ABSTRACT
BACKGROUND: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. METHODS AND RESULTS: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size. CONCLUSIONS: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.
Subject(s)
Aortic Stenosis, Supravalvular , Williams Syndrome , Humans , Williams Syndrome/genetics , Genome-Wide Association Study , Proteomics , Rare Diseases , Aortic Stenosis, Supravalvular/genetics , Aortic Stenosis, Supravalvular/metabolism , Aortic Stenosis, Supravalvular/surgeryABSTRACT
Williams-Beuren syndrome (WBS) and 7q11.23 duplication syndrome (Dup7) are rare neurodevelopmental disorders caused by deletion and duplication of a 1.5 Mb region that includes at least five genes with a known role in epigenetic regulation. We have shown that CNV of this chromosome segment causes dose-dependent, genome-wide changes in DNA methylation, but the specific genes driving these changes are unknown. We measured genome-wide whole blood DNA methylation in six participants with atypical CNV of 7q11.23 (three with deletions and three with duplications) using the Illumina HumanMethylation450k array and compared their profiles with those from groups of individuals with classic WBS or classic Dup7 and with typically developing (TD) controls. Across the top 1000 most variable positions we found that only the atypical rearrangements that changed the copy number of GTF2IRD1 and/or GTF2I (coding for the TFII-IRD1 and TFII-I proteins) clustered with their respective syndromic cohorts. This finding was supported by results from hierarchical clustering across a selection of differentially methylated CpGs, in addition to pyrosequencing validation. These findings suggest that CNV of the GTF2I genes at the telomeric end of the 7q11.23 interval is a key contributor to the large changes in DNA methylation that are seen in blood DNA from our WBS and Dup7 cohorts, compared to TD controls. Our findings suggest that members of the TFII-I protein family are involved in epigenetic processes that alter DNA methylation on a genome-wide level.
ABSTRACT
BACKGROUND: Williams syndrome (WS), a rare neurodevelopmental disorder caused by hemizygous deletion of ~ 25 genes from chromosomal band 7q11.23, affords an exceptional opportunity to study associations between a well-delineated genetic abnormality and a well-characterized neurobehavioral profile. Clinically, WS is typified by increased social drive (often termed "hypersociability") and severe visuospatial construction deficits. Previous studies have linked visuospatial problems in WS with alterations in the dorsal visual processing stream. We investigated the impacts of hemideletion and haplotype variation of LIMK1, a gene hemideleted in WS and linked to neuronal maturation and migration, on the structure and function of the dorsal stream, specifically the intraparietal sulcus (IPS), a region known to be altered in adults with WS. METHODS: We tested for IPS structural and functional changes using longitudinal MRI in a developing cohort of children with WS (76 visits from 33 participants, compared to 280 visits from 94 typically developing age- and sex-matched participants) over the age range of 5-22. We also performed MRI studies of 12 individuals with rare, shorter hemideletions at 7q11.23, all of which included LIMK1. Finally, we tested for effects of LIMK1 variation on IPS structure and imputed LIMK1 expression in two independent cohorts of healthy individuals from the general population. RESULTS: IPS structural (p < 10-4 FDR corrected) and functional (p < .05 FDR corrected) anomalies previously reported in adults were confirmed in children with WS, and, consistent with an enduring genetic mechanism, were stable from early childhood into adulthood. In the short hemideletion cohort, IPS deficits similar to those in WS were found, although effect sizes were smaller than those found in WS for both structural and functional findings. Finally, in each of the two general population cohorts stratified by LIMK1 haplotype, IPS gray matter volume (pdiscovery < 0.05 SVC, preplication = 0.0015) and imputed LIMK1 expression (pdiscovery = 10-15, preplication = 10-23) varied according to LIMK1 haplotype. CONCLUSIONS: This work offers insight into neurobiological and genetic mechanisms responsible for the WS phenotype and also more generally provides a striking example of the mechanisms by which genetic variation, acting by means of molecular effects on a neural intermediary, can influence human cognition and, in some cases, lead to neurocognitive disorders.
Subject(s)
Williams Syndrome , Child, Preschool , Adult , Humans , Child , Haplotypes , Williams Syndrome/complications , Williams Syndrome/genetics , Cerebral Cortex , Cognition , Gray Matter , Lim Kinases/geneticsABSTRACT
BACKGROUND: 7q11.23 duplication (Dup7) is one of the most frequent recurrent copy number variants (CNVs) in individuals with autism spectrum disorder (ASD), but based on gold-standard assessments, only 19% of Dup7 carriers have ASD, suggesting that additional genetic factors are necessary to manifest the ASD phenotype. To assess the contribution of additional genetic variants to the Dup7 phenotype, we conducted whole-genome sequencing analysis of 20 Dup7 carriers: nine with ASD (Dup7-ASD) and 11 without ASD (Dup7-non-ASD). RESULTS: We identified three rare variants of potential clinical relevance for ASD: a 1q21.1 microdeletion (Dup7-non-ASD) and two deletions which disrupted IMMP2L (one Dup7-ASD, one Dup7-non-ASD). There were no significant differences in gene-set or pathway variant burden between the Dup7-ASD and Dup7-non-ASD groups. However, overall intellectual ability negatively correlated with the number of rare loss-of-function variants present in nervous system development and membrane component pathways, and adaptive behaviour standard scores negatively correlated with the number of low-frequency likely-damaging missense variants found in genes expressed in the prenatal human brain. ASD severity positively correlated with the number of low frequency loss-of-function variants impacting genes expressed at low levels in the brain, and genes with a low level of intolerance. CONCLUSIONS: Our study suggests that in the presence of the same pathogenic Dup7 variant, rare and low frequency genetic variants act additively to contribute to components of the overall Dup7 phenotype.
Subject(s)
Autism Spectrum Disorder , Autism Spectrum Disorder/genetics , Chromosome Deletion , DNA Copy Number Variations/genetics , Female , Genomics , Humans , Phenotype , PregnancyABSTRACT
This set of recommendations is designed to assist the pediatrician in caring for children with Williams syndrome (WS) who were diagnosed by using clinical features and with chromosome 7 microdeletion confirmed by fluorescence in situ hybridization, chromosome microarray, or multiplex ligation-dependent probe amplification. The recommendations in this report reflect review of the current literature, including previously peer-reviewed and published management suggestions for WS, as well as the consensus of physicians and psychologists with expertise in the care of individuals with WS. These general recommendations for the syndrome do not replace individualized medical assessment and treatment.
Subject(s)
Williams Syndrome/complications , Adolescent , Adult , Age Factors , Cardiovascular Abnormalities/etiology , Cardiovascular Abnormalities/therapy , Child , Child, Preschool , Constipation/etiology , Constipation/therapy , Dental Care for Children/methods , Facies , Female , Hearing Disorders/etiology , Humans , Hypercalcemia/complications , Hypercalcemia/diagnosis , Hypercalcemia/therapy , Hypothyroidism/etiology , Infant , Male , Nervous System Diseases/diagnosis , Nervous System Diseases/etiology , Nervous System Diseases/therapy , Photography , Physical Examination , Problem Behavior/psychology , Transition to Adult Care , Urinary Tract/abnormalities , Williams Syndrome/genetics , Williams Syndrome/therapy , Young AdultABSTRACT
In order to describe the physical characteristics, medical complications, and natural history of classic 7q11.23 duplication syndrome [hereafter Dup7 (MIM 609757)], reciprocal duplication of the region deleted in Williams syndrome [hereafter WS (MIM 194050)], we systematically evaluated 53 individuals aged 1.25-21.25 years and 11 affected adult relatives identified in cascade testing. In this series, 27% of probands with Dup7 had an affected parent. Seven of the 26 de novo duplications that were examined for inversions were inverted; in all seven cases one of the parents had the common inversion polymorphism of the WS region. We documented the craniofacial features of Dup7: brachycephaly, broad forehead, straight eyebrows, broad nasal tip, low insertion of the columella, short philtrum, thin upper lip, minor ear anomalies, and facial asymmetry. Approximately 30% of newborns and 50% of older children and adults had macrocephaly. Abnormalities were noted on neurological examination in 88.7% of children, while 81.6% of MRI studies showed structural abnormalities such as decreased cerebral white matter volume, cerebellar vermis hypoplasia, and ventriculomegaly. Signs of cerebellar dysfunction were found in 62.3%, hypotonia in 58.5%, Developmental Coordination Disorder in 74.2%, and Speech Sound Disorder in 82.6%. Behavior problems included anxiety disorders, ADHD, and oppositional disorders. Medical problems included seizures, 19%; growth hormone deficiency, 9.4%; patent ductus arteriosus, 15%; aortic dilation, 46.2%; chronic constipation, 66%; and structural renal anomalies, 18%. We compare these results to the WS phenotype and offer initial recommendations for medical evaluation and surveillance of individuals who have Dup7.
Subject(s)
Williams Syndrome/etiology , Adolescent , Child , Child, Preschool , Chromosomes, Human, Pair 7 , Developmental Disabilities/etiology , Developmental Disabilities/genetics , Face/abnormalities , Female , Humans , Infant , Male , Megalencephaly , Pregnancy , Pregnancy Complications/genetics , Williams Syndrome/genetics , Young AdultABSTRACT
Epigenetic dysfunction has been implicated in a growing list of disorders that include cancer, neurodevelopmental disorders, and neurodegeneration. Williams syndrome (WS) and 7q11.23 duplication syndrome (Dup7) are rare neurodevelopmental disorders with broad phenotypic spectra caused by deletion and duplication, respectively, of a 1.5-Mb region that includes several genes with a role in epigenetic regulation. We have identified striking differences in DNA methylation across the genome between blood cells from children with WS or Dup7 and blood cells from typically developing (TD) children. Notably, regions that were differentially methylated in both WS and Dup7 displayed a significant and symmetrical gene-dose-dependent effect, such that WS typically showed increased and Dup7 showed decreased DNA methylation. Differentially methylated genes were significantly enriched with genes in pathways involved in neurodevelopment, autism spectrum disorder (ASD) candidate genes, and imprinted genes. Using alignment with ENCODE data, we also found the differentially methylated regions to be enriched with CCCTC-binding factor (CTCF) binding sites. These findings suggest that gene(s) within 7q11.23 alter DNA methylation at specific sites across the genome and result in dose-dependent DNA-methylation profiles in WS and Dup7. Given the extent of DNA-methylation changes and the potential impact on CTCF binding and chromatin regulation, epigenetic mechanisms most likely contribute to the complex neurological phenotypes of WS and Dup7. Our findings highlight the importance of DNA methylation in the pathogenesis of WS and Dup7 and provide molecular mechanisms that are potentially shared by WS, Dup7, and ASD.
Subject(s)
DNA Methylation/genetics , Epigenesis, Genetic/genetics , Gene Dosage/genetics , DNA Primers/genetics , Gene Frequency , Humans , Real-Time Polymerase Chain Reaction , Sequence Analysis, DNA , Statistics, Nonparametric , Williams SyndromeABSTRACT
To begin to delineate the psychological characteristics associated with classic 7q11.23 duplication syndrome (duplication of the classic Williams syndrome region; hereafter classic Dup7), we tested 63 children with classic Dup7 aged 4-17 years. Sixteen toddlers aged 18-45 months with classic Dup7 and 12 adults identified by cascade testing also were assessed. For the child group, median General Conceptual Ability (similar to IQ) on the Differential Ability Scales-II was 85.0 (low average), with a range from severe disability to high average ability. Median reading and mathematics achievement standard scores were at the low average to average level, with a range from severe impairment to high average or superior ability. Adaptive behavior was considerably more limited; median Scales of Independent Behavior-Revised Broad Independence standard score was 62.0 (mild impairment), with a range from severe adaptive impairment to average adaptive ability. Anxiety disorders were common, with 50.0% of children diagnosed with Social Phobia, 29.0% with Selective Mutism, 12.9% with Separation Anxiety Disorder, and 53.2% with Specific Phobia. In addition, 35.5% were diagnosed with Attention Deficit/Hyperactivity Disorder and 24.2% with Oppositional Defiant Disorder or Disruptive Behavior Disorder-Not Otherwise Specified. 33.3% of the children screened positive for a possible Autism Spectrum Disorder and 82.3% were diagnosed with Speech Sound Disorder. We compare these findings to previously reported results for children with Williams syndrome and argue that genotype/phenotype studies involving the Williams syndrome region offer important opportunities to understand the contribution of genes in this region to common disorders affecting the general population.
Subject(s)
Adaptation, Psychological/physiology , Anxiety Disorders/psychology , Attention Deficit Disorder with Hyperactivity/psychology , Attention Deficit and Disruptive Behavior Disorders/psychology , Williams Syndrome/psychology , Adolescent , Adult , Autism Spectrum Disorder/diagnosis , Child , Child, Preschool , Humans , Infant , Intelligence Tests , Speech Sound Disorder/diagnosis , Williams Syndrome/geneticsABSTRACT
Duplication (dup7q11.23) and deletion (Williams syndrome) of chromosomal region 7q11.23 cause neurodevelopmental disorders with contrasting anxiety phenotypes. We found that 30% of 4- to 12-year-olds with dup7q11.23 but fewer than 5% of children with WS or in the general population met diagnostic criteria for a separation-anxiety disorder. To address the role of one commonly duplicated or deleted gene in separation anxiety, we compared mice that had varying numbers of Gtf2i copies. Relative to mouse pups with one or two Gtf2i copies, pups with additional Gtf2i copies showed significantly increased maternal separation-induced anxiety as measured by ultrasonic vocalizations. This study links the copy number of a single gene from 7q11.23 to separation anxiety in both mice and humans, highlighting the utility of mouse models in dissecting specific gene functions for genomic disorders that span many genes. This study also offers insight into molecular separation-anxiety pathways that might enable the development of targeted therapeutics.
Subject(s)
Anxiety, Separation/genetics , Gene Duplication , Transcription Factors, TFII/genetics , Animals , Child , Child, Preschool , Chromosomes, Human, Pair 7 , Female , Gene Deletion , Humans , Male , Mice , Models, Genetic , Phenotype , Time Factors , Williams Syndrome/geneticsABSTRACT
Multilevel modeling was used to address the longitudinal stability of standard scores (SSs) measuring intellectual ability for children with Williams syndrome (WS). Participants were 40 children with genetically confirmed WS who completed the Kaufman Brief Intelligence Test-Second Edition (KBIT-2; A. S. Kaufman & N. L. Kaufman, 2004 ) 4-7 times over a mean of 5.06 years. Mean age at first assessment was 7.44 years (range â=â 4.00-13.97 years). On average, KBIT-2 Composite IQ, Verbal SS, and Nonverbal SS were stable from 4 to 17 years, although there were significant individual differences in intercept (Composite IQ, Verbal SS, Nonverbal SS) and slope (Composite IQ, Nonverbal SS). Maternal education was significantly related to Verbal SS intercept. No significant sex differences were found. Implications for studies of genotype/phenotype correlations in WS are discussed.
Subject(s)
Intellectual Disability/diagnosis , Intellectual Disability/epidemiology , Intelligence Tests/statistics & numerical data , Models, Psychological , Williams Syndrome/diagnosis , Williams Syndrome/epidemiology , Adolescent , Child , Child, Preschool , Female , Humans , Intellectual Disability/psychology , Longitudinal Studies , Male , Nonverbal Communication , Predictive Value of Tests , Verbal Learning , Williams Syndrome/psychologyABSTRACT
Although it is widely accepted that genes can influence complex behavioral traits such as human temperament, the underlying neurogenetic mechanisms remain unclear. Williams syndrome (WS), a rare disorder caused by a hemizygous deletion on chromosome 7q11.23, including genes important for neuronal migration and maturation (LIMK1 and CLIP2), is typified by a remarkable hypersocial but anxious personality and offers a unique opportunity to investigate this open issue. Based on the documented role of the insula in mediating emotional response tendencies and personality, we used multimodal imaging to characterize this region in WS and found convergent anomalies: an overall decrease in dorsal anterior insula (AI) gray-matter volume along with locally increased volume in the right ventral AI; compromised white-matter integrity of the uncinate fasciculus connecting the insula with the amygdala and orbitofrontal cortex; altered regional cerebral blood flow in a pattern reminiscent of the observed gray-matter alterations (i.e., widespread reductions in dorsal AI accompanied by locally increased regional cerebral blood flow in the right ventral AI); and disturbed neurofunctional interactions between the AI and limbic regions. Moreover, these genetically determined alterations of AI structure and function predicted the degree to which the atypical WS personality profile was expressed in participants with the syndrome. The AI's rich anatomical connectivity, its transmodal properties, and its involvement in the behaviors affected in WS make the observed genetically determined insular circuitry perturbations and their association with WS personality a striking demonstration of the means by which neural systems can serve as the interface between genetic variability and alterations in complex behavioral traits.
Subject(s)
Anxiety/genetics , Chromosomes, Human, Pair 7 , Personality , Social Behavior , Williams Syndrome/genetics , Adolescent , Adult , Anxiety/psychology , Cerebrovascular Circulation , Female , Humans , Lim Kinases/genetics , Male , Microtubule-Associated Proteins/genetics , Williams Syndrome/psychology , Young AdultABSTRACT
Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.
Subject(s)
Abnormalities, Multiple/genetics , DNA-Binding Proteins/genetics , Hematologic Diseases/genetics , Mutation/genetics , Neoplasm Proteins/genetics , Vestibular Diseases/genetics , Abnormalities, Multiple/diagnosis , Alleles , Face/abnormalities , Gene Order , Genetic Testing , Genotype , Hematologic Diseases/diagnosis , Humans , Phenotype , Prognosis , Vestibular Diseases/diagnosisABSTRACT
Inversion of the Williams syndrome (WS) region on chromosome 7q11.23 has previously been shown to occur at a higher frequency in the transmitting parents of children with WS than in the general population, suggesting that it predisposes to the WS deletion. Frohnauer et al. recently reported that the frequency of this inversion is not elevated in the parents of children with WS in Germany relative to the German general population. We have compared Frohnauer et al.'s data to those from three previously published studies (Hobart et al., Bayes et al., Osborne et al.), all of which reported a significantly higher rate of 7q11.23 inversion in transmitting parents than in the general population. Results indicated that Frohnauer et al.'s data are consistent with previously reported frequencies of 7q11.23 inversion in North America and Spain in both transmitting parents and the general population.
ABSTRACT
Williams syndrome (WS), caused by hemizygous deletion of 1.55-1.8 Mb of chromosome 7q11.23, has a recognizable behavior phenotype that is an important diagnostic sign. Individuals with WS are overly friendly, gregarious, empathetic, and loquacious, but have difficulty interpreting social cues and in making and keeping friends. The neurodevelopmental profile is characterized by overall intellectual disability, strength in concrete language, weakness in visuospatial construction, difficulties with sensory modulation, balance, and tool use, and problems with attention and anxiety. Structural and functional MRI studies demonstrate that gray matter deficiency in the intraparietal sulcus alters processing of spatial information in the dorsal stream (spatial) visual pathway, likely contributing to the visuospatial construction disability. Deficient regulation of the amygdala by the oribitofrontal cortex appears to underlie both the social disinhibition and the specific phobia common in WS. Continued study of cognition, behavior, neuroanatomy, and function in WS will continue to elucidate the neurogenetic underpinnings of human behavior.
Subject(s)
Behavior/physiology , Chromosome Deletion , Chromosomes, Human, Pair 7/genetics , Parietal Lobe/pathology , Phenotype , Social Behavior , Williams Syndrome/physiopathology , Adaptation, Psychological/physiology , Humans , Magnetic Resonance Imaging , Space Perception/physiology , Williams Syndrome/geneticsABSTRACT
BACKGROUND: Intellectual disability (ID) affects 2-3% of the population and may occur with or without multiple congenital anomalies (MCA) or other medical conditions. Established genetic syndromes and visible chromosome abnormalities account for a substantial percentage of ID diagnoses, although for approximately 50% the molecular etiology is unknown. Individuals with features suggestive of various syndromes but lacking their associated genetic anomalies pose a formidable clinical challenge. With the advent of microarray techniques, submicroscopic genome alterations not associated with known syndromes are emerging as a significant cause of ID and MCA. METHODOLOGY/PRINCIPAL FINDINGS: High-density SNP microarrays were used to determine genome wide copy number in 42 individuals: 7 with confirmed alterations in the WS region but atypical clinical phenotypes, 31 with ID and/or MCA, and 4 controls. One individual from the first group had the most telomeric gene in the WS critical region deleted along with 2 Mb of flanking sequence. A second person had the classic WS deletion and a rearrangement on chromosome 5p within the Cri du Chat syndrome (OMIM:123450) region. Six individuals from the ID/MCA group had large rearrangements (3 deletions, 3 duplications), one of whom had a large inversion associated with a deletion that was not detected by the SNP arrays. CONCLUSIONS/SIGNIFICANCE: Combining SNP microarray analyses and qPCR allowed us to clone and sequence 21 deletion breakpoints in individuals with atypical deletions in the WS region and/or ID or MCA. Comparison of these breakpoints to databases of genomic variation revealed that 52% occurred in regions harboring structural variants in the general population. For two probands the genomic alterations were flanked by segmental duplications, which frequently mediate recurrent genome rearrangements; these may represent new genomic disorders. While SNP arrays and related technologies can identify potentially pathogenic deletions and duplications, obtaining sequence information from the breakpoints frequently provides additional information.
Subject(s)
Genome, Human/genetics , Genomic Instability/genetics , Intellectual Disability/complications , Intellectual Disability/genetics , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide/genetics , Williams Syndrome/complications , Base Sequence , Chromosome Aberrations , Chromosomes, Human, Pair 7/genetics , DNA Copy Number Variations , Developmental Disabilities/complications , Developmental Disabilities/genetics , Humans , Molecular Sequence Data , Phenotype , Segmental Duplications, Genomic , Williams Syndrome/geneticsABSTRACT
Elastin haploinsufficiency is responsible for a significant portion of the Williams syndrome (WS) phenotype including hoarse voice, supravalvar aortic stenosis (SVAS), hernias, diverticuli of bowel and bladder, soft skin, and joint abnormalities. All of the connective tissue signs and symptoms are variable in the WS population, but few factors other than age and gender are known to influence the phenotype. We examined a cohort of 205 individuals with WS for mutations in SERPINA1, the gene that encodes alpha-1-antitrypsin (AAT), the inhibitor of elastase. Individuals with classic WS deletions and SERPINA1 genotypes PiMS or PiMZ were more likely than those with a SERPINA1 PiMM genotype to have joint dislocation or scoliosis. However, carrier status for AAT deficiency was not correlated with presence of inguinal hernia or with presence or severity of SVAS. These findings suggest that genes important in elastin metabolism are candidates for variability in the connective tissue abnormalities in WS.
Subject(s)
Alleles , Genetic Predisposition to Disease , Joint Dislocations/complications , Joints/pathology , Scoliosis/complications , Williams Syndrome/complications , alpha 1-Antitrypsin Deficiency/genetics , Aortic Stenosis, Supravalvular/complications , Aortic Stenosis, Supravalvular/diagnostic imaging , Child , Female , Gene Frequency/genetics , Genetic Association Studies , Humans , Joint Dislocations/genetics , Male , Radiography , Scoliosis/diagnostic imaging , Scoliosis/genetics , Spine/diagnostic imaging , Spine/pathology , Ultrasonography , Williams Syndrome/geneticsABSTRACT
We report on a study of genetic counseling to 43 adults with Williams syndrome (WS). Participants were initially asked what they knew about how WS occurs. Genetic counseling was provided with a focus on the basic genetics of WS, recurrence risk, and on participants' attitudes toward socio-cultural topics. Forty-nine percent indicated that they would be okay or happy if their baby had WS, 44% said they would be sad or upset, and 5% were unsure. The sad/upset group was significantly older than the okay/happy group and a significantly higher proportion of the former group indicated that they did not plan to have children. During the post-counseling session participants were questioned to determine if they recalled the facts previously presented. Eighty-one percent correctly gave the odds that their child would have WS. Fifty-three percent considered the 50-50 odds to be a high chance. After genetic counseling, 61% were able to state something that had been taught and 88% indicated that they would want to test their baby for WS before birth. Ninety-eight percent would recommend genetic counseling to others. Findings indicate that based on the type of genetic counseling provided in this study, the majority of individuals with WS-a genetic disorder associated with intellectual disability but with relative strengths in (concrete) language and in verbal rote memory-are able to learn simple facts about the genetics of WS and are eager to respond to socio-cultural questions regarding topics typically included in genetic counseling sessions.
Subject(s)
Genetic Counseling , Williams Syndrome/genetics , Adult , Child , Child Care , Female , Humans , Learning , Male , Middle Aged , Reproduction , Risk Factors , Surveys and Questionnaires , Young AdultABSTRACT
In the nearly 50 years since the description of Williams syndrome by [Williams et al. (1961); Circulation 24:1311-1318], the focus of scientific inquiry has shifted from identification, definition, and description of the syndrome in small series to genotype-phenotype correlation, pathophysiologic investigation in both humans and in animal models, and therapeutic outcomes in large cohorts. Study of this rare syndrome has provided insight into the structure and function of the extracellular matrix, has contributed to understanding of genomic structure and rearrangement, and is beginning to elucidate genetic underpinnings of learning, language, and behavior. The results of current research not only recommend interventions that can be implemented now, but also identify areas requiring additional investigation, and suggest future therapeutic approaches.
Subject(s)
Williams Syndrome/pathology , Animals , Genetic Association Studies , Humans , Williams Syndrome/complications , Williams Syndrome/geneticsABSTRACT
Williams syndrome (WS) is a multisystem disorder caused by deletion of about 1.55 Mb of DNA (including 26 genes) on chromosome 7q11.23, a region predisposed to recombination due to its genomic structure. Deletion of the Williams syndrome chromosome region (WSCR) occurs sporadically. To better define chance for familial recurrence and to investigate the prevalence of genomic rearrangements of the region, 257 children with WS and their parents were studied. We determined deletion size in probands by metaphase FISH, parent-of-origin of the deleted chromosome by molecular genetic methods, and inversion status of the WSCR in both parents by interphase FISH. The frequency of WSCR inversion in the transmitting parent group was 24.9%. In contrast, the rate of inversion in the non-transmitting parent group (a reasonable estimate of the rate in the general population) was 5.8%. There were no significant gender differences with respect to parent-of-origin for the deleted chromosome or the incidence of the inversion polymorphism. There was no difference in the rate of spontaneous abortion for mothers heterozygous for the WSCR inversion relative to mothers without the inversion. We calculate that for a parent heterozygous for a WSCR inversion, the chance to have a child with WS is about 1 in 1,750, in contrast to the 1 in 9,500 chance for a parent without an inversion.
Subject(s)
Chromosome Inversion/genetics , Parents , Polymorphism, Genetic , Williams Syndrome/genetics , Alleles , Child , Chromosome Mapping , Confidence Intervals , Female , Gene Dosage/genetics , Humans , In Situ Hybridization, Fluorescence , Male , Odds Ratio , Recombination, Genetic/genetics , Repetitive Sequences, Nucleic Acid/geneticsABSTRACT
Williams syndrome (WS) is a rare genetic disorder caused by the deletion of approximately 25 genes on chromosome 7q11.23 and is characterized by both hypersociability and increases in specific phobia and anticipatory anxiety regarding non-social entities or circumstances. Alterations in amygdala reactivity and prefrontal regulation consistent with the observed behavioral pattern of social versus non-social abnormalities have been previously demonstrated in individuals with WS (Meyer-Lindenberg et al., 2005). However, in that study, the social stimulus (faces) matching task was more difficult than the non-social scene (IAPS stimuli) matching task, making it impossible to disambiguate the relative contributions of task difficulty and stimulus type (social versus non-social). In the present study, we examined the performance of the same group of participants with WS and normal IQs during a more cognitively demanding task using the same scene stimuli as in the prior study. Confirming previous findings, the results indicated (a) a differential response of prefrontal regions as a function of task difficulty and (b) a persistently increased activation of the amygdala to non-social scenes by individuals with WS regardless of cognitive load. These data provide further evidence of disruption in amygdala-prefrontal circuitry in individuals with WS.