Williams-Beuren Region Duplication Syndrome

A number sign (#) is used with this entry because the phenotype is caused by duplication of genes lying within the critical region for Williams-Beuren syndrome (WBS; 194050) on chromosome 7q11.23.

Description

The chromosome 7q11.23 duplication syndrome is a multisystem developmental disorder with variable manifestations, most commonly speech delay and mild craniofacial anomalies, and an increased incidence of congenital anomalies such as heart defects, diaphragmatic hernia, and cryptorchidism. Many patients have cognitive defects ranging from mental retardation to autism, although some have normal cognitive abilities (summary by Van der Aa et al., 2009).

Clinical Features

Somerville et al. (2005) described a boy with growth retardation, mild dysmorphism, and overall developmental delay with a severe impairment in expressive language. Receptive language was found to be in the low average range for age. Hearing was normal. Dysmorphic features included dolichocephaly, high and narrow forehead, long eyelashes, high and broad nose, short philtrum, high-arched palate, dental malocclusion (specifically, anterior open bite), retrognathia, and asymmetric crying face. The patient had bilateral simian creases, and the left hand was smaller than the right. On neurologic examination he was noted to have very mild dysmetria and mild difficulty with tandem gait and unipedal stance. Somerville et al. (2005) found that their patient carried an exact tandem duplication of the chromosomal locus on 7q11.23 that is deleted in Williams-Beuren syndrome. The severe delay in expressive language observed in the patient was a characteristic distinct from the normal articulation and fluent expressive language observed in persons with WBS. The results suggested that specific genes at 7q11.23 are exquisitely sensitive to dosage alterations that can influence human language and visuospatial capabilities. Somerville et al. (2005) tabulated the clinical and neurobehavioral differences between WBS and WBS region duplication.

Depienne et al. (2007) reported a boy with delayed development, markedly delayed language and speech development, and autism. He showed hypersensitivity to noise, stereotypic behavior, hyperactivity, aggressive outbursts, and hyperphagia. Mild dysmorphic features included retrognathia and incomplete folding of the helix of both ears. Brain MRI showed mild dilatation of the left temporal horn and a small arachnoid cyst in the temporal fossa. He was found to have a de novo paternally-derived interstitial duplication of the entire Williams-Beuren critical region on 7q11.23. The patient was identified from 206 patients with an autism spectrum disorder.

Berg et al. (2007) identified 7 probands with dup(7)(q11.23) using array-based comparative genomic hybridization (CGH). All presented as children with psychomotor and developmental delay and significant language impairment. Although each had minor variable dysmorphic features, including prominent forehead, high nasal bridge, long nasal tip, or folded ears, there were no particularly striking or reproducible facial features. Cognitive testing showed relative sparing of visuocognitive skills with severe speech delay. The children also exhibited multiple behavioral features usually associated with autism spectrum disorder (209850), including difficulties in communication and eye contact, repetitive actions, and anxiety or withdrawal. Some also had disruptive or aggressive behavior. Two parents, who appeared to be clinically unaffected, also carried the duplication, suggesting phenotypic variability. Berg et al. (2007) noted that the severe language disorder and autistic features were in stark contrast to that observed in patients with Williams-Beuren syndrome.

Torniero et al. (2007) reported a 13-year-old girl, ascertained because of a seizure at age 12 years and neuronal migration defects, who was found to have the 7q11.23 duplication syndrome. She had serious difficulty with expressive language in the absence of severe mental retardation or marked dysmorphic features. However, she did have moderate mental retardation and some dysmorphic features such as low-set ears and bilateral clubfoot. Brain MRI revealed abnormal development of the cerebral cortex in the left temporal lobe, which showed a simplified gyral pattern, and increased cortical thickness. Torniero et al. (2007) suggested that the WBS critical region might harbor dosage-sensitive genes controlling the molecular machinery of neuronal migration, with regional specificity and lateralization.

Torniero et al. (2008) reported a boy and his mother with the 7q11.23 duplication. The boy was ascertained because of a cortical malformation. At 6 months of age, he showed psychomotor delay. Clinical examination at 8 months of age revealed mild trigonocephaly, low-set, posteriorly rotated ears, sparse anterior scalp hair, left eye with exotropia, bulbous nasal tip, ogival palate, short philtrum with thin lips, short lingual frenulum, short neck, bilateral pes cavum, severe motor delay, and hypotonia. Other features included marked drooling, poor eye tracking, and speech delay. Brain MRI showed a simplified gyral pattern, with areas of cortical thickening, slightly open opercular fissures, dilated perivascular spaces, subcortical white matter interspersed with radial migration abnormalities, poorly formed hippocampi, and a markedly hypoplastic vermis. The mother had normal early developmental milestones but developed seizures around age 1 year. She had difficulties in school and stopped her studies after the first 8 years of compulsory school. As an adult, she had poor expressive language skills with simple sentences, phonology deficits, and defective articulation.

Van der Aa et al. (2009) reported 14 patients with the chromosome 7q11.23 duplication syndrome, including 9 familial and 5 de novo cases. All patients were identified by either array-based MLPA or by array CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation, and all had a 1.4- to 1.5-Mb duplication, which was the reciprocal product of the WBS critical region. The most consistent clinical finding was speech delay. Cognitive abilities ranged from normal to moderate mental retardation; 5 patients and 1 father with the duplication had autistic features. There was an increased incidence of neonatal hypotonia and congenital anomalies, including persistent ductus arteriosus, diaphragmatic hernia, cryptorchidism and nonspecific brain abnormalities on MRI. Many patients had mild, specific dysmorphic features, including a high broad nose, short philtrum, thin lips, and straight eyebrows.

Morris et al. (2015) reported the clinical characteristics, medical problems, and natural history of 64 patients with 7q11 duplication syndrome, including 48 probands, 5 sibs of probands, and 11 parents or grandparents from 9 families. The most common indication for genetic testing was developmental delay, followed by autism spectrum disorder. Of 38 patients in whom brain imaging studies were available, 31 had abnormal findings. Growth hormone deficiency, which had not previously been identified in patients with this syndrome, was identified in 5 probands. The authors suggested evaluations and health surveillance/treatment.

WBS Triplication Syndrome

Beunders et al. (2010) reported a boy with triplication of the WBS critical region and a severe phenotype. At age 13 months, he had a square face, broad forehead, short palpebral fissures, thin eyebrows, a broad nasal bridge, small alae nasi, thin lips, and mild retrognathia. He also had Duane anomaly of the left eye. He later showed delayed motor and language development and behavioral abnormalities, including aggression, destructive and obsessive behavior, sleep disturbances, autistic features, and self-mutilation. At age 38 months, he was extremely anxious, made little contact, and showed no expressive language. Array CGH revealed an increased dosage on chromosome 7q11.23, and a 1.25-Mb triplication was confirmed by FISH and MLPA analysis. The distal breakpoint was common with other WBS distal breakpoints, but the proximal breakpoint was atypical, located between the FZD9 (601766) and BAZ1B (605681) genes. The FZD9 and FKBP6 (604839) genes, which are deleted in most WBS patients and duplicated in patients with the duplication, were not triplicated. The triplication appeared de novo. Beunders et al. (2010) noted that the clinical features were similar to, but more severe than, that observed in patients with a duplication of this region.

Molecular Genetics

In patients with delayed development, markedly delayed language development, and dysmorphic features, Somerville et al. (2005) and Depienne et al. (2007) identified duplication of the Williams-Beuren critical region on 7q11.23. The patient reported by Somerville et al. (2005) had 3 distinct alleles at 3 loci. In each case, only 1 of the alleles was present in the father, indicating that the patient had inherited 2 different copies of the WBS region from his mother. Analysis of the maternal grandparents showed that the duplicated chromosome in the proband contained segments of chromosome 7 that were inherited independently from each maternal grandparent. These analyses indicated that the meiotic interchromosomal recombination that led to the duplication took place in the mother's germ cells, making it a new rearrangement.

Levy et al. (2011) studied 887 families from the Simons Simplex Collection of relatively high functioning ASD families. They identified 75 de novo CNVs in 68 probands (approximately 8% of probands). Only a few were recurrent. Variation at the 16p11.2 locus was detected in more than 1% of patients (10 of 858), with deletions present in 6 and duplications in 4. In addition, the duplication at 7q11.2 of the Williams syndrome region was also seen as a recurrent CNV.

Sanders et al. (2011) examined 1,124 ASD simplex families from the Simons Simplex Collection. Each of the families was comprised of a single proband, unaffected parents, and in most kindreds an unaffected sib. Sanders et al. (2011) found significant association of ASD with de novo duplications of 7q11.23. They also identified rare recurrent de novo CNVs at 5 additional regions, including 16p13.2. Sanders et al. (2011) found that probands carrying a 16p11.2 or 7q11.23 de novo CNV were indistinguishable from the larger ASD group with respect to IQ, ASD severity, or categorical autism diagnosis.

Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 7q11.23 duplication was identified in 16 cases and 1 control for a p value of 0.0046 and a frequency of 1 in 984 cases.

Genotype/Phenotype Correlations

Mervis et al. (2012) found that patients with WBS duplication syndrome had significantly higher levels of separation anxiety (see 607834) compared to patients with WBS and to the general population. Using a parental assessment form with review by a psychologist, Mervis et al. (2012) determined that 8 (29.6%) of 27 children with WBS duplication syndrome had separation anxiety disorder compared to only 9 (4.2%) of 214 patients with WBS. In addition, the proportion of WBS duplication patients with the disorder was significantly higher than in the general population (2.3%). Similar findings were obtained using a second assessment tool. Compared to mice with 1 or 2 copies of the Gtf2i gene (601679), which is within the WBS gene interval, transgenic mice with 3 or 4 copies of the Gtf2i gene showed significantly increased maternal separation-induced anxiety as measured by ultrasonic vocalizations. The findings implicated a role for the GTF2I gene in separation anxiety.

Pathogenesis

Strong et al. (2015) assessed genomewide DNA methylation in whole blood in 20 children with Williams syndrome (194050), 10 children with Dup7 (WBS duplication syndrome), and 15 typically developing children using the Infinium HumanMethylation450 BeadChip array. The authors found that regions that were differentially methylated in both Williams syndrome and Dup7 displayed a significant and symmetrical gene dose-dependent effect, such that Williams syndrome typically showed increased and Dup7 showed decreased DNA methylation. Differentially methylated genes were significantly enriched with genes in pathways involving neurodevelopment, autism spectrum disorder candidate genes, and imprinted genes. Using alignment with ENCODE data, Strong et al. (2015) also found the differentially methylated regions to be enriched with CTCF (604167) binding sites. The authors found that one of the most differentially methylated genes was the ankyrin repeat domain 30B gene (ANKRD30B; 616565), which showed striking dose-dependent DNA methylation changes spanning 11 different probes across the promoter. ANKRD30B is found only in primates and is expressed in brain, breasts, and testes. Other genes showing significant dose-dependent DNA methylation included RFPL2 (605969) and the protocadherin cluster including PCDHA (604966), PCDHB (604967), and PCDHG (604968). There were changes in DNA methylation outside promoter regions of the RGS2 (600861) gene, implicated in anxiety, panic disorder, and schizophrenia. Differential methylation across ANKRD30B, RFPL2, and RGS2 was confirmed by pyrosequencing and real-time PCR analysis. Strong et al. (2015) also found differential methylation enrichment among autism spectrum disorder genes including HDAC4 (605314), SHANK2 (603290), DYRK1A (600855), SHANK3 (606230), NRXN1 (600565), CNTNAP2 (604569), and ANKRD11 (611192). Strong et al. (2015) concluded that, 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 neurologic phenotypes of WS and Dup7, and suggested that variation in DNA methylation is important in the pathogenesis of Williams syndrome, Dup7, and potentially autism spectrum disorders.

Population Genetics

Van der Aa et al. (2009) estimated the population frequency of the chromosome 7q11.23 duplication syndrome to be 1 in 13,000 to 20,000.