Xq28 duplications

Xq28 duplications and microduplications

An Xq28 duplication means that the cells of the body have a small but variable amount of extra genetic material from one of their 46 chromosomes the X chromosome. These duplications can be variable in size but those that are too small to be visible under the microscope are called microduplications. For healthy development, chromosomes should contain just the right amount of genetic material (DNA) not too much and not too little. Like most other chromosome disorders, having an extra part of chromosome X may increase the risk of birth defects, developmental delay and intellectual disability. However, the problems depend on whether the affected person is male or female, and what and how much genetic material is duplicated. Background on chromosomes Chromosomes are structures which contain our DNA and are found in almost every cell of the body. Every chromosome contains hundreds to thousands of genes which may be thought of as individual instruction booklets (or recipes) that contain all the genetic information telling the body how to develop, grow and function. Chromosomes (and genes) usually come in pairs with one member of each chromosome pair being inherited from each parent. Most cells of the human body have a total of 46 (23 pairs of) chromosomes. The egg and the sperm cells, however have 23 unpaired chromosomes, so that when the egg and sperm join together at conception, the chromosomes pair up and the number is restored to 46. Of these 46 chromosomes, 44 are grouped in 22 pairs, numbered 1 to 22 approximately from the largest to the smallest. The remaining two are the sex chromosomes that determine biological sex. Males have one X chromosome and one Y chromosome, and females have two X chromosomes. Early in embryonic development in females, one of the two X chromosomes (either the one inherited from the mother or the one inherited from the father) is randomly (by chance) and permanently inactivated in all the bodys cells (other than egg cells). This phenomenon is called X-inactivation. Because the inactivation is random some cells in the female body may have an inactive X chromosome inherited from the father, while other cells have an inactive X chromosome inherited from the mother. Chromosome duplications A sperm cell from the father and an egg cell from the mother each has just one copy of each chromosome. When they join together they form a single cell that now carries two copies of each chromosome. This cell must make many copies of itself (and all the chromosomes and genetic material) in order to make the many billions of cells that form during human growth and development. Sometimes during the formation of the egg or sperm cells or during this complicated copying and replication process, parts of the chromosomes break off or become arranged differently than usual. Boys with an Xq28 duplication have one intact chromosome Y, but their chromosome X has an extra piece of the long arm of chromosome X. Girls with an Xq28 duplication have one intact chromosome X, but the second copy has an extra piece of the long arm. Girls can generally cope with the extra part of chromosome X because only one X chromosome in any cell is fully active. The other copy is switched off by the X2

inactivation process. A process known as skewed X-inactivation means that the X chromosome with the duplication is the one that is usually switched off (inactivated). Therefore in girls any extra (duplicated) parts of the X chromosome are also mostly switched off and so play little or no role in development which is why a duplication of Xq28 has a milder effect or most often no effect at all in girls. Very rarely girls with Xq28 duplication on one of their X chromosomes might not preferentially inactivate the this X with the duplication in all cells (instead the normal X is inactivated in some or all cells) and could show some features of the an Xq28 duplication. As boys have only one copy of the X chromosome it is always fully active, and therefore the duplicated part is also fully active. Although the exact numbers and types of genes that are included in the duplication are often not known, the extra copies of some genes usually have an effect on a boys learning and physical development. Therefore it is believed that most of the clinical difficulties are caused by having two copies (instead of the usual one) of a one or a number of genes. We are still learning more the about the specific jobs or functions of the genes in this region (see Ongoing Research involving Xq28 on page 12). Also, it is important to keep in mind that a childs other genes, environment and unique personality help to determine future development, needs and p arm achievements. Looking at Xq28 Each chromosome has a short or petit (p) arm (shown at the top in the diagram on the right) and a long (q) arm (the bottom part of the chromosome). Chromosomes cant be seen with the naked eye but if they are stained and magnified under a microscope it is possible to see that each one has a distinctive pattern of light and dark bands that look like horizontal stripes under a microscope. You can see these bands in the diagram. They are numbered outwards starting from where the short and long arms meet (the centromere). By looking at your childs chromosomes in this way, it is possible to see what material is duplicated, if the duplicated piece is large enough. The duplicated piece can be small or large. Because the amount of material duplicated is often small and impossible to see on a routine chromosome test, your child may have been told their chromosome analysis was normal. In fact, in many individuals the Xq28 duplication may be missed. A technique in the laboratory called FISH can help detect a duplication, but only if the person ordering the test actually suspected that there was an abnormality of a specific region of chromosome Xq28. The newest test now available for patient care is called a microarray comparative genomic hybridisation (array CGH) test. An array CGH test can detect an Xq28 duplication (and many others as well) even when the doctor ordering the test does not even suspect this diagnosis. 3

centromere q arm

Boys with a pure Xq28 duplication can generally be divided into two groups: Group 1 have larger duplications of Xq28 (which may also include duplications of Xq27 and/or Xq26) which are visible under the microscope (Sanlaville 2004, Van Esch 2005; del Gaudio 2006) Group 2 have smaller duplications of a part of Xq28 that usually encompasses the methyl CpG binding protein 2 (MECP2) gene. This is why an Xq28 duplication is sometimes called MECP2 duplication syndrome (Ariani 2004; Meins 2005; Van Esch 2005; del Gaudio 2006; Smyk 2008; Madrigal 2007; Friez 2006) Extremely rarely, cells with a normal chromosome make-up are found as well as cells with extra material from Xq28. This is called mosaicism and can, in some cases, lessen the effects of the extra chromosome material. Results of the chromosome test Your geneticist or genetic counsellor will be able to tell you about the point(s) where the chromosome has broken in your child. You will almost certainly be given a karyotype which is shorthand notation for their chromosome make-up. With an Xq28 duplication, the results are likely to read something like the following example: 46 XY dup (X) (q28) dn 46,XY,dup(X)(q28)dn The total number of chromosomes in your childs cells The two sex chromosomes: XY indicates a male, XX indicates a female A duplication means that there is an extra amount of DNA The duplication consists of material from chromosome X The chromosome has broken in one place, q28, material from this point to the end of the long arm of chromosome X is included in the duplication The duplication occurred de novo (or as a new event). The parents chromosomes have been checked and no duplication or other chromosome change has been found at Xq28. The duplication is very unlikely to be inherited so the recurrence risk for the parents to have another child with the duplication is very small. If the karyotype is followed by mat the duplication has been inherited from the childs mother; if it is pat the duplication has been inherited from the father

In addition to, or instead of a karyotype you may be given the results of molecular analysis such as FISH or array CGH for your child. In this case the results are likely to read something like one of the following examples: An example of FISH analysis: 46 XY dup (X) (q28) 46,XY,dup(X)(q28).ish dup(X)(RP11-119A22++) The total number of chromosomes in your childs cells The two sex chromosomes: XY indicates a male, XX indicates a female A duplication means that there is an extra amount of DNA The duplication consists of material from chromosome X The chromosome has broken in one place, q28, material from this point until the end of the long arm of chromosome X is included in the 4

duplication ish The analysis was by FISH dup A duplication (X) The duplication consists of material from chromosome X RP11-119A22++ A region of DNA known as RP11-119A22 has been detected in two copies instead of the usual one copy An example of array CGH: arr Xq28(152,940,458-153,016,382)x3 Here a technology known as array-CGH has shown a duplication at Xq28. The duplicated fragment is from the base pair (the chemicals in the DNA molecule that form the ends of the rungs of its ladder-like structure, see diagram on the right) number 152,940,458 counting from the top of the chromosome through to the base pair number 153,016,382 (see diagram below). This means that about 75,924 base pairs are duplicated. This is usually expressed as 75.9 Kb (1 Kb = 1,000 base pairs). You may wish to compare your child with others with the same duplication. Its important to remember that the same duplication can have different effects on different people and there will be differences between your child and others with an apparently similar karyotype. It is very important to see your child as an individual and not to rely on direct comparisons with others who appear to have the same karyotype. After all, each of us is unique. ~56,270,00 base pairs ~155,270,00 base pairs

Sources The information in this leaflet is drawn partly from the published medical literature. The firstnamed author and publication date are given to allow you to look for the abstracts or original articles on the internet in PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). If you wish, you can obtain most articles from Unique. In addition, this leaflet draws on information from two surveys of members of Unique conducted in 2009, referenced Unique. When this leaflet was written Unique had 10 boys with a pure Xq28 duplication without loss or gain of material from any other chromosome. These members range in age from a child of three years to an adult aged 30 years. There are more people, described in the medical literature and 10 members of Unique, who have a loss or gain of material from another chromosome arm as well as an Xq28 duplication, usually as a result of a chromosome change known as a translocation. As these people do not show the effects of a pure duplication, they are not considered in this leaflet. Unique holds a list of the cases described in the medical literature and the karyotypes of those in Unique; this is available to members on request.

Most common features of a duplication of Xq28 in boys Every boy with an Xq28 duplication is unique and so each person will have different medical and developmental concerns. Additionally, no one person will have all of the features listed in this guide. However a number of common features of duplications of Xq28 have emerged: Hypotonia (floppiness or unusually low muscle tone) in newborn babies and infants Delayed or absent speech and language Learning (intellectual) disability Progressive neurological conditions such as seizures and spasticity (a disorder in which certain muscles are continuously contracted. This contraction causes tightness and stiffness of the muscles and may interfere with gait and movement) Recurrent respiratory infections Girls with an Xq28 duplication Large duplications of Xq28 have been observed in a number of girls. In the vast majority of cases, a girl with an Xq28 duplication is unaffected due to the process known as X-inactivation (see Chromosome duplications on page 2-3). However, there are three girls at Unique who are mildly affected by an Xq28 duplication. A 3-year-old had feeding problems which necessitated a gastrostomy tube (feeding direct into the stomach) and fundoplication (a surgical operation to improve the valve action between the stomach and food passage) and she has growth hormone injections. She has an asymmetric body with one side longer than the other. She has mild speech and physical delays but no intellectual delay. An 8-year-old girl had speech and motor delays but at aged 8 has caught up and is a healthy, happy, friendly girl. A 32-year-old woman had learning difficulties as a child and as an adult has problems assimilating new information. She also had some speech problems as a child and pronunciation difficulties have persisted into adulthood. From the age of 12 years she has had seizures which are well controlled (Unique).

Boys with an Xq28 duplication Hypotonia in newborn babies and

infants

Girls with an Xq28 duplication

Generally girls are unaffected, but in rare cases they may have:

Delayed or absent speech and

language

Short stature Mild delays in speech and language Mild learning difficulties Mild motor delays Body asymmetry

Learning (intellectual) disability Progressive neurological conditions

such as seizures and spasticity

Recurrent respiratory infections

How common are Xq28 duplications in boys? Duplications of Xq28 have been rarely detected and only around 60 boys have been reported in the published medical literature (Friez 2006; Echenne 2009). What is the outlook? The outlook for a boy with an Xq28 duplication depends on what segment of chromosome Xq28 has been duplicated and how this has disrupted early development in the womb. As far as we know the oldest nab with an Xq28 duplication is 30 years old (see Adults with an Xq28 duplication page 12). One paper reported that six out of 11 boys with an Xq28 duplication died (from secondary recurrent respiratory infections or pneumonia) before 25 years of age. In this report the boys also had severe functional problems of the bowel and/or bladder which are thought to have predisposed to respiratory infections by restricted lung capacity. As far as we are aware, none of the Unique boys with Xq28 duplications have died (Friez 2006; Unique). Pregnancy and birth The vast majority of mothers carrying babies with Xq28 duplications experienced no pregnancy problems, had a normal delivery and only discovered their baby was affected after the birth. However, of the four families who have told us about their pregnancy experiences, one baby was small for gestational age and had a low birth weight. There are no reports in the medical literature of any pregnancy or birth complications (Unique). Newborn Typically babies with a duplication of Xq28 are floppy (hypotonic) in the newborn period. This can result in delay reaching the baby developmental milestones (such as sitting, rolling, crawling and walking) and also cause feeding problems (Unique). Growth and feeding Baby boys with an Xq28 duplication generally have a normal birth weight with an average of 3.3 kilos (7lb 4oz). One Unique baby and one baby in the medical literature had a low birth weight (below 2.6 kilos or 5lb 12oz) at term (Vasquez 1995; Unique). Range of birth weights at Unique and in the medical literature (at or near term): 2.5 kilos (5lb 8oz) to 4.3 kilos (9lb 8oz) For those boys with a duplication of Xq28, feeding difficulties are a major area of concern for families. Some babies are described as failure to thrive. This term is used to describe a baby who has poor weight gain and physical growth failure over a period of time. The hypotonia that is common in babies with an Xq28 duplication can lead to difficulties with sucking and swallowing, and/or latching onto the breast. One study reports that more than 50 per cent (15/29) of boys have severe feeding problems. One baby in the medical literature benefited from a temporary nasogastric tube (NGtube, passed up the nose and down the throat) and two babies at Unique needed a gastrostomy tube (a G-tube) in order to meet their nutritional needs (Vasquez 1995; Goodman 1998; Lammer 2001; Van Esch 2005; Friez 2006; Echenne 2009; Sanlaville 2009; Unique). The hypotonia can also affect their food passage and contribute to gastro-oesophageal 7

(GO) reflux (in which feeds return readily up the food passage). This can generally be well controlled by giving feeds slowly, positioning a baby semi-upright for feeds and where necessary raising the head of the end of the bed for sleeping. Feed thickeners and prescribed medicines to inhibit gastric acid may control reflux. If these measures are not enough, some babies benefit from a fundoplication (Friez 2006; Sanlaville 2009; Unique). Boys with a duplication of Xq28 usually have normal growth and are of normal height and weight, although there are two reports in the medical literature of boys who have growth retardation (Sanlaville 2009; Unique). Appearance Children with a duplication of Xq28 sometimes have facial features in common. The most common feature is unusually large ears. They may also have a flat nasal bridge. Facial hypotonia can result in an inverted V-shaped (tented) upper lip, open mouth and drooling. Microcephaly (an unusually small head) has also been reported in a number of boys. However, these facial features can be very subtle and children look little different compared to other children and may closely resemble their siblings or parents (Van Esch 2005; Friez 2006; Unique). Learning Intellectual disabilities affect boys with an Xq28 duplication, with most children severely affected and a small minority profoundly affected. One boy described in the medical literature who has a very small duplication of 250 kilobases has a moderate learning disability. As a result of this, children will need support and may benefit from early intervention programmes and thrive best in a special learning environment (Madrigal 2007; Echenne 2009; Unique). He has a good memory and loves music and TV 4 years His memory is not good 16 years Speech and communication Speech is delayed or absent in boys with an Xq28 duplication. Two boys in the medical literature are reported to have limited speech. Some children use sign language to help to communicate their needs and wants and many children have long term speech therapy to help their communication skills. Children use gestures, facial expressions and vocal noises to indicate their needs and express their feelings. One Unique child with no formal speech is very expressive with his eyes and smiles (Van Esch 2005; Friez 2006; Unique). There are many reasons for the absent or delayed speech, including the link between the ability to learn and the ability to speak. The hypotonia experienced by many children results in weakness in the mouth muscles which in addition to insufficient sucking, can also affect the development of speech (Unique). He does not use words but screams and points 4 years He has no speech 16 years 8

Development: sitting, moving, walking (gross motor skills) Boys with an Xq28 duplication are typically slow to reach their developmental motor milestones. The evidence in the medical literature and at Unique is that boys with an Xq28 duplication sit between 7 months and 4 years (average 19 months); crawl between 14 months and 6 years (average 31 months) and walk on average at age 26 months (range 14 months to 3 years). Independent walking is not possible for all boys. Some children need support (such as a standing frame, walking frame, wheelchair and/ or support boots) while learning to walk. Many children have ataxia which means absence of order. People with ataxia have problems with co-ordination so often walk unsteadily or clumsily (Van Esch 2005; Echenne 2009; Unique). There are several reasons for these motor delays including the hypotonia that affects the vast majority of boys with an Xq28 duplication and physiotherapy and occupational therapy can be beneficial. Hypotonia often improves as children mature, however, in boys with a duplication of Xq28 the hypotonia often progresses to spasticity (or muscle hypertonicity) in later childhood or teen years. The spasticity usually affects the legs more than the arms (Van Esch 2005; Friez 2006; Echenne 2009; Unique). Development: hand-eye co-ordination and dexterity (fine motor skills) There is very little information on fine motor skills of boys with an Xq28 duplication, however, hypotonia can also affect fine motor skills in children with an Xq28 duplication and they may take longer to reach for and grab toys and hold a bottle or cup. Many children have occupational therapy in order to help improve these skills (Unique). Medical concerns Immunity An increased susceptibility to infections seems to be common in boys with a duplication of Xq28. Recurrent respiratory infections are especially common. In one study almost all of the 18 individuals had needed mechanical ventilation on at least one occasion, and four of the five who were aged over 15 years had tracheostomies. A tracheostomy is a surgical procedure in which an opening is created in the front of the trachea (windpipe). A tracheostomy tube is inserted through the opening and into the trachea. If a persons airway (the tube that connects the mouth and nose to the lungs) is blocked or unusable, the opening that is created during a tracheostomy allows them to breathe freely. As well as helping someone to breathe, a tracheostomy can also be used to remove unwanted fluids produced by the lungs or throat. However, in another study of five boys none had frequent infections (Friez 2006; Echenne 2009). The increased susceptibility to infections seen in some boys with an Xq28 duplication could be explained in part by contributing factors such as reflux and swallowing difficulties which are common in these boys. Another explanation is that low levels of an infection-fighting antibody, IgA (immunoglobulin A), are found in some boys with an Xq28 duplication. IgA plays an important role in defending the body against infection that invades the body through the mucous membranes, such as the nose, eyes, lungs and intestines. Therefore, people with low IgA are more susceptible to infections and colds. However, a low level of IgA is frequently found in typically developing children. Early detection of infection and the use of antibiotics is prudent (del Gaudio 2006; Friez 2006; Unique). 9

 Seizures
Seizures affect around a half of all boys with an Xq28 duplication. The onset of seizures varies widely from very early childhood to a number of boys whose first seizure occurs around or after the age of 20. Medication has been effective at controlling seizures in many boys, although for some their seizures have become resistant to medication (Sanlaville 2009; Unique).

Genital anomalies
Minor anomalies of the genitals are common in boys with chromosome disorders. Cryptorchidism (undescended testes) has been noted in a number of boys with an Xq28 duplication. The testicles can be brought down by a straightforward surgical operation if they do not descend of their own accord in time. Hypoplastic (underdeveloped) genitalia has also been reported. Hypospadias (where the hole usually sited at the end of the penis is on the underside instead) has also been seen in one boy in the medical literature. Micropenis (a small penis) has been reported in one boy with an Xq28 duplication (Vasquez 1995; Goodman 1998; Lammer 2001; Meins 2007; Unique).

Brain
Brain imaging has shown that a number of boys with an Xq28 duplication have brain anomalies. Some boys have delayed myelination. Myelin is the substance that covers nerve cells (much like the plastic coating covering the wire in an electric cable). Myelination, the formation of myelin, is an ongoing process that starts in the womb and continues after birth and into middle age and in some boys with an Xq28 duplication the myelination process seems to normalise. Two boys had hydrocephalus (a build-up of fluid on the brain) which resolved with no intervention. More rarely, described in only one boy, is agenesis of the corpus callosum (ACC). The corpus callosum is the largest connective pathway in the brain. It is made up of more than 200 million nerve fibres that connect the left and right sides (hemispheres) of the brain. ACC is a birth defect in which the corpus callosum is partially or completely absent, resulting in poorly connected or disconnected brain hemispheres. Each hemisphere of the brain is specialised to control movement and feeling in the opposite half of the body, and each hemisphere specialises in processing certain types of information (such as language or spatial patterns). Thus, to co-ordinate movement or to think about complex information, the hemispheres must communicate with each other. The corpus callosum is the main, although not the only, connector that allows that communication (Friez 2006; Echenne 2009; Unique).

Digestion
One problem is constipation which affects a number of Unique boys with an Xq28 duplication and has also been reported in the medical literature. Dietary changes and/or medication can help to manage the problem. One report of a series of boys with an Xq28 duplication described severe functional problems of the bowel from the newborn period onwards. In several children regular enemas were necessary and dilatation of the bowel affected respiratory function (Goodman 1998; Clayton-Smith 2009; Unique).

10

 Vision
The vision of boys who have a duplication of Xq28 seems to be largely unaffected. One Unique boy had a squint (strabismus), where one or both eyes can turn inwards, outwards or upwards. Many squints are convergent (the eyes cross) and many children need surgery to re-align the eyes. Another Unique boy had Horners syndrome (a disruption in the nerves that supply the eye) in his right eye. One boy in the medical literature had mild long sight (hypermetropia) (Meins 2007; Unique).

Hearing
Like vision, hearing appears to be largely unaffected in boys with an Xq28 duplication. One boy in the medical literature had bilateral (affects both ears) deafness. Another boy in the medical literature had glue ear, where there is a build-up of fluid in the middle ear. Glue ear usually resolves as children get older and the ear tubes widen and become more vertical resulting in improved drainage of the middle ear. Therefore, any hearing loss caused by glue ear is usually temporary. However, persistent fluid in the middle ear and glue ear can reduce a child's hearing at a time that is critical for speech and language development. Therefore, while glue ear persists, many children will need a grommet (a small ventilation tube) inserted into the eardrum (Van Esch 2005; Friez 2006; Unique).

Heart problems
Heart (cardiac) conditions do not appear to be a common feature of an Xq28 duplication, having been reported rarely in the medical literature. One boy had dilated aortic root (the aortic root, see diagram, becomes enlarged which can result in leakage of blood back through the aortic valve) and one had coarctation of the aorta (a narrowing of the aorta where the ductus arteriosus, see diagram, inserts). None of the boys at Unique had a heart condition (Madrigal 2007; Unique).

Coarctation of the aorta occurs here

Aortic root

11

 Feet
The feet of those with an Xq28 duplication are often perfectly formed. However, some foot anomalies have been described both at Unique and in the medical literature. These anomalies include high arches, flat feet, puffy feet and/or feet that turn inwards. Generally the foot anomalies may mean that children require special insoles or inserts in their shoes or special supportive footwear (Friez 2006; Unique).

Teeth
Generally speaking, children with chromosome disorders appear to have somewhat more dental problems than their peers, therefore high quality treatment and frequent dental appointments are recommended (del Gaudio 2006; Unique).

Other concerns
Scoliosis (curvature of the spine) has been reported in one Unique boy. Three boys in the medical literature had inguinal hernias. An inguinal hernia is one where the bulge is tissue from the intestines and is located in the lower abdomen (groin). An inguinal hernia may require surgery. One boy at Unique had kidney (vesico-ureteral) reflux (where the urine flows upwards from the bladder back to the kidney, potentially damaging the kidneys). Two boys in the medical literature suffered from frequent urinary tract infections (Vasquez 1995; Goodman 1998; Lammer 2001; Friez 2006; Unique). Behaviour Children with an Xq28 duplication are typically pleasant, calm and sociable. However, they are as vulnerable to frustration as other children with a communication difficulty and temper tantrums and aggression can present carers with challenges (Unique). Behaviour within the autistic spectrum has been reported both in the published medical literature and in a number of Unique children. Some children do not have a diagnosis of autistic spectrum disorder (ASD) but show some autistic tendencies or traits. The autistic tendencies that have been noted include limited range of facial expression, decreased eye contact, repetitive behaviours, self-stimulating behaviours and repeating movements like head shaking or wringing their fingers. A diagnosis of autism can be extremely helpful in accessing services and tailoring the educational and behavioural therapy to meet the specific needs of a child with autism (Meins 2005; del Gaudio 2006; Friez 2006; Unique). Aggressive behaviour or mood disorders have been described in a small minority of boys. One boy described in the medical literature showed autistic features at the age of 4 years which disappeared two or three years later. Between the age of 15 and 20 years he developed a mood disorder and had oppositional behaviour but these disappeared by the age of 20 years (he is now 26 years old). One boy in the medical literature was described as shy (Meins 2005; Van Esch 2005; del Gaudio 2006; Echenne 2009; Unique). Boys with an Xq28 duplication seem to share a love of music (Unique). He is happy but has some behavioural problems 4 years They both love music brothers aged 16 years and 30 years 12

Puberty Unfortunately, there is no information available on puberty in both males with an Xq28 duplication, either at Unique or in the medical literature. Adults with an Xq28 duplication To date, there are very few adults known to have an Xq28 duplication. Unique has one adult member of 30 years old. He loves music. His memory is not good and he has ASD and needs fulltime care. He has no speech and uses a wheelchair (Unique). Two brothers of 25 years and 33 years have been described in the medical literature. Both had swallowing difficulties and one had a feeding tube. Due to recurrent pneumonia both had had a tracheostomy. A 24-year-old man is also described in the medical literature. He has a profound learning disability. A 26-year-old man has a low IQ but his learning disability has not worsened over time. He had autism as a child but outgrew it. He has mastered walking and the ataxia he had when younger has lessened over time. He has epilepsy. His 20-year-old nephew is also described. He is not affected by autism. He also suffers from epilepsy but less severely than his uncle (Van Esch 2005; Friez 2006; Echenne 2009). Ongoing research involving Xq28 The features of an Xq28 duplication are likely to be a result of the extra copy of one or a number of different genes found in this region. The increasing use of molecular techniques such as array CGH and FISH in the research laboratory has allowed detection of microduplications of Xq28 that are not detectable with a microscope and enables more accurate definition of the breakpoints. This, in turn, enables researchers to study more accurately which parts of the chromosome are duplicated and attempt to correlate certain regions with the different clinical features of the condition. The size and position of the duplicated region found varies ranging from a small duplication of 0.2 megabases (one megabase or Mb= one million base pairs of DNA) to larger ones of more than 2Mb but consistently include MECP2 and L1 cell adhesion molecule (L1CAM), as well as seven intervening genes (see diagram below) (del Gaudio 2006). MECP2 is thought to be one of the genes responsible for the features of an Xq28 duplication or microduplication. Studies indicate that boys with two copies (instead of the usual one) of MECP2 have learning disabilities. Additionally, there is one boy reported in the medical literature with three copies of MECP2 who is affected more severely than those with two (del Gaudio 2006). Furthermore, studies in mice have shown that mice that have twice the normal levels of MeCP2 develop the features of an Xq28 duplication (Luikenhuis 2004; Collins 2004). Further evidence that MECP2 has an important role in the features of an Xq28 duplication is that there has recently been one report of a duplication of Xq28 which does NOT include the MECP2 gene in a boy who is unaffected by the duplication (Lugtenberg 2006).These studies pinpoint increased levels of MECP2 as the gene (or one of the genes) responsible for the features of an Xq28 duplication. Mutations or deletion of MECP2 causes a completely different syndrome (Rett syndrome) affecting mainly girls. L1CAM is found in high levels in the nervous system. So far no duplications that involve only L1CAM have been reported so it is not known if this gene is associated with any of the features seen with an Xq28 duplication. 13

Genes: L1CAM

Features: ?

MECP2

Learning disability

FLNA1

Intestinal pseudo-obstruction

GDI1

Learning disability?

It is important to note however, that some boys have larger duplications that include many other genes. The full extent of phenotypes due to duplication of other genes is not completely understood. However, boys who also have duplication of the Filamin A (FLNA) gene have been shown to be at risk for intestinal pseudo-obstruction (a disorder of the digestive system that affects the movement of food through the intestines), although none of the boys at Unique are known to have intestinal pseudoobstruction. Mutations in the gene GDI1 have been associated with learning disability. However, the consequence(s) of a duplication of GDI1 is not yet known(Bienvenu 1998; Clayton-Smith 2009). It is important to remember that while identifying the gene(s) responsible for certain features of an Xq28 duplication is interesting and may help guide future studies, it does not lead directly to immediate improved treatment. Additionally, even if the supposedly responsible gene is present in three copies instead of the normal two it does not always mean that the associated feature(s) will be present. Other genetic and environmental factors often have a role in determining the presence or absence of a particular feature. Why did this happen? A blood test to check both parents chromosomes is needed to find out why the Xq28 duplication occurred. In the majority of cases a boy inherits the Xq28 from his mother (a carrier) who is either not at all affected or only mildly affected by the duplication. In some cases the Xq28 duplication occurred when both parents have normal chromosomes. The term that geneticists use for this is de novo (dn) which means new. De novo Xq28 duplications are thought to be caused by a change that occurred when the parents sperm or egg cells formed or possibly during formation and copying of the early cells after the egg and sperm joined. 14

Some Xq28 duplications are accompanied by a loss of material from another chromosome. This can be a de novo change or it can be a result of a rearrangement in one parents chromosomes. This is usually a rearrangement known as a balanced translocation in which material has swapped places between chromosomes. As no genetically important material has been lost or gained, the parent usually has no clinical or developmental problems, although they may have difficulties with fertility or childbearing. Balanced translocations involving one or more chromosomes are not rare: one person in 560 has one, making a total world population of over 12 million balanced translocation carriers. In a few people, the cells containing the Xq28 duplication chromosome exist alongside cells with a normal chromosome number and arrangement. This situation, known as mosaicism, typically arises after fertilisation and can lessen the impact of the duplication. Whether the duplication is inherited or de novo, what is certain is that as a parent there is nothing you did to cause the Xq28 duplication and nothing you could have done would have prevented it from occurring in your baby. No environmental, dietary, workplace or lifestyle factors are known to cause these chromosome changes. No one is to blame when this occurs and nobody is at fault and there is no reason for anyone to feel guilty. Can it happen again? The possibility of having another pregnancy with an Xq28 duplication depends on the parents chromosomes. If both parents have normal chromosomes when their blood cells are tested, the duplication is very unlikely to happen again. However, if the mother is a carrier, the risk of having another affected boy is 25 per cent and the risk for having a carrier girl is 25 per cent for each pregnancy. Since carrier girls generally have skewed inactivation resulting in the Xq28 duplication being inactivated, girls are normally unaffected by the duplication. In addition, if either parent has a chromosome rearrangement involving Xq28, the possibility is greatly increased of having other affected pregnancies. In the case of de novo duplications, the possibility exists that the mother can have mosaicism and therefore only carries the duplicated X chromosome in her ova or egg cells (or only in some of these cells). Because this type mosaicism cannot be ruled out in de novo cases, the risk to subsequent pregnancies in de novo cases is considered to be between one and five per cent. To date, no cases of men transmitting the duplication have been reported. This is because, as far as we know, all boys/men who have the duplication have MECP2 duplication syndrome. Parents should have the opportunity to meet a genetic counsellor to discuss their specific recurrence risks and options for prenatal and preimplantation genetic diagnosis (PGD). PGD requires the use of in vitro fertilisation and embryo biopsy, and only healthy embryos are transferred to the mothers uterus. If the parents choose to conceive naturally, prenatal diagnosis options include chorionic villus sampling (CVS) and amniocentesis to test the babys chromosomes. For an Xq28 or MECP2 duplication a specific test known as MLPA (multiplex ligation-dependent probe amplification) can be carried out (on samples from both CVS and amniocentesis) to determine whether the baby carries the duplication or not. Testing is generally very accurate, although not all of these tests are available in all parts of the world. 15

Support and Information

Rare Chromosome Disorder Support Group, PO Box 2189, Caterham, Surrey CR3 5GN, UK Tel/Fax: +44(0)1883 330766 info@rarechromo.org www.rarechromo.org
This leaflet is not a substitute for personal medical advice. Families should consult a medically qualified clinician in all matters relating to genetic diagnosis, management and health. The information is believed to be the best available at the time of publication. It was compiled by Unique and reviewed by Dr Damien Sanlaville, Hospices Civils de Lyon, France; Professor Dian Donnai, University of Manchester, UK and by Professor Maj Hultn BSc, PhD, MD, FRCPath, Professor of Reproductive Genetics, University of Warwick, UK. 2010 Copyright Unique 2010
Rare Chromosome Disorder Support Group Registered in England and Wales Charity Number 1110661 Company Number 5460413

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