Autism, language delay and mental retardation in a patient with 7q11 duplication

Background

Chromosomal rearrangements, arising from unequal recombination between repeated sequences, are found in a subset of patients with autism. Duplications involving loci associated with behavioural disturbances constitute an especially good candidate mechanism. The Williams–Beuren critical region (WBCR), located at 7q11.23, is commonly deleted in Williams–Beuren microdeletion syndrome (WBS). However, only four patients with a duplication of the WBCR have been reported to date: one with severe language delay and the three others with variable developmental, psychomotor and language delay.

Objective and Methods

In this study, we screened 206 patients with autism spectrum disorders for the WBCR duplication by quantitative microsatellite analysis and multiple ligation‐dependent probe amplification.

Results

We identified one male patient with a de novo interstitial duplication of the entire WBCR of paternal origin. The patient had autistic disorder, severe language delay and mental retardation, with very mild dysmorphic features.

Conclusion

We report the first patient with autistic disorder and a WBCR duplication. This observation indicates that the 7q11.23 duplication could be involved in complex clinical phenotypes, ranging from developmental or language delay to mental retardation and autism, and extends the phenotype initially reported. These findings also support the existence of one or several genes in 7q11.23 sensitive to gene dosage and involved in the development of language and social interaction.     

Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome

Interstitial deletions of 7q11.23 cause Williams–Beuren syndrome, one of the best characterized microdeletion syndromes. The clinical phenotype associated with the reciprocal duplication however is not well defined, though speech delay is often mentioned. We present 14 new 7q11.23 patients with the reciprocal duplication of the Williams–Beuren syndrome critical region, nine familial and five de novo. These were identified by either array-based MLPA or by array-CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation with an estimated population frequency of 1:13,000–1:20,000. Variable speech delay is a constant finding in our patient group, confirming previous reports. Cognitive abilities range from normal to moderate mental retardation. The association with autism is present in five patients and in one father who also carries the duplication. There is an increased incidence of hypotonia and congenital anomalies: heart defects (PDA), diaphragmatic hernia, cryptorchidism and non-specific brain abnormalities on MRI.Specific dysmorphic features were noted in our patients, including a short philtrum, thin lips and straight eyebrows. Our patient collection demonstrates that the 7q11.23 microduplication not only causes language delay, but is also associated with congenital anomalies and a recognizable face.     

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.     

Supernumerary ring chromosome 7 mosaicism: case report, investigation of the gene content, and delineation of the phenotype

We report a girl with severe retardation of expressive speech development carrying a small, supernumerary ring chromosome derived from the proximal region of the long arm of chromosome 7. The r(7) chromosome is present in 50% of lymphocytes. We also review the six additional cases with a supernumerary r(7) chromosome reported in the literature. Among these patients, a severe retardation of productive language capabilities is seen as a shared clinical feature, irrespective of the degree of mosaicism as detected in blood. The dysmorphisms in these patients are minor and no shared congenital abnormalities seen. We, therefore, recommend chromosomal investigations in children with unexplained, disproportionately retarded expressive speech performance. Because speech and language acquisition are subject to genetic influences, we investigated whether there are genes on the r(7) chromosome that may affect brain development or function in a dosage-dependent manner. We found that both in our patient and in four patients described by others, the supernumerary r(7) chromosome contains the region from the centromere up to marker D7S613 located at 7q11.23. We speculate that the effects on speech acquisition are mediated by the supernumerary copies of the STX1A and LIMK1 genes, which are both located in this region and known to suppress neurite growth when overexpressed in vitro.     

Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region.

PURPOSE: Williams-Beuren syndrome is among the most well-characterized microdeletion syndromes, caused by recurrent de novo microdeletions at 7q11.23 mediated by nonallelic homologous recombination between low copy repeats flanking this critical region. However, the clinical phenotype associated with reciprocal microduplication of this genomic region is less well described. We investigated the molecular, clinical, neurodevelopmental, and behavioral features of seven patients with dup(7)(q11.23), including two children who inherited the microduplication from one of their parents, to more fully characterize this emerging microduplication syndrome. METHODS: Patients were identified by array-based comparative genomic hybridization. Clinical examinations were performed on seven affected probands, and detailed cognitive and behavioral evaluations were carried out on four of the affected probands. RESULTS: Our findings confirm initial reports of speech delay seen in patients with dup(7)(q11.23) and further delineate and expand the phenotypic spectrum of this condition to include communication, social interactions, and repetitive interests that are often observed in individuals diagnosed with autism spectrum disorders. CONCLUSIONS: Array-based comparative genomic hybridization is a powerful means of detecting genomic imbalances and identifying molecular etiologies in the clinic setting, including genomic disorders such as Williams-Beuren syndrome and dup(7)(q11.23). We propose that dup(7)(q11.23) syndrome may be as frequent as Williams-Beuren syndrome and a previously unrecognized cause of language delay and behavioral abnormalities. Indeed, these individuals may first be referred for evaluation of autism, even if they do not ultimately meet diagnostic criteria for an autism spectrum disorder.     

Deletions at chromosome regions 7q11.23 and 7q36 in a patient with Williams syndrome

We report on a patient with Williams syndrome and a complex de novo chromosome rearrangement, including microdeletions at 7q11.23 and 7q36 and additional chromosomal material at 7q36. The nature of this additional material was elucidated by spectral karyotyping and first assigned to chromosome 22. Subsequent fluorescence in situ hybridization (FISH) experiments showed that it consisted of satellite material only. Refinement of the 7q36 breakpoint was performed with several FISH probes, showing a deletion distal to the triphalangeal thumb (TPT) region. The phenotype of the patient principally results from the microdeletion of the 7q11.23; the small deletion at 7qter and the extra satellite material may not be of clinical significance.     

Duplication/deletion mosaicism of the 7q(21.1 --> 31.3) region

Mosaicism for structural aberrations is a rare event and the coexistence of a cell line with a duplication and another with a deletion of the same chromosome segment is even more infrequent. We report a boy with a 46,XY,del(7q)/46,XY,dup(7q) mosaicism. High-resolution cytogenetic analysis and fluorescent in situ hybridization (FISH) performed at birth showed a trisomy for region 7q21.1 to 7q31.3 in 90% of metaphases analyzed and monosomy for the same region in 10% of metaphases. At the age of 12 months, karyotype on peripheral blood and exfoliated urinary epithelial cells was 46,XY,dup(7)(q21.1q31.3) in all cells analyzed. The patient presented malformations and psychomotor retardation. His phenotype is compared with other previously case reports describing patients with an interstitial duplication of 7(q21 or q22 --> q31.3). Due to the absence of a normal cell line, we propose a post-zygotic origin of the abnormality during the first mitotic division and a progressive loss of the deleted cells during pre- and post-natal development by selective pressure. The patient described here emphasizes the possible existence of an undetectable cell line in patients previously diagnosed of pure partial 7q trisomy or monosomy to explain the great clinical variability between reported patients. We also describe the culture of urinary epithelial cells in order to perform cytogenetic analysis as a useful non-invasive method.     

The common inversion of the Williams-Beuren syndrome region at 7q11.23 does not cause clinical symptoms

Williams-Beuren syndrome (WBS) is caused by a approximately 1.5 million base pair deletion at 7q11.23. A common inversion of the region, WBSinv-1, exists as a polymorphism but was also found in individuals with WBS-like features but no deletion, suggesting it could cause clinical symptoms. We performed a full clinical, developmental and genetic assessment of two previously reported individuals with clinical symptoms and WBSinv-1 but no 7q11.23 deletion. We also examined expression of genes at 7q11.23 in individuals in the general population who have WBSinv-1. We show that individuals with clinical symptoms and WBSinv-1 do not show significant clinical or psychological overlap with individuals with WBS. In addition, a 1.3 Mb duplication of part of the velocardiofacial syndrome region on chromosome 22q11.2 was found in one participant with WBSinv-1 and clinical symptoms. We also demonstrate that individuals with WBSinv-1 show normal expression of genes from the WBS region. These results suggest that WBSinv-1 does not cause clinical symptoms and we advise caution when diagnosing individuals with atypical presentation of rare syndromes. Whole genome analysis may reveal previously unidentified copy number variants that could contribute to syndromic features.     

Supravalvular aortic stenosis cosegregates with a familial 6;7 translocation which disrupts the elastin gene

Supravalvular aortic stenosis (SVAS) is an autosomal dominant disorder characterized by abnormalities of development of the great vessels. SVAS is also commonly part of Williams syndrome. Linkage to the elastin gene on chromosome 7q11 has recently been reported in two kindreds with SVAS. Previous reports of patients with 7q11 deletions have noted great vessel abnormalities in some. We report on a family in which SVAS is cosegregating with a balanced reciprocal translocation, t(6:7) (p21.1;q11.23), providing further evidence that SVAS is the result of mutation of elestin at 7q11.23 region. The propositus of the translocation family has some minor anomalies which occur in Williams syndrome, Suggesting that elestin abnormalities may cause some of the abnormalities found in Williams syndrome. © 1993 Wiley-Liss, Inc. © 1993 Wiley-Liss, Inc.     

A balanced de novo inv(7)(p14.3q22.3) disrupting PDE1C and ATXN7L1 in a 14-year old developmentally delayed boy

We report a 14 year old male patient ascertained for developmental delay, carrying a de novo pericentric inversion on chr(7)(p14.3q22.3). Sequencing revealed that the breakpoints overlap a LTR sequence on 7q22.3 and a LINE on 7p14.3. A TTTAAA motif was found in proximity of the breakpoints on both arms. In addition the sequencing detected several small micro-rearrangements, deletion, duplication, insertion, at the breakpoints. No significant sequence identity exists between the 7p14.3 and 7q22.3 breakpoints. These features at the breakpoint junctions suggest that the inversion was triggered by the TTTAAA motif, LTR and LINE and healed by a Non Homologous End Joining (NHEJ) mechanism. The genes ATXN7L1 and PDE1C are disrupted by the inversion. PDE1C is responsible for the hydrolysis of the second messenger molecules cAMP and cGMP and is highly expressed in the human heart and certain brain regions. In mice, Pde1c is expressed in migrating neuronal cells within the central nervous system during early embryo development. Although neuronal migration disorder was not seen in our patient, this is the first patient described with haploinsufficiency of PDE1C possibly causing developmental delay.     

Characterization of a de novo balanced translocation t(9;18)(p23;q12.2) in a patient with oculoauriculovertebral spectrum

We report a patient presenting with oculoauriculovertebral spectrum and a de novo balanced reciprocal translocation t(9;18)(p23;q12.2). Physical mapping of the translocation breakpoints by fluorescent in situ hybridization showed that the breakpoints are located in two regions encompassing gene deserts. An additional paternally inherited duplication in 18p11.23p11.31 was identified by array-CGH. We discuss the possible involvement of these chromosomal abnormalities in OAVS.     

Tandem duplication of the terminal band of the long arm of chromosome 7 (dir dup (7)(q36----qter)).

We report on a new case of a single band duplication of the long arm of chromosome 7, dir dup (7)(q36----qter). The major manifestations are developmental delay (particularly speech), frontal bossing, macrocrania, and constant drooling. When compared with other cases involving a 7q duplication of various segments, our patient has a few minor anomalies. This case illustrates the genotype/phenotype correlation in a child with a single band duplication which has resulted in duplication of 7q36----qter. A tabulation of reported cases with duplication of various segments of 7q is provided, which may serve as an aid for clinicians.     

Familial Williams-Beuren syndrome showing varying clinical expression

Williams-Beuren syndrome (WBS) is a contiguous gene syndrome that occurs mainly sporadically, with an estimated frequency of 1:13,700 to 1:25,000 [Grimm and Wesselhoeft, 1980; Martin et al., 1984; Udwin, 1990]. The cases of monozygotic twins concordant for WBS and dizygotic twins discordant for the syndrome have been reported. In addition, a few familial cases have been described since 1993. The clinical diagnosis has been supported by molecular genetic findings in only two patients, however. We herein report on two families in which the WBS was inherited in girls from their mothers. All four patients showed the typical hemizygous deletion at 7q11.23 [46,XX, ish,del(7)(q11.23q11.23) (ELN/LIMK1/D7S-613x1, D7S486/D7S522x2)], but the clinical picture was strikingly variable within and between families.     

Characterisation of a non-recurrent familial translocation t(7;9)(q11.23;p24.3) points to a recurrent involvement of the Williams–Beuren syndrome region in chromosomal rearrangements

Recurrent and non-recurrent chromosomal rearrangements seem to reflect susceptibility to DNA rearrangements due to the presence of recombinogenic motifs in at least one partner chromosomal region. While specific genomic motifs such as AT-rich repeats, fragile sites and Alu repeats are often found in recurrent translocations, the molecular mechanisms underlying non-recurrent chromosomal rearrangements remain largely unknown. Here, we map the breakpoint region of a non-recurrent translocation, t(7;9)(q11.23;p24.3), present in a healthy woman who inherited the apparently balanced translocation from her mother and transmitted the same rearrangement to two sons—respectively healthy and aborted. Characterisation by a two-step FISH analysis, first with BAC clones and then with small locus-specific probes, restricted the breakpoint intervals to 8–10 kb. Both regions contained specific Alu sequences, which, together with the flanking low copy repeat block Ac in 7q11.23, might stimulate the translocation. We noted that, although the translocation is non-recurrent, 7q11.23 is recurrently involved in different chromosomal rearrangements, supporting the hypothesis that the 7q11.23 genomic structure is prone to recombination events.     

Trisomy 11 and a complex t(11;11;22) in a patient with acute myelomonocytic leukemia (AML-M4) following myelodysplasia (MDS): a cytogenetic study of a mechanism of leukemogenesis

We describe a 73-year-old man diagnosed with acute myelomonocytic leukemia (AML-M4) following myelodysplasia with trisomy 11 and with a t(11;11;22). This is the first case with both abnormalities present in the same cells and with the t(11;11;22) involving a chromosome 11 already duplicated at 11q23. This band contains the MLL gene that undergoes partial tandem duplication in patients with +11, which is "promiscuous," being translocated with a large number of genetic partners. Our patient had a complex karyotype that was completely defined by in situ hybridization. This technique demonstrated that the t(11;11;22) derivative with a duplication of band 11q23 carried from three to four copies of MLL. Two copies of the gene were close to each other and centromeric to the break-point region. Therefore, a partial tandem duplication of the MLL gene might have happened before the occurrence of t(11;11;22). Considering the associated chromosome defects, the monosomy for the long arm of chromosome 7, due to an unbalanced translocation t(7;17), further underlines the possibility that a partial tandem duplication of the MLL gene might have taken place.     

New chromosomal syndromes

Mental retardation occurs in 2-3% of the general population either in isolation or in combination with facial dysmorphism and/or malformations. Chromosomal abnormalities are a most common etiology. Karyotype displays chromosome aberrations in about 10% of patients but it has a limited resolution (5 Mb). Recently, the development of new molecular cytogenetic tools, especially array CGH, allowed to detect smaller abnormalities and increased the diagnosis capability of 15-20%. Among these newly detected rearrangements, some of them are recurrent and define new recognized syndromes. We will first briefly explain the non-allelic homologous recombination (NAHR) mechanism that underlines the origin of recurrent microdeletions and microduplications. Then we will describe eight new syndromes, four microdeletions (del 17q21.31, del 3q29, del 15q24, del 2q32.3q33) and four microduplications (dup 22q11.2, dup 7q11.23, dup 17p11.2, duplication of MECP2). A better knowledge of these new recurrent chromosomal syndromes will allow to improve care for patients, to develop targeted chromosomal diagnosis and to identify genes involved in neurocognitive functions.     

Duplication 8q12: confirmation of a novel recognizable phenotype with duane retraction syndrome and developmental delay

Duane retraction syndrome (DRS) is a rare congenital strabismus condition with genetic heterogeneity. DRS associated with intellectual disability or developmental delay is observed in several genetic diseases: syndromes such as Goldenhar or Wildervanck syndrome and chromosomal anomalies such as 12q12 deletion. We report on the case of a patient with DRS, developmental delay and particular facial features (horizontal and flared eyebrows, long and smooth philtrum, thin upper lip, full lower lip and full cheeks). We identified a duplication of the long arm of chromosome 8 (8q12) with SNP-array. This is the third case of a patient with common clinical features and 8q12 duplication described in the literature. The minimal critical region is 1.2 Mb and encompasses four genes: CA8, RAB2, RLBP1L1 and CHD7. To our knowledge, no information is available in the literature regarding pathological effects caused by to overexpression of these genes. However, loss of function of the CHD7 gene leads to CHARGE syndrome, suggesting a possible role of the overexpression of this gene in the phenotype observed in 8q12 duplication patients. We have observed that patients with 8q12 duplication share a common recognizable phenotype characterized by DRS, developmental delay and facial features. Such data combined to the literature strongly suggest that this entity may define a novel syndrome. We hypothesize that CHD7 duplication is responsible for a part of the features observed in 8q12.2 duplication.     

A de novo 8q22.2-24.3 duplication in a patient with mild phenotype

We report a new case of 8q interstitial duplication in a patient with dysmorphic features, umbilical hernia, cryptorchidism, short stature, congenital heart defect and mild mental retardation (MR). Chromosome analysis with high resolution QFQ bands showed 46,XY, 8q+, which was interpreted as a partial duplication of the distal long arm of chromosome 8 (q22 → qter). This chromosomal aberration was further characterized using fluorescence in situ hybridization (FISH) analyses with multiple DNA probes and array-CGH (Comparative Genomic Hybridization) experiment which demonstrated a de novo direct duplication (8)(q22.2-q24.3). We have compared this case with other partially trisomic 8q patients reported in literature and highlighted the common clinical features in 8q22-8q24 duplication syndrome.     

A gene-dosage PCR method for the detection of elastin gene deletions in patients with Williams syndrome

Williams syndrome (WS) is a multisystem developmental disorder associated with microdeletions at 7q11.23 that involve several genes, including the elastin gene. Using genomic DNA from a panel of normal individuals and WS patients with established hemizygosity of the elastin gene locus, we have developed a quantitative polymerase chain reaction (PCR)-based gene-dosage assay that rapidly detects the loss of one allele of the elastin gene. Using this procedure, we also studied a family in which the proband was previously diagnosed with WS and her mother with a balanced 7q translocation [t(7:11)(q34;q13)]. Using DNA isolated from buccal smears obtained from several individuals in this family we were able to establish normal disomy at 7q in all family members except for the proband, in which we established hemizygosity at the elastin gene locus. We were also able to successfully infer normal disomy in an unborn child in this family. The rapid diagnostic procedure described here may have a variety of applications, including fine mapping of deletion breakpoints at 7q11.23 associated with WS.