Genetics is the study of genes whereas epigenetics is the study of how those genes are turned on or off (gene expression). BWS results from various abnormalities affecting the proper expression of genes that control growth within a specific region of chromosome 11(11p15.5). This region is referred to as the BWS critical region.
Approximately 80% of people with BWS have no family history of this syndrome. For these people, BWS is usually caused by epigenetic changes that appear to occur randomly (sporadically). More rarely, BWS is caused by genetic changes that are passed down from a parent (inherited). Approximately 5-10% of patients have BWS due to a family history of the syndrome. About 14% of patients with BWS have an unknown cause for diagnosis.
Everyone has two copies of every gene, one received from the father and one received from the mother. In most people, both genes are “turned on” or active. However, some genes are “turned off” or preferentially silenced based upon which parent that gene came from (a process known as genomic imprinting). Genomic imprinting is controlled by marks on the DNA called methylation. Proper genomic imprinting is necessary for normal development and defective imprinting on chromosome 11 can lead to BWS. Several genes that control growth on chromosome 11 are imprinted, which means that the gene is only active from the mother’s chromosome or the father’s chromosome but not both.
Imprinted genes tend to be clustered or grouped together. Chromosome 11p15.5 has two imprinting cluster regions known as imprinting centers 1 and 2 (IC1 and IC2). Several specific imprinted genes are located in these regions. The improper imprinting of these two regions leads to the improper expression of the genes located within the regions, playing a role in the development of BWS. These genes include H19 (a gene that signals not to grow), IGF2 (insulin-like growth factor II), KCNQ10T1 (LIT1), and CDKN1C (p57[KIP2])(a gene that signals not to grow).
H19 is a long noncoding RNA thought to play a role in inhibiting growth. IGF2 is a growth factor. KCNQ10T1 is a noncoding RNA and CDKN1C is a cell cycle regulator and tumor suppressor. Researchers believe that the paternally-expressed genes promote growth and that the maternally-expressed genes act as tumor suppressor genes or inhibit growth. Normally, H19 and CDKN1C are expressed from the maternal chromosome and IGF2 and KCNQ1OT1 are expressed from the paternal chromosome. Improper methylation in the BWS critical region can lead to an imbalance of the “grow” and “don’t grow” signals, leading to overgrowth.
Gain of methylation (hypermethylation) at imprinting center 1 (IC1 GOM) occurs in about 5% of patients with BWS. This leads to decreased H19 expression and increased IGF2 expression.
Imprinting center 2 (IC2) is associated with KvDMR, a chemical switch found on the KCNQ1 gene. Loss of methylation (hypomethylation) at KvDMR of imprinting center 2 (IC2 LOM) occurs in about 50% of people with BWS. This leads to increased KCNQ10T1 (long QT intronic transcript 1 [LIT1]) expression and decreased CDKN1C expression.
Imprinting errors may also be caused by a chromosomal abnormality known as uniparental disomy (UPD). UPD occurs when a person receives both copies of a chromosome (or part of a chromosome) from one parent instead of receiving one copy from each parent. Approximately 20% of people with BWS have UPD. In BWS, both copies of chromosome 11 are received from the father (paternal uniparental disomy (pUPD)). As a result, there are too many active paternally-expressed genes (IGF2) in this region and not enough maternally-expressed genes (H19, CDKN1C). Uniparental paternal disomy occurs after fertilization (post-zygotic), and therefore the risk of recurrence is extremely low.
Mosaic genome-wide paternal uniparental isodisomy (GWpUPD) occurs in about 10% of BWS due to pUPD (approximately 2% of all patients with BWS). In the case of GWpUPD, every chromosome is inherited from the father in the cells that carries the abnormality, instead of just chromosome 11 as in pUPD. GWpUPD is associated with a greater tumor risk. The severity of GWpUPD varies according the number of cells affected and where the affected cells are located within the patient.
Abnormal changes (mutations) of the CDKN1C gene have been detected in some individuals with BWS. The loss of proper expression or “underexpression” of the gene is thought to play an important role in causing the disorder. Approximately 5% of people with BWS are found to have mutations of the CDKN1C gene. The mutation is inherited as an autosomal dominant trait, which means that only one copy of the mutated gene is needed to pass down the disorder. However, CDKN1C is normally only maternally expressed, and therefore, the offspring will only be affected (i.e. have BWS) if the mutation is passed from mother to offspring. Approximately 40% of individuals with a family history of BWS have mutations of the CDKN1C gene. Mutations in CDKN1C can also occur randomly without the mother carrying the change (de novo mutation). Patients with BWS due to CDKN1C changes have a 50% risk of passing the mutation to their children.
Research has shown that small deletions (microdeletions) affecting imprinting center 1 (IC1) of chromosome 11p15.5 may be the cause of familial BWS in some people. Approximately 1-2% of patients with BWS have deletions involving 11p15.5. Microdeletions of the KCNQ10T1 (LIT1) gene have also been identified in some people with BWS. These microdeletions appear to cause BWS when inherited maternally; when inherited paternally, the disorder does not develop. Small duplications (microduplications), affecting imprinting center 1 (IC1) of chromosome 11p15.5 inherited from the father can also cause BWS. These microduplications can also occur randomly (de novo).
Approximately 2-4% of cases of BWS are due to various chromosomal abnormalities involving the 11p15.5 chromosomal region. This includes chromosomal inversions or rearrangements (translocations) or the presence of extra chromosomal material (duplications).
Phenotype genotype correlation: Researchers are investigating if specific causes of BWS are associated with specific symptoms (genotype-phenotype correlation). Research indicates that omphalocele and macroglossia are more common in individuals with defects of IC2 or a mutation of the CDKN1C gene. Patients with pUPD are at a greater risk for lateralized overgrowth and hyperinsulinism. Individuals with defects of IC1 or pUPD appear to be at a greater risk of developing an associated tumor such as Wilms tumor. Patients with pUPD are also have a greater risk of developing a liver tumor (hepatoblastoma). The different molecular types of BWS each carry a different tumor risk. More research is necessary to determine how the specific causes of BWS correlate with the various symptoms of the disorder.
BWS affects males and females in equal numbers. It is estimated to occur in 1 in 10,340 individuals in the general population. Because people who are mildly affected may go undiagnosed, it is difficult to determine the true frequency of BWS in the general population.
There is no specific increased risk for BWS within specific race/ethnicity populations although the clinical presentations may vary between groups.
Research suggests that patients conceived with assistive reproductive technology (ART), such as in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI), may be at a greater risk of developing disorders resulting from genomic imprinting (such as BWS) than the general population. A recent study revealed a tenfold increased risk for BWS in patients conceived via ART, with a prevalence of one in 1,126 patients. The majority of patients with BWS who are conceived through ART have BWS due to IC2 LOM. More research is necessary to determine the exact relationship between such technologies and the development of BWS.
Studies have also shown that the frequency of twin pregnancies is more common in the BWS population than in the general population. However, twins with BWS tend to present with varying levels of severity (discordance) making it challenging for physicians to diagnose and manage twins with BWS.
Symptoms of the following disorders can be similar to those of BWS. Comparisons may be useful for a differential diagnosis:
Simpson-Golabi-Behmel syndrome is an X-linked recessive genetic disorder due to mutations in the GPC3 or GPC4 genes. Simpson-Golabi-Behmel syndrome is characterized by overgrowth before and after birth (macrosomia); a particular facial appearance including widely-spaced eyes (hypertelorism), coarse facial features, an abnormally large mouth (macrostomia), an abnormally large head (macrocephaly), an abnormally large tongue (macroglossia), and mild to severe intellectual disability. (For more information on this disorder, choose “Simpson dysmorphia” as your search term in the Rare Disease Database.)
Perlman syndrome is an extremely rare genetic disorder due to recessive mutations in the DIS3L2 gene located on chromosome 2q37.1. Perlman syndrome is characterized by overgrowth before and after birth (macrosomia), distinctive facial features, abnormally enlarged internal organs (organomegaly), the presence of fragments (rests) of embryonic tissue in the kidney (nephroblastomatosis), and a predisposition to developing Wilms tumor.
Sotos syndrome is a rare genetic disorder due to sporadic mutations of the NSD1 gene located on chromosome 5q35.3. Sotos syndrome is an autosomal dominant disorder, meaning only one copy of the mutated gene is necessary for a patient to be affected. Sotos syndrome is characterized by excessive growth both before and after birth (prenatally and postnatally). Newborns typically demonstrate advanced bone growth, abnormally large hands and/or feet, and characteristic facial features. Characteristic facial abnormalities may include an unusually large head (macrocephaly) that may appear elongated (dolichocephalic) with an abnormally prominent forehead (frontal bossing); widely-spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures), a highly-arched roof of the mouth (palate), protrusion of the lower jaw (prognathism); and/or a pointed chin. Affected infants and patients may also demonstrate developmental abnormalities including delays in reaching developmental milestones (e.g., sitting, crawling, and walking), delays in coordination of muscular and mental activity (psychomotor retardation), and delays in language skills. (For more information on this disorder, choose “Sotos” as your search term in the Rare Disease Database.)
Weaver syndrome, also known as Weaver-Smith syndrome, is an extremely rare disorder autosomal dominant disorder due to mutations in the EZH2 gene located on chromosome 7q36.1. Weaver syndrome is characterized by accelerated growth. Facial features of an affected patient can include a high broad forehead, a typically round face, widely spaced eyes (ocular hypertelorism), and an abnormally small jaw. Patients often have increased muscle tone (hypertonia) and joint problems. (For more information on this disorder, choose “Weaver” as your search term in the Rare Disease Database.)