Interstitial deletion of chromosome 7q in a patient with Williams syndrome and infantile spasms

Interstitial deletion of 7q11.23–q21.11 was identified by cytogenetic methods in a 4-year-old boy with Williams syndrome (WS) and infantile spasms. Deletion of the elastin (ELN) gene and the DNA polymorphic markers, D7S1870, D7S2490, D7S2518, and D7S2421, were identified in the patient, but the loci for D7S653 and D7S675 were not involved. Zackowski et al. (1990) reported that 6 of 16 patients with the interstitial deletion of 7q11.2–q22 had abnormal electro encephalograms, or seizures, or both, and that infantile spasms were present in 2 of the 6 patients. WS is a well defined developmental disorder characterized by distinct facial features, gregarious personality, and congenital heart defects. Seizures are not generally associated with this syndrome. WS commonly is characterized by deletion of the loci for ELN and D7S1870, but not those for D7S2490, D7S2518, or D7S2421. This suggests that a gene responsible for infantile spasms is located in the 2.7-cM interval between loci D7S1870 and D7S675. Received: April 27, 1998 / Accepted: May 29, 1998     

Detection of deletions at 7q11.23 in Williams-Beuren syndrome by polymorphic markers

INTRODUCTION:

Williams-Beuren syndrome (WBS; OMIM 194050) is caused by a hemizygous contiguous gene microdeletion at 7q11.23. Supravalvular aortic stenosis, mental retardation, overfriendliness, and ocular and renal abnormalities comprise typical symptoms in WBS. Although fluorescence in situ hybridization is widely used for diagnostic confirmation, microsatellite DNA markers are considered highly informative and easily manageable.

OBJECTIVES:

This study aimed to test the microsatellite markers for the diagnosis of Williams-Beuren syndrome, to determine the size and parental origin of microdeletion, compare the clinical characteristics between patients with different sizes of the deletion and parental origin.

METHODS:

We studied 97 patients with clinical diagnosis of Williams-Beuren syndrome using five microsatellite markers: D7S1870, D7S489, D7S613, D7S2476 and D7S489_A.

RESULTS AND DISCUSSION:

Using five markers together, the result was informative in all patients. The most informative marker was D7S1870 (78.4%), followed by D7S613 (75.3%), D7S489 (70.1%) and D7S2476 (62.9%). The microdeletion was present in 84 (86.6%) patients and absent in 13 (13.4%) patients. Maternal deletions were found in 52.4% of patients and paternal deletions in 47.6% of patients. The observed size of deletions was 1.55 Mb in 76/84 patients (90.5%) and 1.84 Mb in 8/84 patients (9.5%). SVAS as well as ocular and urinary abnormalities were more frequent in the patients with a deletion. There were no clinical differences in relation to either the size or parental origin of the deletion.

CONCLUSION:

Using these five selected microsatellite markers was informative in all patients, thus can be considered an alternative method for molecular diagnosis in Williams-Beuren syndrome.     

Parallel deletion and duplication at 7q11.23 in a silent carrier for two reciprocal syndromic disorders

Partial deletions at chromosome 7q11.23 are causative for the autosomal-dominant Williams–Beuren syndrome (WBS), whereas the partial duplication of this region leads to the 7q11.23 duplication syndrome. Both syndromes are highly penetrant and occur with a frequency of 1:7500–10,000 (WBS) and 1:13,000–20,000 (7q11.23 duplication syndrome). They are associated with multiple organ defects, intellectual disability, and typical facial dysmorphisms showing broad phenotypic variability. The 7q11.23 region is susceptible to chromosomal rearrangements due to flanking segmental duplications and regions of long repetitive DNA segments. Here, we report on a family with two children affected by WBS and clinically unaffected parents. Interestingly, metaphase fluorescence in situ hybridization (FISH) revealed a deletion on 7q11.23 in the father. Intensive genetic testing, using interphase FISH, whole genome sequencing and optical genome mapping led to the confirmation of a 1.5 Mb deletion at one 7q11.23 allele and the identification of a reciprocal 1.8 Mb duplication at the other allele. This finding is highly important regarding genetic counseling in this family. The father is a silent carrier for two syndromic disorders, thus his risk to transmit a disease-causing allele is 100%. To the best of our knowledge we, here, report on the first case in which the phenotype of a microdeletion/microduplication syndrome was compensated by its reciprocal counterpart.     

A novel human homologue of the Drosophila frizzled wnt receptor gene binds wingless protein and is in the Williams syndrome deletion at 7q11.23

Williams syndrome (WS) is a developmental disorder with a characteristic personality and cognitive profile that is associated, in most cases, with a 2 Mb deletion of part of chromosome band 7q11.23. By applying CpG island cloning methods to cosmids from the deletion region, we have identified a new gene, called FZD3. Dosage blotting of DNA from 11 WS probands confirmed that it is located within the commonly deleted region. Sequence comparisons revealed that FZD3, encoding a 591 amino acid protein, is a novel member of a seven transmembrane domain receptor family that are mammalian homologs of the Drosophila tissue polarity gene frizzled. FZD3 is expressed predominantly in brain, testis, eye, skeletal muscle and kidney. Recently, frizzled has been identified as the receptor for the wingless (wg) protein in Drosophila. We show that Drosophila as well as human cells, when transfected with FZD3 expression constructs, bind Wg protein. In mouse, the wg homologous Wnt1 gene is involved in early development of a large domain of the central nervous system encompassing much of the midbrain and rostral metencephalon. The potential function of FZD3 in transmitting a Wnt protein signal in the human brain and other tissues suggests that heterozygous deletion of the FZD3 gene could contribute to the WS phenotype.      

Delineation of the common critical region in Williams syndrome and clinical correlation of growth,heart defects,ethnicity, and parental origin

Williams syndrome (WS) is a neurodevelopmental disorder with a variable phenotype. Molecular genetic studies have indicated that hemizygosity at the elastin locus (ELN) may account for the cardiac abnormalities seen in WS, but that mental retardation and hypercalcemia are likely caused by other genes flanking ELN. In this study, we defined the minimal critical deletion region in 63 patients using 10 microsatellite markers and 5 fluorescence in situ hybridization (FISH) probes on chromosome 7q, flanking ELN. The haplotype analyses showed the deleted cases to have deletions of consistent size, as did the FISH analyses using genomic probes for the known ends of the commonly deleted region defined by the satellite markers. In all informative cases deleted at ELN, the deletion extends from D7S489U to D7S1870. The genetic distance between these two markers is about 2 cM. Of the 51 informative patients with deletions, 29 were maternal and 22 were paternal in origin. There was no evidence for effects on stature by examining gender, ethnicity, cardiac status, or parental origin of the deletion. Heteroduplex analysis for LIMK1, a candidate gene previously implicated in the WS phenotype, did not show any mutations in our WS patients not deleted for ELN. LIMK1 deletions were found in all elastin-deletion cases who had WS. One case, who has isolated, supravalvular aortic stenosis and an elastin deletion, was not deleted for LIMK1. It remains to be determined if haploinsufficiency of LIMK1 is responsible in part for the WS phenotype or is simply deleted due to its close proximity to the elastin locus. Am. J. Med. Genet. 78:82–89, 1998. © 1998 Wiley-Liss, Inc.     

A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome

The phenotype of patients with a chromosome 1q43q44 microdeletion (OMIM; 612337) is characterized by intellectual disability with no or very limited speech, microcephaly, growth retardation, a recognizable facial phenotype, seizures, and agenesis of the corpus callosum. Comparison of patients with different microdeletions has previously identified ZBTB18 (ZNF238) as a candidate gene for the 1q43q44 microdeletion syndrome. Mutations in this gene have not yet been described. We performed exome sequencing in a patient with features of the 1q43q44 microdeletion syndrome that included short stature, microcephaly, global developmental delay, pronounced speech delay, and dysmorphic facial features. A single de novo non-sense mutation was detected, which was located in ZBTB18. This finding is consistent with an important role for haploinsufficiency of ZBTB18 in the phenotype of chromosome 1q43q44 microdeletions. The corpus callosum is abnormal in mice with a brain-specific knock-out of ZBTB18. Similarly, most (but not all) patients with the 1q43q44 microdeletion syndrome have agenesis or hypoplasia of the corpus callosum. In contrast, the patient with a ZBTB18 point mutation reported here had a structurally normal corpus callosum on brain MRI. Incomplete penetrance or haploinsufficiency of other genes from the critical region may explain the absence of corpus callosum agenesis in this patient with a ZBTB18 point mutation. The findings in this patient with a mutation in ZBTB18 will contribute to our understanding of the 1q43q44 microdeletion syndrome.     

Wilms' tumor in patients with 9q22.3 microdeletion syndrome suggests a role for PTCH1 in nephroblastomas

Nephroblastoma (Wilms'' tumor; WT) is the most common renal tumor of childhood. To date, several genetic abnormalities predisposing to WT have been identified in rare overgrowth syndromes. Among them, abnormal methylation of the 11p15 region, GPC3 and DIS3L2 mutations, which are responsible for Beckwith–Wiedemann, Simpson–Golabi–Behmel and Perlman syndromes, respectively. However, the underlying cause of WT remains unknown in the majority of cases. We report three unrelated patients who presented with WT in addition to a constitutional 9q22.3 microdeletion and dysmorphic/overgrowth syndrome. The size of the deletions was variable (ie, from 1.7 to 8.9 Mb) but invariably encompassed the PTCH1 gene. Subsequently, we identified a somatic PTCH1 nonsense mutation in the renal tumor of one patient. In addition, by array comparative genomic hybridization method, we analyzed the DNA extracted from the blood samples of nine patients with overgrowth syndrome and WT, but did not identify any deleterious chromosomal imbalances in these patients. These findings strongly suggest that patients with constitutional 9q22.3 microdeletion have an increased risk of WT, and that PTCH1 have a role in the pathogenesis of nephroblastomas.     

A 1 Mb de novo deletion within 11q13.1q13.2 in a boy with mild intellectual disability and minor dysmorphic features

We report a 11 year old male patient ascertained for mild intellectual disability and minor dysmorphic features, carrying a 1 Mb de novo deletion on chromosome 11q13.1q13.2 detected by aCGH. This is the first report of a deletion in this region in a patient presenting with intellectual impairment and mild dysmorphic traits. The 1 Mb deleted area encompasses 47 RefSeq genes, including Cornichon homologue 2 (CNIH2), Cofilin-1 (CFL1) and neuronal PAS domain-containing protein 4 (NPAS4), which are highly expressed in the central nervous system. Knockout of the CNIH2 and CFL1 orthologues in animals results in migration disturbances, while low or no expression of Npas4 in mice results in impairment of memory and learning. These three genes have previously been suggested as candidate genes for neurological disorders.     

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype,epilepsy and autistic traits

Williams Beuren syndrome (WBS) is a multisystemic disorder caused by a hemizygous deletion of 1.5 Mb on chromosome 7q11.23 spanning 28 genes. A few patients with larger and smaller WBS deletion have been reported. They show clinical features that vary between isolated SVAS to the full spectrum of WBS phenotype, associated with epilepsy or autism spectrum behavior. Here we describe four patients with atypical WBS 7q11.23 deletions. Two carry ∼3.5 Mb larger deletion towards the telomere that includes Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxigenase activation protein gamma (YWHAG) genes. Other two carry a shorter deletion of ∼1.2 Mb at centromeric side that excludes the distal WBS genes BAZ1B and FZD9. Along with previously reported cases, genotype–phenotype correlation in the patients described here further suggests that haploinsufficiency of HIP1 and YWHAG might cause the severe neurological and neuropsychological deficits including epilepsy and autistic traits, and that the preservation of BAZ1B and FZD9 genes may be related to mild facial features and moderate neuropsychological deficits. This report highlights the importance to characterize additional patients with 7q11.23 atypical deletions comparing neuropsychological and clinical features between these individuals to shed light on the pathogenic role of genes within and flanking the WBS region.     

A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome

Patients with 9q34.3 terminal deletion usually show a clinically recognizable phenotype characterized by specific facial features (microcephaly, flat face, arched eyebrows, hypertelorism, short nose, anteverted nostrils, carp mouth and protruding tongue) in combination with severe mental retardation, hypotonia, and other anomalies. We analyzed six unrelated patients with a various 9q34.3 terminal deletion. While having different-sized 9q34.3 deletions, all of these patients shared several distinctive anomalies. These anomalies are likely to arise from a commonly deleted region at distal 9q34.3. Fluorescence in situ hybridization (FISH) analysis using a dozen BAC clones mapped at the 9q34.13-q34.3 region defined the shortest region of deletion overlap (SRO) as a 1-Mb segment proximal to 9qter containing eight known genes. Possible candidate genes delineating specific phenotypes of the 9q34.3 terminal deletion syndrome are discussed.     

A 8.26Mb deletion in 6q16 and a 4.95Mb deletion in 20p12 including JAG1 and BMP2 in a patient with Alagille syndrome and Wolff-Parkinson-White syndrome

We report a child presenting with Alagille and Wolff–Parkinson–White (WPW) syndromes. Standard karyotyping showed a de novo 46,XY,t(1;6)(p31;q16) translocation. Fluorescent in situ hybridization analysis identified a de novo deletion in the 20p12 chromosomal region encompassing JAG1, the major gene responsible for Alagille syndrome. The aberration was further characterized using an Agilent 44K oligonucleotide array, which confirmed the 4.95 Mb 20p12 deletion. An additional 8.26 Mb deletion was identified at the 6q16 translocation breakpoint.To our knowledge, WPW has never been associated with Alagille syndrome. The patient we describe presented with a 6q16 deletion containing 21 genes but no good candidate genes for WPW. The 20p12 deletion included 19 genes among them JAG1 and BMP2. Recently, two unrelated patients with WPW and BMP2 deletions have been reported. Despite a relationship between WPW and JAG1 deletion cannot be excluded, the JAG1 deletion is unlikely responsible for the ventricular preexcitation since WPW has never been associated with Alagille syndrome. Among the other deleted genes in 20p12, BMP2 appears to be a good candidate responsible for the WPW.     

Large deletions encompassing the TCOF1 and CAMK2A genes are responsible for Treacher Collins syndrome with intellectual disability

Mandibulofacial dysostosis is part of a clinically and genetically heterogeneous group of disorders of craniofacial development, which lead to malar and mandibular hypoplasia. Treacher Collins syndrome is the major cause of mandibulofacial dysostosis and is due to mutations in the TCOF1 gene. Usually patients with Treacher Collins syndrome do not present with intellectual disability. Recently, the EFTUD2 gene was identified in patients with mandibulofacial dysostosis associated with microcephaly, intellectual disability and esophageal atresia. We report on two patients presenting with mandibulofacial dysostosis characteristic of Treacher Collins syndrome, but associated with unexpected intellectual disability, due to a large deletion encompassing several genes including the TCOF1 gene. We discuss the involvement of the other deleted genes such as CAMK2A or SLC6A7 in the cognitive development delay of the patients reported, and we propose the systematic investigation for 5q32 deletion when intellectual disability is associated with Treacher Collins syndrome.     

Blepharophimosis,ptosis, epicanthus inversus syndrome with translocation and deletion at chromosome 3q23 in a black African female

Blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) is a rare autosomal dominant disorder whose main features are the abnormal shape, position and alignment of the eyelids. Type I refers to BPES with female infertility from premature ovarian failure while type II is limited to the ocular features. A causative gene, FOXL2, has been localized to 3q23. We report a black female who carried a de novo chromosomal translocation and 3.13 Mb deletion at 3q23, 1.2 Mb 5′ to FOXL2. This suggests the presence of distant cis regulatory elements at the extended FOXL2 locus. In spite of 21 protein coding genes in the 3.13 Mb deleted segment, the patient had no other malformation and a strictly normal psychomotor development at age 2.5 years. Our observation confirms panethnicity of BPES and adds to the knowledge of the complex cis regulation of human FOXL2 gene expression.