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Chromosome 15
The imprinting chromosome - parent-of-origin expression at 15q11-13 causes both Prader-Willi and Angelman syndromes.
Schematic of chromosome 15 showing the short (p) and long (q) arms. Arm ratio per GRCh38 - banding schematic.
Available at Jeen Health
Clinical tests that include this
Overview
Chromosome 15 comprises approximately 102 million base pairs (102 Mb), representing about 3% of the total DNA in each human cell. It carries approximately 600-615 protein-coding genes whose products influence diverse cellular processes, from tissue scaffolding to lysosomal enzyme function. The chromosome is acrocentric, meaning its centromere sits close to one end, producing a short p arm and a much longer q arm. Clinically, chromosome 15 is perhaps most famous for the 15q11-13 region, where parent-of-origin gene expression (genomic imprinting) determines which of two distinct neurogenetic conditions arises when a deletion or uniparental disomy occurs.
Beyond imprinting disorders, chromosome 15 also hosts genes central to connective-tissue integrity (FBN1), lysosomal storage pathways (HEXA), and cardiac muscle contraction (ACTC1, TPM1). Structural rearrangements, deletions, or pathogenic variants within these genes underlie a spectrum of inherited conditions, from Marfan syndrome to Tay-Sachs disease. Within the NHS Genomic Medicine Service, chromosome 15 abnormalities are identified through karyotyping for large-scale rearrangements, chromosomal microarray for microdeletions, and targeted gene panels or whole-genome sequencing for single-gene disorders.
Structure
Like all acrocentric chromosomes (13, 14, 15, 21, 22), chromosome 15 has a centromere positioned near one end, creating a short p arm that is rich in repetitive DNA sequences encoding ribosomal RNA. These ribosomal-gene clusters form part of the nucleolar organiser region, contributing to the nucleolus within the cell nucleus where ribosome assembly takes place. The long q arm extends from the centromere and contains the bulk of chromosome 15's protein-coding genes, including the imprinted cluster at 15q11-13 and larger genes such as FBN1 at 15q21.1.
At the molecular level, the chromosome's DNA double helix wraps around histone proteins to form nucleosomes, which coil into chromatin fibres. During cell division, chromatin condenses further into the familiar X-shaped structure visible under a microscope at metaphase. This packaging compacts the DNA to fit inside the nucleus. During interphase, the degree of chromatin condensation also influences which genes are accessible for transcription, a process particularly important for imprinted regions where only one parental copy is expressed.
Video: What is a karyotype?
Notable regions
The 15q11-13 region is the most clinically significant interval on chromosome 15. It contains a cluster of imprinted genes, meaning that whether the maternal or paternal copy is active depends on which parent contributed the chromosome. When the paternal copy of this region is deleted or both copies come from the mother (maternal uniparental disomy, UPD), the result is Prader-Willi syndrome, characterised by hypotonia in infancy, hyperphagia developing in early childhood, and intellectual disability. Conversely, when the maternal copy is deleted or both copies come from the father (paternal UPD), or when the UBE3A gene itself is mutated, the outcome is Angelman syndrome, presenting with severe developmental delay, happy demeanour, ataxia, and seizures. This single chromosomal region thus illustrates how parent-of-origin expression can determine entirely different clinical phenotypes.
Further down the q arm at 15q21.1 sits FBN1, a large gene encoding fibrillin-1, a glycoprotein that assembles into microfibrils throughout connective tissues. Pathogenic variants in FBN1 cause Marfan syndrome, a multi-system disorder affecting the cardiovascular, skeletal, and ocular systems. Another notable band is 15q26.2, home to IGF1R (insulin-like growth factor 1 receptor). Variants in this gene can lead to growth disorders, and deletions encompassing the region have been associated with intrauterine and postnatal growth restriction. Together, these cytogenetic landmarks underscore chromosome 15's broad impact on development, metabolism, and structural integrity.
Notable genes
FBN1 is perhaps the most widely recognised gene on chromosome 15, given its role in Marfan syndrome. Fibrillin-1 microfibrils not only provide structural support but also regulate the bioavailability of transforming growth factor-beta (TGF-β), linking FBN1 dysfunction to both tissue fragility and aberrant signalling. UBE3A, part of the imprinted cluster at 15q11-13, encodes an E3 ubiquitin ligase essential for neuronal development; maternal-specific expression in the brain means that loss of the maternal copy leads to Angelman syndrome. HEXA, located at 15q23, produces the alpha subunit of beta-hexosaminidase A, the enzyme responsible for degrading GM2 gangliosides in lysosomes; biallelic pathogenic variants cause Tay-Sachs disease, a severe neurodegenerative condition more prevalent in certain populations. ACTC1 and TPM1 both contribute to cardiac muscle contraction: ACTC1 encodes cardiac alpha-actin, while TPM1 produces tropomyosin, and pathogenic variants in either gene can cause hypertrophic or dilated cardiomyopathy. SMAD3, at 15q22.33, is a signalling mediator in the TGF-β pathway, with variants linked to familial thoracic aortic aneurysm and a Loeys-Dietz-like phenotype. Finally, SORD at 15q21.1 encodes sorbitol dehydrogenase, and biallelic loss-of-function variants result in a hereditary neuropathy. This gene roster illustrates chromosome 15's reach into neurogenetics, connective-tissue biology, metabolic pathways, and cardiovascular structure.
Chromosomal disorders
Prader-Willi syndrome arises when the paternally inherited 15q11-13 region is absent or silent. Most commonly this occurs through a de-novo deletion of the paternal copy (approximately 70% of cases), with maternal UPD accounting for most of the remainder. Infants present with severe hypotonia and feeding difficulties, but in early childhood an insatiable appetite emerges, often leading to obesity if dietary intake is not carefully managed. Developmental delay, behavioural challenges, and hypogonadism are also typical features. Diagnosis is confirmed by methylation studies that detect the absence of the paternal methylation pattern, followed by further testing (fluorescence in-situ hybridisation or chromosomal microarray) to distinguish deletion from UPD.
Angelman syndrome results from loss of maternal 15q11-13 function. Around 70% of cases involve a maternal deletion, approximately 2-5% arise from paternal UPD, and roughly 10% are due to pathogenic variants in UBE3A itself; imprinting-centre defects and other mechanisms account for the remainder. Affected individuals show severe speech impairment, a characteristic happy affect with frequent laughter, ataxic gait, and epilepsy. Developmental milestones are significantly delayed. Methylation testing is again the first-line diagnostic approach, followed by targeted UBE3A sequencing if no deletion or UPD is found. Both Prader-Willi and Angelman syndromes are typically sporadic, though recurrence risk can be elevated if a parent carries a balanced translocation involving chromosome 15 or an imprinting-centre mutation. Families are usually referred to NHS clinical genetics services for detailed counselling and discussion of recurrence.
Other structural abnormalities of chromosome 15 include ring chromosome 15, where the chromosome forms a circular structure after loss of genetic material from both ends, and inverted duplication 15q (also known as isodicentric 15), where an extra segment of the long arm is present. The clinical features of these rearrangements depend on the size and gene content of the duplicated or deleted regions, and on whether imprinted genes are involved. Chromosomal microarray is the usual first-tier test for detecting these copy-number changes.
Prenatal screening & diagnosis
Whole-chromosome aneuploidy of chromosome 15 (trisomy 15 or monosomy 15) is generally not compatible with survival to term; mosaic forms occasionally survive but are associated with developmental delay and congenital anomalies. Non-invasive prenatal testing (NIPT) analyses cell-free foetal DNA in maternal blood and primarily screens for the common autosomal trisomies (chromosomes 13, 18, 21) but does not routinely report on chromosome 15. Microdeletions at 15q11-13 are below the resolution of standard NIPT, so they are not detected by that screen.
When ultrasound findings raise concern for a chromosome 15 disorder, or when there is a known family history of a 15q11-13 rearrangement, invasive testing (chorionic villus sampling or amniocentesis) can be offered. A sample of foetal cells is analysed by karyotype, fluorescence in-situ hybridisation targeting 15q11-13, or chromosomal microarray. Chromosomal microarray is typically the first-line test for copy-number variants; karyotype or FISH may be used for specific structural rearrangements or to confirm microarray findings. For couples with a previous child affected by Prader-Willi or Angelman syndrome due to a de-novo deletion, the recurrence risk is low (typically <1%), but those rare families in which a parent carries a chromosome 15 translocation or an imprinting-centre mutation face higher risks and should be counselled by a clinical genetics team. The NHS Fetal Anomaly Screening Programme does not specifically screen for chromosome 15 abnormalities, but any abnormal ultrasound findings would prompt onward referral.
Inheritance & recurrence
Most chromosome 15 abnormalities, including the common deletions causing Prader-Willi and Angelman syndromes, occur de novo. This means they arise as new events during the formation of egg or sperm, or in very early embryonic development, and are not inherited from a parent. The recurrence risk for families with one affected child due to a de-novo deletion is therefore very low, usually quoted at around 1% or less, reflecting the background population risk plus a small chance of germline mosaicism (where a parent harbours the deletion in a subset of their reproductive cells).
However, in a minority of cases, one parent may carry a balanced translocation involving chromosome 15, or an imprinting-centre mutation that disrupts the normal parent-of-origin marking of 15q11-13. In these situations, recurrence risk can be substantially higher, and prenatal diagnosis or preimplantation genetic testing may be discussed as an option, subject to eligibility and regulatory approval. For single-gene disorders on chromosome 15 (Marfan syndrome due to FBN1, Tay-Sachs disease due to HEXA, and so on), inheritance follows Mendelian patterns: autosomal dominant for FBN1, ACTC1, TPM1, and SMAD3 (with each child of an affected parent having a 50% chance of inheriting the variant), and autosomal recessive for HEXA and SORD (requiring both parents to be carriers for a child to be affected). Referral to NHS clinical genetics is recommended whenever a chromosome 15 abnormality is identified, so that families receive tailored genetic counselling, discussion of recurrence risks, and information about reproductive options.
Frequently asked questions
How can the same chromosomal deletion cause two completely different conditions?
At 15q11-13, certain genes are imprinted, meaning only the copy from one parent is active. If the paternal copy is deleted, genes normally expressed only from the father are lost, causing Prader-Willi syndrome. If the maternal copy is deleted, maternally expressed genes such as UBE3A are absent, leading to Angelman syndrome. The DNA change is the same; the parent of origin determines the clinical outcome.
Can non-invasive prenatal testing detect Prader-Willi or Angelman syndrome?
Standard NIPT screens for whole-chromosome aneuploidies (trisomies 13, 18, 21 and sex-chromosome changes) and does not reliably detect the microdeletions at 15q11-13 that cause these syndromes. If there is a known family history or concerning ultrasound findings, diagnostic testing via chorionic villus sampling or amniocentesis, followed by chromosomal microarray or methylation analysis, is required.
If one of my children has Prader-Willi syndrome, what is the chance my next child will have it too?
In most cases, Prader-Willi syndrome arises from a new (de-novo) deletion or uniparental disomy, and the recurrence risk for future pregnancies is very low, typically around 1%. However, if a parent carries a chromosome 15 translocation or an imprinting-centre mutation, the risk can be higher. Your clinical genetics team will arrange testing to clarify your family's specific risk and discuss options.
Are all Marfan syndrome cases caused by chromosome 15?
Yes, Marfan syndrome is caused by pathogenic variants in the FBN1 gene, which is located at 15q21.1 on chromosome 15. Because FBN1 is the only gene known to cause classic Marfan syndrome, any genetic diagnosis of Marfan will trace back to this chromosome. Other conditions with overlapping features (such as Loeys-Dietz syndrome) are caused by genes on different chromosomes.
Why is chromosome 15 called acrocentric, and does that matter clinically?
Acrocentric means the centromere is near one end, creating a very short p arm rich in ribosomal-RNA genes. Clinically, this matters because acrocentric chromosomes can undergo Robertsonian translocations, fusing at their centromeres with other acrocentrics. Such translocations can lead to unbalanced chromosome complements in offspring, although most balanced-carrier parents have healthy children. Your genetics team will explain any translocation findings and associated risks.
Launch-set genes on chromosome 15
Genes on this chromosome that currently have dedicated pages in the library. This list grows as we publish more.