2p16.3 (NRXN1) deletions rarechromo.org Sources and 2p16.3 (NRXN1) deletions references A 2p16.3 deletion is a rare genetic condition caused by a The information in this tiny missing part of one of the body’s 46 chromosomes – guide is drawn partly chromosome 2. For healthy development, from the published chromosomes should contain just the right amount of medical literature. The material – not too much and not too little. Even a tiny first-named author piece of missing material can disrupt development, although it doesn’t always do so. and publication date are given so you can Background on Chromosomes look for the abstracts Chromosomes are structures found in the nucleus of or original articles on the body’s cells. Every chromosome contains thousands the internet in PubMed of genes which may be thought of as individual (www.ncbi.nlm.nih.gov instruction booklets (or recipes) that contain all the /pubmed/). If you wish, genetic information telling the body how to develop, you can obtain most grow and function. Chromosomes (and genes) usually articles from Unique. come in pairs with one half of each chromosome pair However, many being inherited from each parent. Humans have 23 pairs individuals in the of chromosomes giving a total of 46 individual medical literature chromosomes. Of these 46 chromosomes, two are the were diagnosed as a sex chromosomes that determine gender. Females result of several large have two X chromosomes and males have one X studies of people with chromosome and one Y chromosome. The remaining 44 autism spectrum chromosomes are grouped in 22 pairs, numbered 1 to disorder, epilepsy or 22 approximately from the largest to the smallest. Each schizophrenia and chromosome has a short or petit (p) arm and a long (q) there is very little arm, shown on the diagram on page 3. additional information available about these Chromosome Deletions individuals. In A sperm cell from the father and an egg cell from the addition, this leaflet mother each carries just one copy of each chromosome. draws on information When they join together they form a single cell that now from a survey of carries two copies of each chromosome. This cell must members of Unique make many copies of itself (and all the chromosomes conducted in 2013, and genetic material) in order to make all of the many referenced Unique. cells that form during human growth and development. When this guide was Sometimes during the formation of the egg or sperm written in March 2014, cells or during this complicated copying and replication Unique had 25 process, parts of the chromosomes can break off or member families with become arranged differently from usual. People with a a microdeletion at 2p16.3 deletion have one intact chromosome 2, but a 2p16.3 ranging in age piece from the short arm of the other copy is missing. It from a 3-year-old to is believed that most of the clinical difficulties are an adult. probably caused by having only one copy (instead of the 2 usual two) of a gene (or number of genes) from the missing piece. It is important to keep in mind that a child’s other genes, environment and unique personality also help to determine future development, needs and achievements. Looking at 2p16.3 You can’t see chromosomes with the naked eye, but if you stain them and magnify them under a microscope, you can see that each one has a distinctive pattern of light and dark bands. You can see these bands in the diagram of the long arm of chromosome 2 at the bottom on this page. Band 2p16.3 contains around 5.1 million base pairs. This sounds a lot but it is actually quite small and is less 1 base pair = bp than 0.2 per cent of the DNA in each cell and only 2 per 1,000 base pairs = 1kb cent of the DNA on chromosome 2. Base pairs are the 1,000,000 base pairs = 1Mb chemicals in DNA that form the ends of the ‘rungs’ of its ladder-like structure. Even if you magnify the chromosomes as much as possible, to about 850 times life size, a chromosome 2 with the microdeletion at p16.3 looks normal. People who have missing material on a chromosome are said to have a deletion but when the amount is so small that it can’t be seen even under a high-powered microscope, it is called a microdeletion. The 2p16.3 deletion can only be found using molecular or DNA technology, in particular a technique using microarrays (arrayCGH), that shows gains and losses of tiny amounts of DNA throughout the genome and can demonstrate whether particular gene(s) are present or not (Unique has prepared a guide to arrayCGH which can be freely downloaded from (www.rarechromo.org/information/Other/Array%20CGH%20QFN.pdf). One gene, Neurexin 1 (NRXN1) located on 2p16.3, has been suggested as being responsible for most, if not all, of the features of a 2p16.3 deletion (see Research involving 2p16.3 on page 16). This guide includes descriptions of people who have a 2p16.3 microdeletion and also people who have a full or partial deletion of the NRXN1 gene. NRXN1 (50.1Mb-51.2Mb) 47.8Mb 52.9Mb p16.3 1Mb 243Mb p arm centromere q arm The numbers in this diagram refer to the human genome Chromosome 2 build 19 (hg19; see page 4 for more details). Your child’s report may refer to a different human genome build. Please contact Unique or your genetic specialist for any help with understanding the report. 3 Genetic Report Your geneticist or genetic counsellor will be able to tell you about the points where the chromosome has broken in your child. With a 2p16.3 microdeletion, the results are likely to read something like the following example: arr[hg19] 2p16.3 (50,713,464-51,043,557)x1 dn arr The analysis was by array (arr) comparative genomic hybridisation (cgh) hg19 Human Genome build 19. This is the reference DNA sequence that the base pair numbers refer to. As more information about the human genome is found, new ‘builds’ of the genome are made and the base pair numbers may be adjusted 2p16.3 The chromosome involved is 2 and the position of the deletion is in band p16.3 50,713,464-51,043,557 The base pairs between 50,713,464 and 51,043,557 have been shown to be deleted. Take the first long number from the second and you get 330,093 (0.330Mb or 330kb). This is the number of base pairs that are deleted x1 means there is one copy of these base pairs, not two – one on each chromosome 2 – as you would normally expect dn means de novo. The parents’ chromosomes have been checked and no deletion or other chromosome change has been found at 2p16.3. The deletion is very unlikely to be inherited and has almost certainly occurred for the first time in this family with this child. mat means that the deletion has been inherited from the mother; pat means that it has been inherited from the father. How common is the 2p16.3 deletion? It is surprisingly common, almost certainly found as often as much better known syndromes such as Prader-Willi. Several large scale studies have shown that the 2p16.3 deletion occurs in around 1 in 2,500 to 1 in 4,000 people with schizophrenia or developmental delay; and about 1 in 5,000 people not affected by schizophrenia or developmental delay (Kirov 2008; Ching 2010; Schaaf 2012). 4 How much do we know? Comparing different children and adults with 2p16.3 (NRXN1) deletions shows that some effects seem to be very broadly similar. This information guide tells you what is known about those effects. Comparing your child’s array results with others, both in the medical literature and within Unique, can help to build up a general picture of what to expect. But there will still be differences, sometimes quite marked, between your child and others with an apparently similar array result. It is very important to see your child as an individual and not to make direct comparisons with others with the same chromosome test results. After all, each of us is unique. Most common features Every person with a 2p16.3 (NRXN1) deletion 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 information guide. However, a number of common features have emerged: Children are likely to need support with learning. The amount of support needed by each child will vary Seizures Speech and language delay Behavioural difficulties such as autism spectrum disorder Otherwise generally healthy What is the outlook? We can’t be certain yet but there appears to be no reason why people who are healthy should not enjoy a normal lifespan. However, regression has been reported in three out of more than a hundred people in the medical literature (Schaaf 2012). Are there people with a 2p16.3 (NRXN1) deletion who are healthy, have no major birth defects and have developed normally? There are many individuals with either a deletion or disruption to the NRXN1 gene who have developed normally and have no major birth defects, all of whom only discovered they had the deletion when it was detected in their children or they were a control (unaffected) individual in one of the large scale studies. Both fathers and mothers have passed the microdeletion on to their children (Dabell 2012; Béna 2013; Unique).