see also:

• comparison of developmental disorders affecting social development
• wikipedia Williams syndrome / WBS

• the classic form of WBS is rare, affecting 1 in 7,500 children (although earlier studies suggested 1 in 20,000 live births) and is generally sporadic but some have autosomal dominant transmission
• the classical form is one of the Common Microdeletion and Microduplication syndromes (CMMS)
• a neurodevelopmental disorder caused by a heterozygous deletion of contiguous genes at 7q11.23 mediated by nonallelic homologous recombination (NAHR) between large flanking LCRs and facilitated by a structural variant of the region
• an approximately 2Mb paracentric inversion is present in 20%-25% of WBS-transmitting progenitors
  • 4% of these progenitors are carriers of a CNV (Large copy number variants), displaying a chromosome with large deletion of LCRs (low-copy repeats ) and these progenitors appear to convey a 4.6-fold risk of WBS ¹⁾

• intellectual development:
  • most have IQ in the 60-100 range but have better musical skills than expected for IQ
  • many sing or play musical instruments with considerable expertise and auditory memory, and rarely forget a name. Usually read and write poorly and struggle with simple arithmetic
• social development:
  • hyperfocus on eyes; highly verbal; overly sociable; “cocktail party”; high empathy; reduced fear of disapproving faces or strangers but increased fear of non-social fears; in adolescence, often experience social isolation, frustration, and loneliness despite their clear desire to connect to other people; anxiety;
• motor development:
  • dev. delay in coordination, fine motor skills; often gait issues esp. walking down stairs; hyper-reflexic; nystagmus
• speech and language:
  • rich in emotional descriptors, high in prosody (exaggerated rhythm and emotional intensity), and features unusual terms and strange idioms; often harsh, brassy, or hoarse voice
• physical features:
  • “elf-like”;
  • short, thin;
  • failure to thrive infants;
  • puffy eye facies;
  • wide mouth
  • long philtrum
  • long neck
  • cardiac abn. - congenital supravalvular aortic stenosis SVAS (73%), pulmonary artery stenosis (41%), systemic hypertension (55% adults but often occurs by age 5yrs, particularly in those with renal artery stenosis); increased risk of sudden death;
  • pectus excavatum;
  • absolute perfect musical pitch;
  • hyperacusia and phonophobia;
  • impaired spatial processing;
  • dental issues;
  • hallux valgux;
  • many have blue eyes with stellate iris;
  • infantile and adult hypercalcaemia - possibly due to TFII-I haploinsufficiency and subsequent TRPC3 overexpression ²⁾
  • mild to moderate high-frequency sensorineural hearing loss in adulthood;
  • urinary detrusor overactivity and detrusor-sphincter dyssynergia;
  • GIT symptoms:
    • gastro-esophageal reflux (GER), poor suckling, vomiting, constipation, prolonged colic, rectal prolapse, inguinal, umbilical and hiatal hernia, rarely, achalasia

• autism spectrum disorder (ASD)
  • comorbid autism and WBS is more frequent than expected and suggest that the common WBS deletion can result in a continuum of social communication impairment, ranging from excessive talkativeness and overfriendliness to absence of verbal language and poor social relationships. Appreciation of the possible co-occurrence of WBS and autism challenges the common view that WBS represents the opposite behavioral phenotype of autism, and might lead to improved recognition of WBS in individuals diagnosed with autism.³⁾
• attention deficit hyperactivity disorder (ADHD)
• hypothyroidism
• diabetes mellitus

• Omim - genetics of WBS
• genetics of the classic form is usually sporadic although some are inherited
• 7q11.23 deletion causes 90-95% of classic cases
• the extent of deletion in classic cases appears to be⁴⁾:
  • 1.55 Mb (25 genes) in 89%
  • 1.84 Mb (28 genes) in 11%
  • 1Mb (rare) and not involving GTF2IRD1 and GTF2I genes ⇒ mild WBS features, normal IQ
• classic deletion results in the deletion of some 28 genes including:
  • general transcription factor IIi gene (GTF2I):
    • which encodes TFII-I, which suppresses cell-surface accumulation of transient receptor potential C3 (TRPC3) channels, involved in calcium transport in lymphocytes.
    • this is thought to cause the hypercalcaemia and also contributed to the neurologic deficits
    • TFII-I also targets craniofacial development protein 1 (Cfdp1), Sec23 homolog A (Sec23a), and nuclear receptor binding SET domain protein 1 (Nsd1) which all have been implicated in craniofacial abnormalities ⁵⁾
    • interestingly, duplication of this gene is thought to be important in the etiology of autism spectrum disorder (ASD) in individuals with this duplication and in non-duplication cases with severe social interaction problems and repetitive behaviors ⁶⁾
  • general transcription factor IIi RD1 (GTF2IRD1):
    • contributes to the neurologic deficits, craniofacial abnormalities, motor coordination and anxiety, lower body weight, decreased spontaneous and circadian locomotor activity, diminished motor coordination and strength, gait abnormalities, increased anxiety and an elevated endocrinological response to stress, suggesting basal ganglia and potentially cerebellar abnormalities ⁷⁾
    • also causes altered vocalisations ⁸⁾
  • general transcription factor IIi RD2 (GTF2IRD2):
  • CLIP2
  • WBSCR1
  • elastin gene
    • responsible for the cardiovascular defects eg. supravalvular aortic stenosis, hypertension
  • LIM kinase 1 (LIMK1)
    • there is a critical role of LIM kinases in the regulation of the motile responses of cochlear outer hair cells (OHC) and cochlear amplification and this may be the cause of the hyperacusis and progressive hearing loss ⁹⁾
  • NCF1
    • deletion of a functional NCF1 gene copy has been shown to protect a proportion of WBS patients against hypertension, likely through reduced NADPH-oxidase (NOX)-mediated oxidative stress ¹⁰⁾
• the WBS locus is prone to recurrent chromosomal rearrangements, including the microdeletion that causes classic WBS. This is thought to be due to unequal meiotic recombination, probably mediated by the highly homologous DNA that flanks the commonly deleted region;
• Haploinsufficiency of the elastin gene is known to lead to the vascular stenoses in WBS and is also thought to predispose to hypertension;
• ~1.3 Mb tandem duplication at Xp11.23p11.3 in an 11-year-old boy with pleasant personality, hyperactivity, learning and visual-spatial difficulties, relative microcephaly, long face, stellate iris pattern, and periorbital fullness. ¹¹⁾

• these people are generally asymptomatic and have few if any of the WBS features
• the prevalence of this genetic disorder is 1-6% of the general population, but 25-30% in parents of classical WBS patients
• a common inversion, WBSinv-1 does not appear to have clinical features in common with WBS ¹²⁾
• there is little evidence though to suggest that this form is a major predisposing factor of the deletion type classical WBS in their children ¹³⁾