Loss of Baz1b in mice causes perinatal lethality, growth failure, and variable multi-system outcomes.

BAZ1B is one of 25-27 coding genes deleted in canonical Williams syndrome, a multi-system disorder causing slow growth, vascular stenosis, and gastrointestinal complaints, including constipation. BAZ1B is involved in (among other processes) chromatin organization, DNA damage repair, and mitosis, suggesting reduced BAZ1B may contribute to Williams syndrome symptoms. In mice, loss of Baz1b causes early neonatal death. 89.6% of Baz1b-/- mice die within 24 h of birth without vascular anomalies or congenital heart disease (except for patent ductus arteriosus). Some (<50%) Baz1b-/- were noted to have prolonged neonatal cyanosis, patent ductus arteriosus, or reduced lung aeration, and none developed a milk spot. Meanwhile, 35.5% of Baz1b+/- mice die over the first three weeks after birth. Surviving Baz1b heterozygotes grow slowly (with variable severity). 66.7% of Baz1b+/- mice develop bowel dilation, compared to 37.8% of wild-type mice, but small bowel and colon transit studies were normal. Additionally, enteric neuron density appeared normal in Baz1b-/- mice except in distal colon myenteric plexus, where neuron density was modestly elevated. Combined with several rare phenotypes (agnathia, microphthalmia, bowel dilation) recovered, our work confirms the importance of BAZ1B in survival and growth and suggests that reduced copy number of BAZ1B may contribute to the variability in Williams syndrome phenotypes.

Dissociable Cognitive Systems for Recognizing Places and Navigating through Them: Developmental and Neuropsychological Evidence.

Recent neural evidence suggests that the human brain contains dissociable systems for "scene categorization" (i.e., recognizing a place as a particular kind of place, for example, a kitchen), including the parahippocampal place area, and "visually guided navigation" (e.g., finding our way through a kitchen, not running into the kitchen walls or banging into the kitchen table), including the occipital place area. However, converging behavioral data - for instance, whether scene categorization and visually guided navigation abilities develop along different timelines and whether there is differential breakdown under neurologic deficit - would provide even stronger support for this two-scene-systems hypothesis. Thus, here we tested scene categorization and visually guided navigation abilities in 131 typically developing children between 4 and 9 years of age, as well as 46 adults with Williams syndrome, a developmental disorder with known impairment on "action" tasks, yet relative sparing on "perception" tasks, in object processing. We found that (1) visually guided navigation is later to develop than scene categorization, and (2) Williams syndrome adults are impaired in visually guided navigation, but not scene categorization, relative to mental age-matched children. Together, these findings provide the first developmental and neuropsychological evidence for dissociable cognitive systems for recognizing places and navigating through them.SIGNIFICANCE STATEMENT Two decades ago, Milner and Goodale showed us that identifying objects and manipulating them involve distinct cognitive and neural systems. Recent neural evidence suggests that the same may be true of our interactions with our environment: identifying places and navigating through them are dissociable systems. Here we provide converging behavioral evidence supporting this two-scene-systems hypothesis - finding both differential development and breakdown of "scene categorization" and "visually guided navigation." This finding suggests that the division of labor between perception and action systems is a general organizing principle for the visual system, not just a principle of the object processing system in particular.

Neuronal deletion of Gtf2i results in developmental microglial alterations in a mouse model related to Williams syndrome.

Williams syndrome (WS) is a genetic neurodevelopmental disorder caused by a heterozygous microdeletion, characterized by hypersociability and unique neurocognitive abnormalities. Of the deleted genes, GTF2I has been linked to hypersociability in WS. We have recently shown that Gtf2i deletion from forebrain excitatory neurons, referred to as Gtf2i conditional knockout (cKO) mice leads to multi-faceted myelination deficits associated with the social behaviors affected in WS. These deficits were potentially mediated also by microglia, as they present a close relationship with oligodendrocytes. To study the impact of altered myelination, we characterized these mice in terms of microglia over the course of development. In postnatal day 30 (P30) Gtf2i cKO mice, cortical microglia displayed a more ramified state, as compared with wild type (controls). However, postnatal day 4 (P4) microglia exhibited high proliferation rates and an elevated activation state, demonstrating altered properties related to activation and inflammation in Gtf2i cKO mice compared with control. Intriguingly, P4 Gtf2i cKO-derived microglial cells exhibited significantly elevated myelin phagocytosis in vitro compared to control mice. Lastly, systemic injection of clemastine to P4 Gtf2i cKO and control mice until P30, led to a significant interaction between genotypes and treatments on the expression levels of the phagocytic marker CD68, and a significant reduction of the macrophage/microglial marker Iba1 transcript levels in the cortex of the Gtf2i cKO treated mice. Our data thus implicate microglia as important players in WS, and that early postnatal manipulation of microglia might be beneficial in treating inflammatory and myelin-related pathologies.

Cross-sectional and longitudinal assessment of cognitive development in Williams syndrome.

Williams syndrome (WS) is a rare genetic syndrome. As with all rare syndromes, obtaining adequately powered sample sizes is a challenge. Here we present legacy data from seven UK labs, enabling the characterisation of cross-sectional and longitudinal developmental trajectories of verbal and non-verbal development in the largest sample of individuals with WS to-date. In Study 1, we report cross-sectional data between N = 102 and N = 209 children and adults with WS on measures of verbal and non-verbal ability. In Study 2, we report longitudinal data from N = 17 to N = 54 children and adults with WS who had been tested on at least three timepoints on these measures. Data support the WS characteristic cognitive profile of stronger verbal than non-verbal ability, and shallow developmental progression for both domains. Both cross-sectional and longitudinal data demonstrate steeper rates of development in the child participants than the adolescent and adults in our sample. Cross-sectional data indicate steeper development in verbal than non-verbal ability, and that individual differences in the discrepancy between verbal and non-verbal ability are largely accounted for by level of intellectual functioning. A diverging developmental discrepancy between verbal and non-verbal ability, whilst marginal, is not mirrored statistically in the longitudinal data. Cross-sectional and longitudinal data are discussed with reference to validating cross-sectional developmental patterns using longitudinal data and the importance of individual differences in understanding developmental progression.

Levodopa-responsive dystonia, parkinsonism, and treatment-resistant schizoaffective disorder in Williams syndrome.

BACKGROUND: Williams syndrome (WS; chromosome 7q11.23 deletion) is a rare, multisystemic, neurodevelopmental disorder with variable penetrance and expressivity. Although movement and psychiatric disorders are known to occur in individuals with WS, parkinsonism, dystonia, and treatment-resistant schizoaffective disorder have not been formally described. METHODS: We present two unrelated cases of adults with molecularly confirmed WS and typical histories of developmental delays, intellectual/learning disabilities, and treatment-responsive anxiety/mood disorder who developed similar noteworthy neuropsychiatric expressions. We reviewed detailed neuropsychiatric histories, laboratory investigations, neuroimaging, and treatment responses and compared data for the two cases. RESULTS: Both individuals developed treatment-resistant schizoaffective disorder in adulthood requiring multiple trials of antipsychotic treatments. While on clozapine, both patients developed parkinsonism and generalized dystonia with truncal involvement that responded to trials of low-dose levodopa without exacerbating underlying psychotic or affective symptoms. CONCLUSION: This report illustrates the novel occurrence of levodopa-responsive movement disorders and treatment-resistant schizoaffective disorder in individuals with WS, adding to the expanding neuropsychiatric phenotypes, and highlighting potential shared underlying mechanisms. The observed treatment response suggests that levodopa, in relatively low doses, may be safe and useful in ameliorating presumed antipsychotic-associated parkinsonism and tardive dystonia in WS.

Human Genetics of Semilunar Valve and Aortic Arch Anomalies.

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.

Intensive Care Unit Analgosedation After Cardiac Surgery in Children with Williams Syndrome : a Matched Case-Control Study.

OBJECTIVE: Cardiovascular abnormalities are common in patients with Williams syndrome and frequently require surgical intervention necessitating analgesia and sedation in a population with a unique neuropsychiatric profile, potentially increasing the risk of adverse cardiac events during the perioperative period. Despite this risk, the overall postoperative analgosedative requirements in patients with WS in the cardiac intensive care unit have not yet been investigated. Our primary aim was to examine the analgosedative requirement in patients with WS after cardiac surgery compared to a control group. Our secondary aim was to compare the frequency of major ACE and mortality between the two groups. DESIGN: Matched case-control study. SETTING: Pediatric CICU at a Tertiary Children's Hospital. PATIENTS: Patients with WS and age-matched controls who underwent cardiac surgery and were admitted to the CICU after cardiac surgery between July 2014 and January 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Postoperative outcomes and total doses of analgosedative medications were collected in the first six days after surgery for the study groups. Median age was 29.8 (12.4-70.8) months for WS and 23.5 (11.2-42.3) months for controls. Across all study intervals (48 h and first 6 postoperative days), there were no differences between groups in total doses of morphine equivalents (5.0 mg/kg vs 5.6 mg/kg, p = 0.7 and 8.2 mg/kg vs 10.0 mg/kg, p = 0.7), midazolam equivalents (1.8 mg/kg vs 1.5 mg/kg, p = 0.4 and 3.4 mg/kg vs 3.8 mg/kg, p = 0.4), or dexmedetomidine (20.5 mcg/kg vs 24.4 mcg/kg, p = 0.5 and 42.3 mcg/kg vs 39.1 mcg/kg, p = 0.3). There was no difference in frequency of major ACE or mortality. CONCLUSIONS: Patients with WS received similar analgosedative medication doses compared with controls. There was no significant difference in the frequency of major ACE (including cardiac arrest, extracorporeal membrane oxygenation, and surgical re-intervention) or mortality between the two groups, though these findings must be interpreted with caution. Further investigation is necessary to elucidate the adequacy of pain/sedation control, factors that might affect analgosedative needs in this unique population, and the impact on clinical outcomes.

Strategies for the Surgical Management of Highly Aggressive Williams Syndrome Aortopathy: A Three Case Report.

Severe aortopathy in Williams syndrome can sometimes present with an initial ascending aortic pathology, followed in short order by more distal multilevel obstruction and recurrence requiring reintervention. In this series, an early, comprehensive surgical approach using a combination of various access and perfusion strategies yielded excellent long-term results.

Using a community engaged research approach to develop the social skills training program for adults with Williams syndrome.

This article describes the development of a distance-delivered social skills training program for adults with Williams syndrome (SSTP-WS) through a community engaged approach. Throughout six phases of development, the research team received input from adults with Williams syndrome, caregivers, service providers, educators, and researchers on (a) the need for a training program and topics to be addressed (Phase 1), (b) an initial draft of the SSTP-WS (Phase 3), (c) the intervention pilot study (Phase 5), and (d) feedback to provide context for the results of the study (Phase 6). The development of the SSTP-WS resulted in an intervention aligned with the Williams syndrome community's values and needs that supports the unique cognitive and behavioral phenotypes and social characteristics of this low incidence disability population.

Mosaic Williams syndrome: A case report.

Williams syndrome (WS) is a well-known genetic disorder caused by heterozygous microdeletions of the 7q11.23 chromosome region. The main clinical features of the syndrome are characteristic facial dysmorphisms, cardiovascular and endocrine anomalies, short stature, mild-to-moderate intellectual disability, and a recognizable cognitive and behavioral profile. Differently from large chromosomal imbalances and aneuploidies, mosaicism has only rarely been found in microdeletion syndromes, and mosaic cases with WS phenotype have never been reported. We here describe a 51-year-old female patient with the typical clinical features of WS, whose chromosomal microarray analysis and fluorescence in situ hybridization disclosed a 54%-68% germline mosaicism for 7q11.23 deletion.

Transplantation in paediatric patients with MMA requires multidisciplinary approach for achievement of good clinical outcomes.

BACKGROUND: As modern medicine is advancing, younger, small, and more complex children are becoming multi-organ transplant candidates. This brings up new challenges in all aspects of their care. METHODS: We describe the first report of a small child receiving a simultaneous liver and kidney transplant and abdominal rectus sheath fascia transplant on the background of Williams syndrome and methylmalonic acidaemia. At the time of transplantation, the child was 3 years old, weighed 14.0 kg, had chronic kidney disease stage V, and had not yet started any other form of kidney replacement therapy. RESULTS: There were many anaesthetic, medical, metabolic, and surgical challenges to consider in this case. A long general anaesthetic time increased the risk of cardiac complications and metabolic decompensation. Additionally, the small size of the patient and the organ size mis-match meant that primary abdominal closure was not possible. The patient's recovery was further complicated by sepsis, transient CNI toxicity, and de novo DSAs. CONCLUSIONS: Through a multidisciplinary approach between 9 specialties in 4 hospitals across England and Wales, and detailed pre-operative planning, a good outcome was achieved for this child. An hour by hour management protocol was drafted to facilitate transplant and included five domains: 1. management at the time of organ offer; 2. before the admission; 3. at admission and before theatre time; 4. intra-operative management; and 5. post-operative management in the first 24 h. Importantly, gaining a clear and in depth understanding of the metabolic state of the patient pre- and peri-operatively was crucial in avoiding metabolic decompensation. Furthermore, an abdominal rectus sheath fascia transplant was required to achieve abdominal closure, which to our knowledge, had never been done before for this indication. Using our experience of this complex case, as well as our experience in transplanting other children with MMA, and through a literature review, we propose a new perioperative management pathway for this complex cohort of transplant recipients.

Williams Syndrome: Supravalvar Aortic, Aortic Arch, Coronary and Pulmonary Arteries: Is Comprehensive Repair Advisable and Achievable?

Williams syndrome, and various elastin protein mediated arteriopathies, presents a clinical challenge to pediatric cardiovascular specialists. In the severest phenotypes, multilevel obstruction to the systemic and pulmonic arterial systems result in biventricular dysfunction which can be imminently life-threatening. As a longstanding, quaternary referral center for complex pulmonary arteriopathies and pediatric connective tissue disease, Stanford Medicine Children's Health has developed a sizeable experience managing these patients. This manuscript is a summary of our current strategies, with a focus on our surgical techniques, peri-procedural considerations on timing and staging of various interventions, and long-term results.

Re-visiting the 'mysterious myth of attention deficit': A systematic review of the recent evidence.

Based on the inclusive and methodologically rigorous framework provided by Ed Zigler's developmental approach, we previously challenged what we called, 'the mysterious myth of attention deficit', the fallacy of attention as a universal deficit among persons with intellectual disability (ID). In this latest update, we conducted a systematic review of studies of essential components of attention among persons with ID published in the interim since the last iteration of the mysterious myth narrative was submitted for publication approximately a decade ago. We searched the databases PubMed and PsycINFO for English-language peer-reviewed studies published from 1 January 2011 through 5 February 2021. In keeping with the developmental approach, the two essential methodological criteria were that the groups of persons with ID were aetiologically homogeneous and that the comparisons with persons with average IQs (or with available norms) were based on an appropriate index of developmental level, or mental age. Stringent use of these criteria for inclusion served to control for bias in article selection. Articles were then categorised based on aetiological group studied and component of visual attention. Based on these criteria, 18 articles were selected for inclusion out of the 2837 that were identified. The included studies involved 547 participants: 201 participants with Down syndrome, 214 participants with Williams syndrome and 132 participants with fragile X syndrome. The findings from these articles call attention to the complexities and nuances in understanding attentional functioning across homogeneous aetiological groups and highlight that functioning must be considered in relation to aetiology; factors associated with the individual, such as developmental level, motivation, styles and biases; and factors associated with both the task, such as context, focus, social and emotional implications, and levels of environmental complexity.

Sudden Cardiac Arrest During a Sedated Cardiac Magnetic Resonance Study in a Nonsyndromic Child with Evolving Supravalvar Aortic Stenosis Due to Familial ELN Mutation.

Supravalvar aortic stenosis (SVAS) is a less common but clinically important form of left ventricular outflow tract obstruction, and commonly associated with Williams syndrome (WS). SVAS outside of WS may also occur sporadically or in a familial form, often with identifiable mutations in the elastin (ELN) gene. While risk of sudden cardiac death in patients with SVAS has been extensively described in the context of WS, less is known about risk in patients with isolated SVAS. We report a case of a nonsyndromic two-year-old boy with evolving manifestations of SVAS who developed sudden cardiac arrest and death during a sedated cardiac magnetic resonance imaging study. A strong family history of SVAS was present and targeted genetic testing identified an ELN gene mutation in the boy's affected father and other paternal relatives. We review risk factors found in the literature for SCA in SVAS patients and utilize this case to raise awareness of the risk of cardiac events in these individuals even in the absence of WS or severe disease. This case also underscores the importance of genetic testing, including targeted panels specifically looking for ELN gene mutations, in all patients with SVAS even in the absence of phenotypic concerns for WS or other genetic syndromes.

Gesture-speech integration is related to vocabulary skills in children with developmental language disorder, Williams syndrome and typical development.

BACKGROUND: Individuals with developmental language disorder or Williams syndrome are reported to use more gestures than individuals with typical development. However, these two groups differ considerably in visuospatial and language skills, two skills that are hypothesized to shape gesture rate. AIMS: We first examined whether children with both developmental language disorder and children Williams syndrome do indeed use more gestures. Our second aim was to disentangle the role of vocabulary and visuospatial skills in the use of supplementary gestures (i.e., containing unique information). To account for participant heterogeneity, analyses included both group comparisons and vocabulary and visuospatial skills at an individual level. As a third aim, the role of visuospatial skills was further examined in relation to gestures containing spatial content. METHODS & PROCEDURES: In a cross-sectional group design, three participant groups watched and then retold a cartoon: children with typical development (n = 25), children with developmental language disorder (n = 25) and children/young people with Williams syndrome (n = 14). Their narrations were transcribed and hand gestures were coded based on gesture-speech integration (redundant, adds information to particular lexical items, gives information that is entirely absent from speech) and spatial content. Participants' expressive vocabulary and visuospatial skills were measured. OUTCOMES & RESULTS: Between-group comparisons showed that individuals with developmental language disorder or Williams syndrome did indeed use more gestures. Poisson loglinear modelling demonstrated that a relative higher use of supplementary gestures was determined by lower expressive vocabulary skills. Neither the group distinction nor visuospatial skills shaped the supplementary gesture rate nor spatial gesture rate. CONCLUSIONS & IMPLICATIONS: Regardless of neurodevelopmental condition or typical development, a higher use of supplementary gestures was influenced by expressive vocabulary skills. Children with lower vocabulary skills spontaneously capitalized on the multimodality of communication to express constituents that were not present in their verbal speech. This finding is a promising starting point for future gesture intervention studies examining whether implicit modelling of gesture use can encourage gestures even more in these children and if this allows them to achieve higher linguistic complexity. On a methodological note, the observed intra-group skill variability demonstrates that group comparisons need to be complemented with correlational measures accounting for skills at an individual level. WHAT THIS PAPER ADDS: What is already known on the subject Children with developmental language disorder and children with Williams syndrome are more inclined to use gestures than typically developing children. Research conducted in adults with typical development points towards the role of lexical and visuospatial skills in gesture use, but it is unclear how these skills shape gesture use in children with atypical development. What this paper adds to existing knowledge This study compares the rate of gestures that convey meaning that is not expressed in speech between the three aforementioned populations. Novel is the inclusion of the group distinction, individual lexical skills, and visuospatial skills in one encompassing statistical model. What are the potential or actual clinical implications of this work? The inclination to use gestures that replace speech is related to lexical skills. Visuospatial skills do not seem to play a role and should not be considered as a factor when thinking about gesture intervention. Understanding how gestures relate to specific skills is a first step to understanding how gesture interventions can bolster language production.

An infant with suspected missed diagnosis of Williams syndrome failed weaning off CPB after surgical correction of pulmonary stenosis: a case report and literature review.

Williams syndrome (WS) is a rare congenital developmental disorder caused by the deletion of between 26 and 28 genes on chromosome 7q11.23. For patients with WS, in view of the particularity of the supravalvular aortic stenosis, choosing appropriate arterial cannula, maintaining higher perfusion pressure as well as strengthening myocardial protection during cardiopulmonary bypass (CPB) is essential to the clinical outcome. Here, we report a child with pulmonary artery valvular stenosis who failed to wean off CPB because of malignant arrhythmias and cardiac insufficiency after surgical correction of pulmonary valvular stenosis. With the assistance of extracorporeal membrane oxygenation (ECMO), emergency cardiac catheterization revealed supravalvular aortic stenosis (SVAS), which suggests a suspected missed diagnosis of WS. Finally, under the support of ECMO, the cardiac function gradually returned to normal, and the child was discharged 23 days after surgery.

Parental attitudes and beliefs about sexuality of individuals with intellectual disability: Insights from a Brazilian sample of parents of individuals with Williams syndrome.

BACKGROUND: The affective expression of sexual behaviour in individuals with Williams syndrome can lead to risky behaviours, especially if parents do not have information on how to provide sex education or support from specialised professionals. METHOD: The Attitudes to Sexuality Questionnaire for Individuals with Intellectual Disabilities was used to identify parental beliefs, attitudes and concerns about the sexuality and sex education of individuals with intellectual disabilities. The sample comprised 35 parents of individuals with Williams syndrome (mean age 12.8 years (SD = 4.5), 57.1% male). RESULTS: Parents believe in the possibility of marriage and sexual relationships for individuals with intellectual disability when they are older and agree with sexual reproduction in adulthood. Parents consider that sex education, in addition to parental guidance, should be provided by professionals. CONCLUSIONS: This data highlights the need for parents to have clear guidelines on interventions in respect of the sexuality of individuals with intellectual disability.

Quality of life of Brazilian families who have children with Williams syndrome.

This cross-sectional and descriptive study examined the family quality of life (FQoL) among 72 Brazilian families who have children with Williams syndrome, a rare genetic disorder in which most individuals have an intellectual disability, usually mild. Data were collected using sociodemographic and clinical data forms and the Beach Center FQoL Scale. The overall FQoL score was 3.90 ± 0.45, below the limit of four points considered satisfactory. Families felt more satisfied with the family interaction (4.11 ± 0.57), parenting (4.07 ± 0.42), and disability-related support (3.94 ± 0.62) domains, and less satisfied with the family's emotional (3.49 ± 0.73) and physical/material well-being (3.73 ± 0.74) domains. Paternal education, children's cardiopathy and autonomy in activities of daily living explained 24.5% of the variance in the overall FQoL. Measures are necessary to improve the emotional and physical/material well-being of families to reduce the family burden. Monitoring the child's cardiac condition and promoting independence in activities of daily living are also the main procedures.

Emerging mechanisms of elastin transcriptional regulation.

Elastin provides recoil to tissues that stretch such as the lung, blood vessels, and skin. It is deposited in a brief window starting in the prenatal period and extending to adolescence in vertebrates, and then slowly turns over. Elastin insufficiency is seen in conditions such as Williams-Beuren syndrome and elastin-related supravalvar aortic stenosis, which are associated with a range of vascular and connective tissue manifestations. Regulation of the elastin (ELN) gene occurs at multiple levels including promoter activation/inhibition, mRNA stability, interaction with microRNAs, and alternative splicing. However, these mechanisms are incompletely understood. Better understanding of the processes controlling ELN gene expression may improve medicine's ability to intervene in these rare conditions, as well as to replace age-associated losses by re-initiating elastin production. This review describes what is known about the ELN gene promoter structure, transcriptional regulation by cytokines and transcription factors, and posttranscriptional regulation via mRNA stability and micro-RNA and highlights new approaches that may influence regenerative medicine.

Neuropsychological Genotype-Phenotype in Patients with Williams Syndrome with Atypical Deletions: A Systematic Review.

Williams syndrome (WS) is a neurodevelopmental disorder caused by a microdeletion in the q11.23 region of chromosome 7. Recent case series reports and clinical case studies have suggested that the cognitive, behavioral, emotional, and social profile in WS could depend on the genes involved in the deletion. The objective of this systematic review was to analyze and synthesize the variability of the cognitive and behavioral profile of WS with atypical deletion and its probable relationship with the affected genes. The medical subject headings searched were "Williams syndrome," "genotype," "phenotype," "cognitive profile," and "atypical deletion." The studies included were in English or Spanish, with children and adults, and published between January 2000 and October 2022. Twenty-three studies are reported. The characteristics of the participants, the genes involved, the neuropsychological domains and instruments, and the prevalence of the WS cognitive profile criteria were used for the genotype-phenotype analysis. The genes with a major impact on the cognitive profile of WS were (a) LIMK1 and those belonging to the GTF2I family, the former with a greater influence on visuospatial abilities; (b) GTF2IRD1 and GTF2I, which have an impact on intellectual capacity as well as on visuospatial and social skills; (c) FZD9, BAZ1B, STX1A, and CLIP2, which influence the cognitive profile if other genes are also effected; and (d) GTF2IRD2, which is related to the severity of the effect on visuospatial and social skills, producing a behavioral phenotype like that of the autism spectrum. The review revealed four neuropsychological phenotypes, depending on the genes involved, and established the need for more comprehensive study of the neuropsychological profile of these patients. Based on the results found, we propose a model for the investigation of and clinical approach to the WS neuropsychological phenotype.