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Genetics Home Reference: your guide to understanding genetic conditions
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Chromosome 4

Reviewed February 2012

What is chromosome 4?

Humans normally have 46 chromosomes in each cell, divided into 23 pairs. Two copies of chromosome 4, one copy inherited from each parent, form one of the pairs. Chromosome 4 spans about 191 million DNA building blocks (base pairs) and represents more than 6 percent of the total DNA in cells.

Identifying genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. Chromosome 4 likely contains 1,000 to 1,100 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

Genes on chromosome 4 are among the estimated 20,000 to 25,000 total genes in the human genome.

Genetics Home Reference includes these genes on chromosome 4:

  • AGA
  • ANK2
  • ANTXR2
  • CFI
  • CISD2
  • CYP4V2
  • DOK7
  • DRD5
  • DSPP
  • DUX4
  • ENAM
  • ETFDH
  • EVC
  • EVC2
  • FAT4
  • FGA
  • FGB
  • FGFR3
  • FGFRL1
  • FGG
  • FIP1L1
  • FRAS1
  • HADH
  • HTT
  • IDUA
  • KIT
  • KLKB1
  • LETM1
  • MANBA
  • MFSD8
  • MMAA
  • MSX1
  • MTTP
  • NR3C2
  • PDE6B
  • PDGFRA
  • PHOX2B
  • PITX2
  • PKD2
  • QDPR
  • RBPJ
  • SGCB
  • SH3BP2
  • SLC25A4
  • SNCA
  • TET2
  • UCHL1
  • UVSSA
  • WDR19
  • WFS1
  • WHSC1

How are changes in chromosome 4 related to health conditions?

Many genetic conditions are related to changes in particular genes on chromosome 4. This list of disorders associated with genes on chromosome 4 provides links to additional information.

Genetics Home Reference includes these conditions related to genes on chromosome 4:

  • 3-hydroxyacyl-CoA dehydrogenase deficiency
  • abetalipoproteinemia
  • achondroplasia
  • Adams-Oliver syndrome
  • age-related macular degeneration
  • amelogenesis imperfecta
  • aspartylglucosaminuria
  • atypical hemolytic-uremic syndrome
  • autosomal dominant congenital stationary night blindness
  • Axenfeld-Rieger syndrome
  • benign essential blepharospasm
  • beta-mannosidosis
  • Bietti crystalline dystrophy
  • bladder cancer
  • cherubism
  • complement factor I deficiency
  • congenital afibrinogenemia
  • congenital central hypoventilation syndrome
  • congenital hyperinsulinism
  • congenital myasthenic syndrome
  • core binding factor acute myeloid leukemia
  • cranioectodermal dysplasia
  • Crouzonodermoskeletal syndrome
  • dentinogenesis imperfecta
  • Ellis-van Creveld syndrome
  • epidermal nevus
  • essential thrombocythemia
  • facioscapulohumeral muscular dystrophy
  • Fraser syndrome
  • gastrointestinal stromal tumor
  • glutaric acidemia type II
  • Hennekam syndrome
  • Huntington disease
  • hypochondroplasia
  • infantile systemic hyalinosis
  • juvenile hyaline fibromatosis
  • lacrimo-auriculo-dento-digital syndrome
  • late-infantile neuronal ceroid lipofuscinosis
  • limb-girdle muscular dystrophy
  • methylmalonic acidemia
  • mucopolysaccharidosis type I
  • Muenke syndrome
  • multiple system atrophy
  • nephronophthisis
  • neuroblastoma
  • nonsyndromic deafness
  • Parkinson disease
  • PDGFRA-associated chronic eosinophilic leukemia
  • Peters anomaly
  • piebaldism
  • polycystic kidney disease
  • polycythemia vera
  • prekallikrein deficiency
  • primary myelofibrosis
  • progressive external ophthalmoplegia
  • pseudohypoaldosteronism type 1
  • retinitis pigmentosa
  • rheumatoid arthritis
  • Romano-Ward syndrome
  • SADDAN
  • Senior-Løken syndrome
  • tetrahydrobiopterin deficiency
  • thanatophoric dysplasia
  • UV-sensitive syndrome
  • Weyers acrofacial dysostosis
  • Wolf-Hirschhorn syndrome
  • Wolfram syndrome

Changes in the structure or number of copies of a chromosome can also cause problems with health and development. The following chromosomal conditions are associated with such changes in chromosome 4.

cancers

Changes in chromosome 4 have been identified in several types of human cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. For example, rearrangements (translocations) of genetic material between chromosome 4 and several other chromosomes have been associated with leukemias, which are cancers of blood-forming cells.

A specific translocation involving chromosome 4 and chromosome 14 is commonly found in multiple myeloma, which is a cancer that starts in cells of the bone marrow. The translocation, which is written as t(4;14)(p16;q32), abnormally fuses the WHSC1 gene on chromosome 4 with part of another gene on chromosome 14. The fusion of these genes overactivates WHSC1, which appears to promote the uncontrolled growth and division of cancer cells.

facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy is caused by genetic changes involving the long (q) arm of chromosome 4. This condition is characterized by muscle weakness and wasting (atrophy) that worsens slowly over time. It results from changes in a region of DNA known as D4Z4, located near the end of the chromosome at a position described as 4q35. The D4Z4 region consists of 11 to more than 100 repeated segments, each of which is about 3,300 DNA base pairs (3.3 kb) long. The entire D4Z4 region is normally hypermethylated, which means that it has a large number of methyl groups (consisting of one carbon atom and three hydrogen atoms) attached to the DNA. Facioscapulohumeral muscular dystrophy results when the region is hypomethylated, with too few methyl groups attached. In facioscapulohumeral muscular dystrophy type 1 (FSHD1), hypomethylation occurs because the D4Z4 region is abnormally shortened (contracted), containing between 1 and 10 repeats instead of the usual 11 to 100 repeats. In facioscapulohumeral muscular dystrophy type 2 (FSHD2), hypomethylation most often results from mutations in a gene called SMCHD1, which normally hypermethylates the D4Z4 region.

The segment of the D4Z4 region closest to the end of chromosome 4 contains a gene called DUX4. Hypermethylation of the D4Z4 region normally keeps the DUX4 gene turned off (silenced) in most adult cells and tissues. In people with facioscapulohumeral muscular dystrophy, hypomethylation of the D4Z4 region prevents the DUX4 gene from being silenced in cells and tissues where it is usually turned off. Although little is known about the function of the DUX4 gene when it is turned on (active), researchers believe that it influences the activity of other genes, particularly in muscle cells. It is unknown how abnormal activity of the DUX4 gene damages or destroys these cells, leading to progressive muscle weakness and atrophy.

The DUX4 gene is located next to a regulatory region of DNA known as a pLAM sequence, which is necessary for the production of the DUX4 protein. Some copies of chromosome 4 have a functional pLAM sequence, while others do not. Copies of chromosome 4 with a functional pLAM sequence are described as 4qA or "permissive." Those without a functional pLAM sequence are described as 4qB or "non-permissive." Without a functional pLAM sequence, no DUX4 protein is made. Because there are two copies of chromosome 4 in each cell, individuals may have two "permissive" copies of chromosome 4, two "non-permissive" copies, or one of each. Facioscapulohumeral muscular dystrophy can only occur in people who have at least one "permissive" copy of chromosome 4. Whether an affected individual has a contracted D4Z4 region or a SMCHD1 gene mutation, the disease results only if a functional pLAM sequence is also present to allow DUX4 protein to be produced.

PDGFRA-associated chronic eosinophilic leukemia

PDGFRA-associated chronic eosinophilic leukemia is caused by genetic abnormalities that involve the PDGFRA gene, a gene found on chromosome 4. This condition is a type of blood cell cancer characterized by an increased number of eosinophils, a type of white blood cell involved in allergic reactions.

The PDGFRA gene abnormalities are somatic mutations, which are mutations acquired during a person's lifetime that are present only in certain cells. The most common of these abnormalities is a deletion of genetic material from chromosome 4 that removes approximately 800 DNA building blocks (nucleotides) and brings together parts of two genes, FIP1L1 and PDGFRA, creating the FIP1L1-PDGFRA fusion gene. Occasionally, through mechanisms other than deletion, genes other than FIP1L1 are fused with the PDGFRA gene. Rarely, mutations that change single DNA building blocks in the PDGFRA gene (point mutations) cause this condition.

The protein produced from the FIP1L1-PDGFRA fusion gene (as well as other PDGFRA fusion genes) has the function of the PDGFRA protein, which stimulates signaling pathways inside the cell that control many important cellular processes, such as cell growth and division (proliferation) and cell survival. Unlike the normal PDGFRA protein, however, the fusion protein is constantly turned on (constitutively activated), which means the cells are always receiving signals to proliferate. Similarly, point mutations in the PDGFRA gene can result in a constitutively activated PDGFRA protein. When the FIP1L1-PDGFRA fusion gene or point mutations in the PDGFRA gene occur in blood cell precursors, the growth of eosinophils (and occasionally other blood cells) is poorly controlled, leading to PDGFRA-associated chronic eosinophilic leukemia. It is unclear why eosinophils are preferentially affected by this genetic change.

Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 4 at a position described as 4p16.3. The signs and symptoms of this condition are related to the loss of multiple genes from this part of the chromosome. The size of the deletion varies among affected individuals; studies suggest that larger deletions tend to result in more severe intellectual disability and physical abnormalities than smaller deletions.

The region of chromosome 4 that is deleted most often in people with Wolf-Hirschhorn syndrome is known as Wolf-Hirschhorn syndrome critical region 2 (WHSCR-2). This region contains several genes, some of which are known to play important roles in early development. A loss of these genes leads to developmental delay, a distinctive facial appearance, and other characteristic features of the condition. Scientists are working to identify additional genes at the end of the short arm of chromosome 4 that contribute to the characteristic features of Wolf-Hirschhorn syndrome.

other chromosomal conditions

Some deletions of genetic material from the short (p) arm of chromosome 4 do not involve the critical region WHSCR-2. These deletions cause signs and symptoms that are distinct from those of Wolf-Hirschhorn syndrome, including mild intellectual disability and, in some cases, rapid (accelerated) growth. People with this type of deletion usually do not have seizures.

Trisomy 4 occurs when cells have three copies of chromosome 4 instead of the usual two copies. Full trisomy 4, which occurs when all of the body's cells contain an extra copy of chromosome 4, is not compatible with life. A similar but somewhat less severe condition called mosaic trisomy 4 occurs when only some of the body's cells have an extra copy of chromosome 4. The signs and symptoms of mosaic trisomy 4 vary widely and can include heart defects, abnormalities of the fingers and toes, and other birth defects. Mosaic trisomy 4 is very rare; only a few cases have been reported.

Other changes in the number or structure of chromosome 4 can have a variety of effects including delayed growth and development, intellectual disability, distinctive facial features, heart defects, and other medical problems. Changes involving chromosome 4 include an extra piece of the chromosome in each cell (partial trisomy 4), a missing segment of the chromosome in each cell (partial monosomy 4), and a circular structure called a ring chromosome 4. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Is there a standard way to diagram chromosome 4?

Geneticists use diagrams called ideograms as a standard representation for chromosomes. Ideograms show a chromosome's relative size and its banding pattern. A banding pattern is the characteristic pattern of dark and light bands that appears when a chromosome is stained with a chemical solution and then viewed under a microscope. These bands are used to describe the location of genes on each chromosome.

Ideogram of chromosome 4
See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about chromosome 4?

You may find the following resources about chromosome 4 helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What glossary definitions help with understanding chromosome 4?

atom ; atrophy ; bone marrow ; cancer ; cell ; chromosome ; chronic ; critical region ; deletion ; developmental delay ; disability ; DNA ; DNA base ; eosinophils ; fusion gene ; gene ; inherited ; kb ; leukemia ; methyl ; monosomy ; mosaic ; multiple myeloma ; muscle cells ; muscular dystrophy ; mutation ; myeloma ; proliferate ; proliferation ; protein ; ring chromosomes ; syndrome ; translocation ; trisomy ; wasting

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

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  • Buitenhuis M, Verhagen LP, Cools J, Coffer PJ. Molecular mechanisms underlying FIP1L1-PDGFRA-mediated myeloproliferation. Cancer Res. 2007 Apr 15;67(8):3759-66. (http://www.ncbi.nlm.nih.gov/pubmed/17440089?dopt=Abstract)
  • Chen CP, Chern SR, Lee CC, Chang TY, Wang W, Tzen CY. Clinical, cytogenetic, and molecular findings of prenatally diagnosed mosaic trisomy 4. Prenat Diagn. 2004 Jan;24(1):38-44. Review. (http://www.ncbi.nlm.nih.gov/pubmed/14755408?dopt=Abstract)
  • Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003 Mar 27;348(13):1201-14. (http://www.ncbi.nlm.nih.gov/pubmed/12660384?dopt=Abstract)
  • Ensembl Human Map View (http://www.ensembl.org/Homo_sapiens/Location/Chromosome?chr=4;r=4:1-190214555)
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  • Keats JJ, Maxwell CA, Taylor BJ, Hendzel MJ, Chesi M, Bergsagel PL, Larratt LM, Mant MJ, Reiman T, Belch AR, Pilarski LM. Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. Blood. 2005 May 15;105(10):4060-9. Epub 2005 Jan 27. (http://www.ncbi.nlm.nih.gov/pubmed/15677557?dopt=Abstract)
  • Keats JJ, Reiman T, Belch AR, Pilarski LM. Ten years and counting: so what do we know about t(4;14)(p16;q32) multiple myeloma. Leuk Lymphoma. 2006 Nov;47(11):2289-300. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17107900?dopt=Abstract)
  • Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, Snider L, Straasheijm KR, van Ommen GJ, Padberg GW, Miller DG, Tapscott SJ, Tawil R, Frants RR, van der Maarel SM. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010 Sep 24;329(5999):1650-3. doi: 10.1126/science.1189044. Epub 2010 Aug 19. (http://www.ncbi.nlm.nih.gov/pubmed/20724583?dopt=Abstract)
  • Lundin C, Zech L, Sjörs K, Wadelius C, Annerén G. Trisomy 4q syndrome: presentation of a new case and review of the literature. Ann Genet. 2002 Apr-Jun;45(2):53-7. Review. (http://www.ncbi.nlm.nih.gov/pubmed/12119211?dopt=Abstract)
  • Map Viewer: Genes on Sequence (http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=human&MAPS=ideogr,ugHs,genes&CHR=4)
  • South ST, Hannes F, Fisch GS, Vermeesch JR, Zollino M. Pathogenic significance of deletions distal to the currently described Wolf-Hirschhorn syndrome critical regions on 4p16.3. Am J Med Genet C Semin Med Genet. 2008 Nov 15;148C(4):270-4. doi: 10.1002/ajmg.c.30188. (http://www.ncbi.nlm.nih.gov/pubmed/18932125?dopt=Abstract)
  • Tawil R, van der Maarel SM, Tapscott SJ. Facioscapulohumeral dystrophy: the path to consensus on pathophysiology. Skelet Muscle. 2014 Jun 10;4:12. doi: 10.1186/2044-5040-4-12. eCollection 2014. Review. (http://www.ncbi.nlm.nih.gov/pubmed/24940479?dopt=Abstract)
  • UCSC Genome Browser: Statistics (http://genome.cse.ucsc.edu/goldenPath/stats.html)
  • Zollino M, Lecce R, Fischetto R, Murdolo M, Faravelli F, Selicorni A, Buttè C, Memo L, Capovilla G, Neri G. Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet. 2003 Mar;72(3):590-7. Epub 2003 Jan 30. (http://www.ncbi.nlm.nih.gov/pubmed/12563561?dopt=Abstract)
  • Zollino M, Murdolo M, Marangi G, Pecile V, Galasso C, Mazzanti L, Neri G. On the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review. Am J Med Genet C Semin Med Genet. 2008 Nov 15;148C(4):257-69. doi: 10.1002/ajmg.c.30190. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18932124?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: February 2012
Published: November 24, 2014