Williams Syndrome: Musical syntax correlation to neural anatomy and a deletion on

chromosome 7.

Kathryn Barton

Department of Biology

Penn State Abington College, Abington PA 19001

A deletion on chromosome 7 in patients with Williams syndrome results in increased

musical, language, and social skills. Williams syndrome can manifest in low birth weight,  kidney

and dental  difficulties, increased occurrence  of hernias, some elevated blood calcium levels

and heart difficulties,  and distinct facial characteristics.

Williams syndrome is caused by a hemizygous deletion of genes on chromosome

7q11.23 including 28 known coding genes (Schubert, 2008). This neurogenetic disorder occurs

in one in every twenty thousand live births and can cause neonatal hypercalcemia and impaired

cognitive infancy development. The deletion of a band of between 1.6 and 2 million base pairs

causes developmental delay, and disorders involving the vascular tissue, connective tissue,

central nervous system and various outward atypical appearances (Joyce, et al., 1996). The

most common vascular tissue disorder is supravalvular aortic stenosis (SVAS) caused by

haploinsufficency of the ELN gene, which has been mapped to chromosome 7q11.23 (Donnai,

and Karmiloff-Smith, 2000). There is usually a general weakness in connective tissue which can

cause joint limitation. Mental retardation is most always apparent along with a short stature

and facial anomalies (Schubert, 2008). However, there are four strong areas in individuals with

Williams syndrome which include social drive, facial processing, language, and music (Levitin, et

al., 2003).
 Twenty-eight coding genes are known in the region of deletion for Williams syndrome.

The region consists of a single copy gene of about 1.2 million base pairs flanked by blocks A, B,

and C which are composed of low-copy-repeat sequences. The order of the blocks on the

chromosome is A-B-C centromeric, A-B-C medial, and A-B-C telomeric part of the locus

(Schubert, 2008). Williams syndrome is a genetic disorder that comes about sporadically, and

the deletion occurs regardless of whether the sperm or egg was the carrier of the affected

chromosome. However, if a parent has oligosymptomatic pattern having sparse or mild

symptoms, Williams syndrome can be inherited via autosomal dominance, but only a few of

these cases have been reported. Deletions are caused by interchromosomal reshuffling in the

homologous chromosome 7 which results in a misalignment of gametes during meiosis. Non-

allelic homologous recombination (NAHR) creates a deletion and a reciprocal acentric

chromosome. Intrachromosomal reshuffling of sister chromatids also results in misalignment of

gametes during meiosis but in fewer cases of individuals with Williams syndrome (Schubert,

2008). A low percentage of individuals with Williams syndrome had a parent with a paracentric

inversion of the region on chromosome 7 which resulted in the syndrome. The parent does not

show any signs of the syndrome. The inversion is due to the misalignment of interchromatid

pairs. The inverted chromosome region causes mispairing during meiosis and would further

result in a deletion and or a reciprocal duplication. Unequal crossing-over in the skewed base

pairs in the telomeric and medial B blocks of the Williams syndrome region may occur in either

the inverted loop or a non-inverted region. A crossing over in the loop of the Williams

syndrome region has a high risk for miscarriage. A duplication of the Williams syndrome region
on chromosome 7 results from the same mechanism as the deletions but at half the rate

(Schubert, 2008).

The region of genes which is deleted and results in Williams syndrome controls and

codes for various important proteins and signaling receptors. In ninety six percent of individuals

with Williams syndrome there is a deletion of a single copy of the elastin gene which encodes

tropelastin (Martens, Wilson, and Ruetens, 2008). Elastin is the most prevalent extracellular

matrix protein. Haploinsufficiency for ELN causes most of the vascular disorders for individuals

with Williams syndrome including SVAS (Donnai, and Karmiloff-Smith, 2000). A heterozygous

point mutation can also cause SVAS; in mice the symptoms were also high blood pressure,

constriction of arteries and stiff arterial walls (Schubert, 2008). Typical Williams syndrome

individuals have a full deletion of the gene LIMK1 which encodes a tyrosine kinase. A result of

this protein is the development of the cellular process in which a defect could inhibit or hinder

the development of the central nervous system (Donnai, and Karmiloff-Smith, 2000). LIMK1 is

involved in the development and morphology of the brain and formation and maintenance of

neuromuscular synapses. This gene also aids in the control of cognitive function. The gene FZD9

codes for a transmembrane receptor at the cell surface. In an experiment done on mice, a

heterozygous geneotype developed neuroanatomical defects in the development of the

hippocampus in which there is an increase in the number of apoptotic cells and a decrease in

the total number of granule cells. The gene also creates defects in visuospatial tasks and a

higher rate of seizures. However, Williams syndrome patients with the heteroxygous loss of

FZD9 usually do not develop abnormalities in the immune system (Schubert, 2008). The BAZ1B

protein is important in the process of replication, transcription, and chromatin maintenance.

Haploinsufficiency of BAZ1B can cause increased chromosomal condensation and impaired

transcription leading to abnormal vitamin D metabolism and hypercalcaemia. MLXIPL binds to a

carbohydrate response factor in the promoter of gluclose-regulated and lipogenic genes and

activates gene expression. RFC2 is required for elongation of primed DNA templates with help

of proliferating-cell nuclear antigens. It is involved in replication, repair, and modification of

DNA. CLIP2 plays a major role in motor and cognitive attributes in individuals with Williams

syndrome. The protein is rich in neurons of the hippocampus, piriform cortex, olfactory bulb,

and inferior olive. The GTF2IRD1 gene is involved in transcriptional regulation, signal

transduction, immune response and chromatin remodeling. The gene is also involved in

regulation of craniofacial and skeletal development. Mutant mice express behavior that are

similar to those humans with Williams syndrome. STX1A plays a great role in exocytosis in

neuronal cells, is related to neurotransmitter release, and may directly modulate ion channels

in exocrine and muscular cells (Schubert, 2008).The Wnt gene is a signaling gene which directs

early cell division and differentiation (Thompson, et al., 2005).

There are many other genes in the region on chromosome 7 which have an effect on the

phenotypes, but the specific gene to a specific anomaly is unknown. Cognitive function,

behavior, and facial features are among the phenotypes that have not been directly related to a

specific gene. In the classical case of Williams syndrome mental retardation, hyper-sociability,

strengths in language skills, and an impairment in visual spatial activities are prominent but do

not have specific genes correlated to the deficits (Schubert, 2008). Mental retardation can

range from mild to severe; the mean IQ range is 51-70 (Donnai, and Karmiloff-Smith, 2000).
 The gene LIMK1, as noted earlier has been suggested to affect the development of the

central nervous system. In most individuals with Williams syndrome there is disturbance in

development of the brain. This gene may have a direct correlation with the neuroanatomy of

Williams syndrome individuals. There is an overall reduction of gray and white matter in the

brain of those diagnosed with Williams syndrome. There is a disproportionate reduction in the

thalamus and occipital lobes more so than in just the general gray and white matter

(Thompson, et al., 2005). However, the density and complexity of the gray matter has shown an

increase in the amygdala, anterior cingulated cortex, orbital and medial prefrontal cortices,

superior temporal gyrus, bilateral fusiform gyri, and insular cortex which are all areas that play

a key roles in emotion and face processing (Reiss, et al., 2004). There is also increased cortical

thickness in the perisylvian cortex which is imperative for language understanding, and in the

general area surrounding the cortex but only in the right hemisphere. The right hemisphere of

the brain processes linguistic and musical syntax and prosody. A thinner cortex may imply

neural packing, but the thicker cortex in Williams syndrome may explain the strengths in

language. In both hemispheres there was an increase in cortical complexity but more so in the

left hemisphere. In the Heschl’s gyrus, an auditory area, there is a thickening and notable larger

cells (Thompson, et al., 2005). In the splenium and isthmus there is a narrowing of the corpus

callosum, which is the connection between the two hemispheres of the brain, and the dorsal

extent of the central sulcus is shortened, which is the groove that separates the parietal and

frontal lobes (Martens, Wilson, and Ruetens, 2008).

Williams syndrome is highly characterized by specific language skills and a hyper

sociable personality. The language skills of an individual with Williams syndrome are equal to
that of his or her typical age group's mental age.  Typical expressive skills are noted in

articulation and word fluency.   These children show similar literal language skills, but show

difficulty with language requiring more complex skills and comprehension.  As a result actual

conversation is difficult for them.  An individual with Williams syndrome may appear to lead the

conversation and change the subject.  This occurs as they have difficulty with receptive

comprehension.   True practical language is difficult, yet social greetings and storytelling is more

easily handled (Martens, Wilson, and Ruetens, 2008). Due to the increased  sensitivity to pitch,

the sound of language and the pattern in which it  is spoken,  are better attended to by those

with Williams syndrome.  They tend to focus more on the sound than the actual words and

their meaning (Donnai, and Karmiloff-Smith, 2000) . As a result, Children with WS tend to have

more difficulty holding a conversation due to their failure to respond correctly to questions

requiring logic   and clarification. Development of speaking and language processing follows a

different trajectory in WS than in the normal control group (Martens, Wilson, and Ruetens,

2008) . 

More characterizations of Williams syndrome are hyper sociability, tendency to being

more anxious, easily distracted, and are commonly diagnosed with attention deficit

hyperactivity disorder (ADHD). There are also issues with social relationships with peers but

only at a younger age as individuals with Williams syndrome mature relationship issues tend to

disperse (Martens, Wilson, and Ruetens, 2008). Individuals with developmental delays may be

able to live and thrive with limited assistance; however, it is not the case with many Williams

syndrome individuals. Many are unable to perform household chores or obtain and keep a

skilled job; this does depend on the severity of the mental retardation and development of the
individual. Children diagnosed with Williams syndrome express heightened fears that only

increase with adulthood. Fears expressed more often include fears of being burned in a fire,

getting lost, were being in a vehicle accident, the unknown, failure, criticism and in general

spooky things (Martens, Wilson, and Ruetens, 2008).

Motor skills and facial recognition processing is hindered in individuals with Williams

syndrome but are relatively matched to mental age controls (Donnai, and Karmiloff-Smith,

2000). The dorsal visual stream processes information about the position of an object whereas

the ventral stream processes the recognition of faces and objects. MRIs of Williams syndrome

brains show that the ventral stream is intact but still delayed and the dorsal stream is hindered

(Martens, Wilson, and Ruetens, 2008). Williams syndrome individuals have a relative strength in

acknowledging and differentiating faces and objects which may be related to the increase in

gray matter in the facial processing areas of the brain. When in conversation individuals tend to

have an intense gaze which may be due to the impairment of the dorsal stream (Reiss, et al.,

2004).

Musicality in individuals with Williams syndrome has not been researched as intently.

Williams syndrome individuals have a love of music and listen to it more than controls (Maher,

2001). This is not stating that those with Williams syndrome are musicians without lessons.

Individuals with Williams syndrome who were exposed to music classes and lessons are studied

to increase the knowledge of the possible linkage between chromosome 7 and auditory areas

of the brain. The environment and external development of a person with Williams syndrome

have key roles in the music ability. The control groups in studies concerning music come from

equivalent backgrounds of exposure to music and lessons as those with Williams syndrome.
There are many Williams syndrome individuals who have not had the privilege of being exposed

to music. However, it is said that many individuals with Williams syndrome have perfect or near

perfect pitch, which is the ability to hear a note and identify it and the reverse (Martens,

Wilson, and Ruetens, 2008). Rhythm plays a key role in all music; it is also one of the first things

a person is taught about music. Williams syndrome individuals were found to be equal to the

age controls in reproducing a rhythm. Although errors occurred, the individuals with Williams

syndrome created a rhythm, albeit not correct, in the same style as the original rhythm,

whereas the control did not produce an error in the same style (Levitin, et al., 2003). Williams

syndrome musicians were said to be more like Jazz musicians in a jam style environment,

creating rhythms that were creative derivatives of the original rhythm (Maher, 2001). Persons

with Williams syndrome who play an instrument tend to play and practice more than the

control group. There is a higher passion for music and an intense emotional response from

individuals with Williams syndrome than the control group (Levitin, et al., 2003). Williams

syndrome individuals are said to be enthralled by sounds, sitting for hours listening to music,

the sounds of cars and vacuums, and other such sounds which is known as hyertimbria.

Affected individuals also have hyperacusis which is sensitivity to loud sounds. The effects of

music and sounds tend to engage a person with Williams syndrome for a longer time period

than a control person. Williams syndrome individuals were rated higher in musical

accomplishment as well. Some scientists have suggested that the genes for music and social

behavior have co-evolved due to the similarities in both. The expressive language may be

correlated to the expressiveness upon hearing music and when playing an instrument (Levitin,

et al., 2003). Upon listening to music there is a general positive emotion when listening to
music in a major key, whereas when listening to music in a minor key there is negative feeling,

usually sadness, mixed with anxiety (Martens, Wilson, and Ruetens, 2008). When listening to

music William syndrome individuals have a considerable bilateral temporal lobe activation

which is not present when listening to noise or silence. A larger area of the brain, including

structures such as the amygdala, cerebellum and brain stem, is utilized to process music in

those with Williams syndrome. The amygdala, which may contribute to the processes of

cognition, emotion, motivation, and involvement of emotion when listening to music, has a

higher activation in those with Williams syndrome than in the control (Levitin, et al., 2004).

Individuals affected with Williams syndrome share the a basic genetic anomaly,  yet

show diverse abilities.   The region in which the deletion occurs in individuals with Williams

syndrome carries many important genes that have known direct results in phonotypical

anomalies. Elastin is an important protien of the human cardiac system; the aorta is comprised

of about fifty percent elastin (Donnai, and Karmiloff-Smith, 2000). In an experiment done by

Joyce, et al. (1996), approximately ninety six percent of classical William syndrome cases have

hemizygosity of the ELN gene causing SVAS and other cardiovascular disorders. LIMK1 is

another gene that in classical William syndrome cases has been deleted. The gene encodes

tyrosine kinase that inactivates cofilin. This in turn may affect the development of the central

nervous system (Donnai, and Karmiloff-Smith, 2000). Often these individuals show strong social

skills, resulting in Williams syndrome being referred to as the “cocktail party syndrome.” Many

individuals will express a music ability that is increased in expression and musicality in

comparison to the control groups.  Each individual has potential that can lead to a productive

life, given the assistance each individual receives from family, educators, and community.  
Williams syndrome affects males and females equally, and its occurrence is noted across all

ethnic groups and throughout the world.