseases. Almost 75% of males have experienced recurrent sinopulmonary infections such as otitis media, pneumonia, and/or upper respiratory tract infections. Likewise, around 70% of affected males have a history of atopic diseases, namely, asthma, eczema, and allergic rhinitis. It is worth noting that almost all the males with recurrent sinopulmonary infections were also the ones who had atopic diseases, making this peculiar combination somewhat a "signature" feature of the syndrome in affected males.

In contrast, none of the heterozygous affected females have been reported to have either recurrent sinopulmonary infections or atopic diseases (see Table 2).

Anthropometric abnormalities. Obesity is seen in nearly one quarter of affected males (i.e., 5/19), but in only one of 16 heterozygous females.

Tall stature was identified in three affected males and no heterozygous females. However, males and females showed similar prevalence of acquired microcephaly (~5%).

Nonspecific facial dysmorphic features. The most common facial feature associated with the syndrome in both sexes was a tall forehead, with more than half of affected males (58%) and heterozygous females (56%) having this feature. Tall forehead is followed in prevalence by thick and broad vermilion of the lower lip, reported in one quarter of affected males (26%) and fewer than half of heterozygous females (44%). The third most common discernible feature in both sexes is large ears, seen in 21% of affected males and 19% of heterozygous females (see Table 2 and Figure 1). Other less common facial features include sparse scalp hair and sparse eyebrows, a thin vermilion of the lower lip, an elongated and smooth philtrum, and long eyelashes.

Two additional features involving the morphology of the nose appear to discriminate by sex among affected individuals. While three reported males have a bulbous nose, no heterozygous female has been reported with this feature. In contrast, heterozygous females appeared to be nearly twice as likely as affected males (19% vs 11%, respectively) to have a high nasal root and depressed nasal bridge, long eyelashes, large ears, and depressed nasal bridge.

The following additional findings (either rare manifestations of the condition or rare, unrelated co-occurrences) have each been reported in a single male unless otherwise specified:

• Limb and digital anomalies
  • A single palmar crease
  • Fetal finger pads
  • Rocker bottom feet
  • Pes valgus
  • Pes planus
  • Metatarsus adductus
  • Sandal gap
  • 2-3 toe syndactyly
  • Short second toe
  • Short heel cords
  • Arthrogryposis of the lower limbs with bilateral clubfoot [Ballout et al 2020]
• Skeletal anomalies
  • Kyphoscoliosis (1 male / 2 male fetuses and 1 heterozygous female. In 1 male fetus, kyphoscoliosis was associated with thoracic vertebral malformations and unilateral missing ribs.)
  • Sacral agenesis
  • Hip dysplasia
• Sensorineural hearing loss
• Genitourinary malformations [Ballout et al 2020]
  • Micropenis with hypospadias
  • Bilateral grade I hydronephrosis
  • Cryptorchisim with phimosis
• Imperforate anus [Ballout et al 2020]
• Motor mannerisms and stereotypy (1 male, 1 heterozygous female) [Ballout et al 2020]
• Recurrent seizures (1 heterozygous female) [Ballout et al 2020]
• Eye anomalies/refractive error
  • Strabismus (2 males)
  • Myopia
  • Astigmatism
• Micrognathia (3 males and 1 heterozygous female)
• A café au lait macule with multiple facial freckles (1 heterozygous female) [Ballout et al 2020]
• Esophageal atresia with tracheoesophageal fistula, associated with cleft lip and cleft palate (2 males)
• Atrial septal defects (2 males, 1 of whom had a concomitant patent ductus arteriosus, while the other had a ventricular septal defect)
• Hemihyperplasia (1 heterozygous female)
• Hypothyroidism (1 heterozygous female)
• Generalized hypotonia that is worse on one side of the body [Ballout et al 2020]
• Multiple malignancies with no underlying hereditary cancer syndromes identified on genetic testing [Ballout et al 2020]

X-chromosome inactivation in heterozygous females. X-chromosome inactivation analyses are reported to be skewed in ten of 13 heterozygous females with int22h1/int22h2-mediated Xq28 duplication who have been studied. However, the skewed inactivation of an X chromosome has been found to be inconsistent and somewhat nonspecific; that is, X-chromosome inactivation has been shown to occur at nearly equal frequencies in the normal X chromosome and the X chromosome containing the duplication. Moreover, no association could be appreciated between the X-chromosome inactivation pattern and the corresponding cognitive phenotype in the studied females, with random and skewed inactivation patterns being seen at nearly equal rates in heterozygous females with or without intellectual disability [El-Hattab et al 2015]. However, it is also worth noting that X-chromosome inactivation analyses have not been performed for all heterozygous females with the duplication.

Genotype-Phenotype Correlations

The region located between int22h1 and int22h2 on Xq28, which is the segment typically duplicated in int22h1/int22h2-mediated Xq28 duplication syndrome, includes several genes: FUNDC2, MTCP1, BRCC3, VBP1, RAB39B, CLIC2, and part of F8. However, the cognitive and neurobehavioral manifestations seen in individuals with the syndrome has been speculated to be the result of increased dosages of CLIC2 and RAB39B (see Molecular Genetics), based on the consistent detection of both loci within the smallest region of overlap between the duplicated segments of all affected individuals identified to date.

An atypical shortened version (~0.26 Mb) of the classic 0.5-Mb duplication reported in int22h1/int22h2-mediated Xq28 duplication syndrome has been reported in a newborn male, with his duplicated segment spanning only the centromeric half of the classically involved segment; that is, his duplication extended from 154.1 Mb to ~154.3 Mb of the q28 region of the X chromosome in the reference genome (NCBI Build GRCh37/hg19) [Ballout et al 2020]. This proband was a recently identified nine-week-old infant at the time of reporting. As such, it is currently unclear how much of the typical phenotype of the syndrome he may develop.

For information about other Xq28 duplications with partially overlapping breakpoints compared to the int22h1/int22h2-mediated Xq28 duplication syndrome, see Genetically Related Disorders.

Prevalence

Int22h1/int22h2-mediated Xq28 duplication has been reported in only 35 individuals (19 males and 16 females) to date [El-Hattab et al 2011, Lannoy et al 2013, Vanmarsenille et al 2014, El-Hattab et al 2015, Ballout et al 2020]. As a result, exact estimates on the prevalence of this duplication remain unknown.

Vanmarsenille et al [2014] estimated its prevalence at 1:1,000 among males with X-linked intellectual disability syndromes. In the absence of population-based studies, however, and due to the rarity of the syndrome, this may be an overestimate.

Evaluations Following Initial Diagnosis

In order to establish the extent and severity of manifestations in individuals with the int22h1/int22h2-mediated Xq28 duplication syndrome, Table 3 summarizes the different evaluations recommended to be performed (if not already performed as part of the evaluation that led to the diagnosis):

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

It is relevant from clinical and family planning standpoints to evaluate the genetic status of asymptomatic relatives of an affected individual in order to identify as early as possible those who would benefit from early intervention services.

Targeted duplication analysis can be performed by quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), or interphase FISH (iFISH) to test the relatives of a proband who is known to have the int22h1/int22h2-mediated Xq28 duplication.

Note: Clinically asymptomatic children identified as having the familial duplication should be assessed and monitored regularly for neurodevelopmental delays and neurobehavioral abnormalities.

See Genetic Counseling for issues related to the testing of at-risk relatives, from a genetic counseling perspective.

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 are no registered, recruiting, or ongoing clinical trials for int22h1/int22h2-mediated Xq28 duplication syndrome as of the chapter posting date.

Mode of Inheritance

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

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the int22h1/int22h2-mediated Xq28 duplication; therefore, he does not require further testing.
• In contrast, in a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (i.e., a carrier). Note: If a woman has more than one affected child and no other affected relatives and if the duplication cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If the proband is the only affected family member (i.e., a simplex case), the mother may be heterozygous for the duplication; or the duplication may have occurred de novo in the proband, in which case the mother is not heterozygous. Alternatively, the mother of the proband may have germline mosaicism.
• Most of the mothers of the individuals reported to date with the int22h1/int22h2-mediated Xq28 duplication syndrome have been found to be heterozygous (i.e., carriers) for the duplication.
• Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication is recommended for the mother of a proband. Note: Testing of maternal leukocyte DNA may not always detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Parents of a female proband

• A female proband may have inherited an int22h1/int22h2-mediated Xq28 duplication from her mother or, theoretically, her father if he has germline mosaicism. Alternatively, the duplication may have occurred de novo in the proband. De novo int22h1/int22h2-mediated Xq28 duplications were recently reported in two heterozygous females [Ballout et al 2020].
• Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication is recommended for the mother of a proband.

Sibs of a proband

• The risk to sibs of a male proband of inheriting the duplication depends on the genetic status of the mother. (However, if the proband is female, the risk to sibs of inheriting the duplication depends on the genetic status of the mother and, theoretically, the father because of the possibility of paternal germline mosaicism.)
• If the mother is heterozygous for the int22h1/int22h2-mediated Xq28 duplication, the chance of transmission of the duplication is 50% in each pregnancy.
  • Males who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be affected.
  • Females who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be heterozygous and will therefore be likely have a milder phenotype than affected males or be clinically unaffected (see Clinical Description).
• If the proband represents a simplex case (i.e., a single occurrence within the family), and the int22h1/int22h2-mediated Xq28 duplication cannot be detected in the leukocyte DNA of the mother, the risk to sibs of inheriting the duplication is low, albeit greater than that of the general population due to the possibility of maternal germline mosaicism. (Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.)

Offspring of a male proband. Only one affected male, recently reported, has been known to reproduce, having a healthy 16-year-old son [Ballout et al 2020].

Offspring of a female proband. Females heterozygous for the int22h1/int22h2-mediated Xq28 duplication have a 50% chance of transmitting the duplication to offspring in each pregnancy:

• Males who inherit the int22h1/int22h2-mediated Xq28 duplication will be affected.
• Females who inherit the int22h1/int22h2-mediated Xq28 duplication will be heterozygous, often exhibiting a milder phenotype than affected males or, alternatively, being clinically unaffected (see Clinical Description).

Other family members. The genetic risk of other family members depends on the genetic status of the proband's mother. If the mother is heterozygous for the int22h1/int22h2-mediated Xq28 duplication, her family members (e.g., her biological mother and sibs) may also have the duplication.

Note: Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication in the proband can help identify the family member in whom a de novo duplication occurred. Such information can help to determine the genetic risk of extended family members.

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/preimplantation genetic 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 at risk of having a child with the int22h1/int22h2-mediated Xq28 duplication syndrome.

Prenatal Testing and Preimplantation Genetic Testing

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

Pregnancies not known to be at increased risk for an 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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The int22h1/int22h2-mediated Xq28 duplication breakpoints are located at 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 the int22h1 and int22h2 loci [El-Hattab et al 2011].

It is worth noting that a third homologous region, int22h3, is located 0.6 Mb telomeric to int22h1, or about 0.1 Mb telomeric to int22h2. Until recently, no duplications involving the int22h3 locus (which is in opposite orientation to int22h1) had been identified. However, in the recent case series by Ballout et al [2020], a heterozygous female and her affected brother were both reported to have an atypical and telomerically shifted version of the int22h1/int22h2-mediated Xq28 duplication (cases 4 and 5), in which the distal breakpoint falls within the int22h3 region, rather than int22h2 (see Genetically Related Disorders). Interestingly, both reported individuals exhibited features consistent with and resembling those seen in individuals with int22h1/int22h2-mediated Xq28 duplication syndrome [Ballout et al 2020].

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, the int22h1/int22h2-mediated Xq28 duplication does not result in hemophilia A because the complete copy of F8 is preserved after formation of this duplication [El-Hattab et al 2011].

Genes of interest in this region. The 0.5-Mb duplicated region between int22h1 and int22h2 includes several genes. However, the intellectual disability of individuals with the int22h1/int22h2-mediated Xq28 duplication syndrome has been speculated to be likely due to increased dosages of two of those genes in particular: RAB39B and CLIC2 [Andersen et al 2014, El-Hattab et al 2015].

• CLIC2 encodes the unique intracellular transmembrane chloride channel 2 (CLIC2) protein, present in cardiac and skeletal muscle cells where it functions as a regulator of calcium release via the ryanodine receptor 2 (RyR2) [Board et al 2004, Meng et al 2009]. A missense pathogenic variant in CLIC2 has been reported to be associated with a distinct form of X-linked intellectual disability syndrome in two brothers having intellectual disability, cardiomegaly, atrial fibrillation, heart failure, and seizures [Takano et al 2012].
• RAB39B encodes a specific member of the Rab family of GTPases that is highly expressed in central nervous system neurons, particularly in the hippocampus, where it has been shown to play a key role in the trafficking of an AMPA glutamate receptor (GluA2) and facilitate synaptogenesis and neuronal branching [Ng & Tang 2008, Mignogna et al 2015].
  • Loss-of-function pathogenic variants in RAB39B reported in two families have been associated with intellectual disability, autism spectrum disorders, epilepsy, and microcephaly [Giannandrea et al 2010]. Loss-of-function pathogenic variants in RAB39B have also been associated with early-onset Parkinson disease [Wilson et al 2014, Lesage et al 2015].
  • In contrast, increased dosages of RAB39B have been reported in four males to be associated with intellectual disability and neurobehavioral abnormalities [Vanmarsenille et al 2014]. Overexpression of Rab39b in mouse primary hippocampal neurons was then shown to result in decreased neuronal branching and total number of synapses, suggesting that increased dosages of RAB39B disrupt neuronal branching [Vanmarsenille et al 2014].

Author Notes

Rami A Ballout, MD is currently a postdoctoral research fellow at the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH). He is interested in pursuing further training in pediatric genetics, with a special emphasis on lysosomal storage diseases, cholesterol metabolism disorders, and intellectual disability syndromes.
Websites: www.researchgate.net; orcid.org

Christian P Schaaf, MD, PhD, FACMG is director and chairman of the Institute of Human Genetics at Heidelberg University (Germany). He specializes in the genetics of intellectual disability and autism spectrum disorder.

Acknowledgments

We wish to thank all the patients and their families/caregivers and overseeing physicians, without whom none of the original studies cited in this chapter would have been conducted.

Revision History

• 25 February 2021 (ma) Comprehensive update posted live
• 10 March 2016 (bp) Review posted live
• 31 July 2015 (aweh) Original submission

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]
• Ballout RA, Dickerson C, Wick MJ, Al-Sweel N, Openshaw AS, Srivastava S, Swanson LC, Bramswig NC, Kuechler A, Hong B, Fleming LR, Curry K, Robertson SP, Andersen EF, El-Hattab AW. Int22h1/Int22h2-mediated Xq28 duplication syndrome: de novo duplications, prenatal diagnoses, and additional phenotypic features. Hum Mutat. 2020;41:1238-49. [PMC free article: PMC7292747] [PubMed: 32112660]
• Board PG, Coggan M, Watson S, Gage PW, Dulhunty AF. CLIC-2 modulates cardiac ryanodine receptor Ca2+ release channels. Int J Biochem Cell Biol. 2004;36:1599-612. [PubMed: 15147738]
• 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]
• Lesage S, Bras J, Cormier-Dequaire F, Condroyer C, Nicolas A, Darwent L, Guerreiro R, Majounie E, Federoff M, Heutink P, Wood NW, Gasser T, Hardy J, Tison F, Singleton A, Brice A, et al. Loss-of-function mutations in RAB39B are associated with typical early-onset Parkinson disease. Neurol Genet. 2015;1:e9. [PMC free article: PMC4821081] [PubMed: 27066548]
• 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]
• Mignogna ML, Giannandrea M, Gurgone A, Fanelli F, Raimondi F, Mapelli L, Bassani S, Fang H, Van Anken E, Alessio M, Passafaro M, Gatti S, Esteban JA, Huganir R, D'Adamo P. The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition. Nat Commun. 2015;6:6504. [PMC free article: PMC4383008] [PubMed: 25784538]
• Ng EL, Tang BL. Rab GTPases and their roles in brain neurons and glia. Brain Res Rev. 2008;58:236-46. [PubMed: 18485483]
• 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]
• Wilson GR, Sim JC, McLean C, Giannandrea M, Galea CA, Riseley JR, Stephenson SE, Fitzpatrick E, Haas SA, Pope K, Hogan KJ, Gregg RG, Bromhead CJ, Wargowski DS, Lawrence CH, James PA, Churchyard A, Gao Y, Phelan DG, Gillies G, Salce N, Stanford L, Marsh AP, Mignogna ML, Hayflick SJ, Leventer RJ, Delatycki MB, Mellick GD, Kalscheuer VM, D'Adamo P, Bahlo M, Amor DJ, Lockhart PJ. Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with alpha-synuclein pathology. Am J Hum Genet. 2014;95:729-35. [PMC free article: PMC4259921] [PubMed: 25434005]