Delineation of a critical region on chromosome 18 for the del(18)(q12.2q21.1) syndrome

Deletions involving the long arm of chromosome 18 have been reported in many patients. Most of these deletions are localized in the distal half of the long arm (18q21.1 --> qter) and are detectable by standard cytogenetic analysis. However, smaller interstitial deletions leading to a recognizable phenotype and residing in the region around chromosome band 18q12.3 (bands q12-q21) are less common. Here we report on an interstitial deletion of less than 1.8 Mb within chromosomal band 18q12.3. The phenotypic features of the propositus correspond well with those observed in patients with larger cytogenetically detectable deletions encompassing chromosome band 18q12.3. The deletion enabled us to define a critical region for the following features of the del(18)(q12.2q21.1) syndrome: hypotonia, expressive language delay, short stature, and behavioral problems.     

Recurrent interstitial deletions of proximal 18q: a new syndrome involving expressive speech delay

Most deletions of the long arm of chromosome 18 involve some part of the most distal 30 Mb. We have identified five individuals with cytogenetically diagnosed interstitial deletions that are all proximal to this commonly deleted region. The extent of their deletions was characterized using molecular and molecular cytogenetic techniques. Each participant was assessed under the comprehensive clinical evaluation protocol of the Chromosome 18 Clinical Research Center. Three of the five individuals were found to have apparently identical interstitial deletions between positions of 37.5 and 42.5 Mb (18q12.3-->18q21.1). One individual's deletion was much larger and extended from a more proximal breakpoint position of 23 Mb (18q11.2) to a more distal breakpoint at 43 Mb (18q21.1). The fifth individual had a proximal breakpoint identical to the other three, but a distal breakpoint at 43.5 Mb (18q21.1). The clinical findings were of interest because the three individuals with the smaller deletions lacked major anomalies. All five individuals were developmentally delayed; however, the discrepancy between their expressive and receptive language abilities was striking, with expressive language being much more severely affected. This leads us to hypothesize that there are genes in this region of chromosome 18 that are specific to the neural and motor planning domains necessary for speech. Additionally, this may represent a previously underappreciated syndrome since these children do not have the typical clinical abnormalities that would lead to a chromosome analysis.     

372 kb microdeletion in 18q12.3 causing SETBP1 haploinsufficiency associated with mild mental retardation and expressive speech impairment

Several cases of interstitial deletion encompassing band 18q12.3 are described in patients with mild dysmorphic features, mental retardation and impairment of expressive language. The critical deleted region contains SETBP1 gene (SET binding protein 1). Missense heterozygous mutations in this gene cause Schinzel-Giedion syndrome (SGS, MIM#269150), characterized by profound mental retardation and multiple congenital malformations. Recently, a 18q12.3 microdeletion causing SETBP1 haploinsufficiency has been described in two patients that show expressive speech impairment, moderate developmental delay and peculiar facial features. The phenotype of individual with partial chromosome 18q deletions does not resemble SGS. The deletion defines a critical region in which SETBP1 is the major candidate gene for expressive speech defect. We describe an additional patient with the smallest 18q12.3 microdeletion never reported that causes the disruption of SETBP1. The patient shows mild mental retardation and expressive speech impairment with striking discrepancy between expressive and receptive language skills. He is able to communicate using gestures and mimic expression of face and body with surprising efficacy. The significant phenotypic overlap between this patient and the cases previously reported enforce the hypothesis that SETBP1 haploinsufficiency may have a role in expressive language development.     

Novel homozygous deletions of chromosomal band 18q22 in pancreatic adenocarcinoma identified by STS marker scanning.

The identification of homozygous deletions in sporadic neoplasms has been pivotal in the positional cloning of several tumor suppressor genes. Chromosomal arm 18q harbors the DPC4, SMAD2, and DCC genes and is suspected on the basis of high frequencies of allelic loss to harbor additional tumor suppressor genes. We applied high-resolution sequence-tagged site (STS) marker scanning to a panel of 106 pancreatic adenocarcinomas to identify novel regions of homozygous deletions on 18q. Three homozygous deletions were identified. Physical mapping of these deletions showed them to be nonoverlapping, but clustered in an approximately 7- to 10-Mb region of chromosome band 18q22. Each deletion spanned physical distances of nearly 1.3 to 3 Mb. A number of transcribed genes map within these deletions. The identification of these homozygous deletions might aid in the identification of novel tumor suppressor genes on chromosomal arm 18q. Genes Chromosomes Cancer 25:370-375, 1999.     

A de novo 1.1-1.6 Mb subtelomeric deletion of chromosome 20q13.33 in a patient with learning difficulties but without obvious dysmorphic features

We report on a de novo submicroscopic deletion of 20q13.33 identified by subtelomeric fluorescence in situ hybridization (FISH) in a 4-year-old girl with learning difficulties, hyperlaxity and strabismus, but without obvious dysmorphic features. Further investigations by array-based comparative genomic hybridization (array-CGH) and FISH analysis allowed us to delineate the smallest reported subterminal deletion of chromosome 20q, spanning a 1.1-1.6 Mb with a breakpoint localized between BAC RP5-887L7 and RP11-261N11. The genes CHRNA4 and KCNQ2 implicated in autosomal dominant epilepsy are included in the deletion interval. Subterminal 20q deletions as found in the present patient have, to our knowledge, only been reported in three patients. We review the clinical and behavioral phenotype of such "pure" subterminal 20q deletions.     

Higher frequency of uncommon 1.5-2 Mb deletions found in familial cases of 22q11.2 deletion syndrome

Familial 22q11.2 deletions have been reported as a 6%-28% of the total affected cases of 22q11.2 microdeletion syndrome (del22q11.2). Different deletion genotypes have been described for this disorder, with a predominant 3 Mb deletion present in 90% of the cases, a less common 1.5-2 Mb deletion in 8%, and atypical smaller deletions in 2%. We have studied 15 cases of del22q11.2 from 6 families (two of them three-generation families) that were previously diagnosed through FISH. We have sized the deleted region by allele genotyping of 12-16 polymorphic markers in all cases, and we have found three families affected with the 1.5-2 Mb deletion, two affected with the 3 Mb deletion, and one in which the deletion size could not be determined. This predominance of the smaller 1.5-2 Mb deletions in our familial cases differs from the minor frequency observed in sporadic cases of del22q11.2. This finding suggests that small deletions are more linked to familial inheritance than large ones, possibly due to psychosocial or biological factors associated with differences in the phenotype. Deletion sizing on routine diagnosis may help characterizing the inheritability of 22q11.2 microdeletion syndrome.     

De novo deletion of chromosome 2q24.2 region in a mentally retarded boy with muscular hypotonia

To date, more than 100 cases with a deletion of chromosome 2q have been identified, although studies reporting small interstitial deletions involving the 2q24.2-q24.3 region are still rare. Here, we have described the genotype and the phenotype of a boy with a 5.3 Mb de novo deletion in this region, identified by SNP array analysis. The selected region included 20 genes, of which 4 are prominently expressed in the brain. Their combined haplo-insufficiency could explain the main clinical features of this patient which included mental retardation, severe hypotonia, joint laxity and mild dysmorphic traits.     

A de novo 3.54 Mb deletion of 17q22-q23.1 associated with hydrocephalus: a case report and review of literature

We describe a female newborn with a de novo 3.54 megabase (Mb) deletion of 17q22-q23.1 (chr17:53,072,536-56,612,662, hg18) including genes from MSI2 to BCAS3 detected by oligonucleotide array comparative genomic hybridization (aCGH). Prenatal ultrasound examination noted oligohydramnios and ventriculomegaly in the fetus. Postnatal examination found hypotonia, macrocephaly, arachnodactyly of fingers and toes, dysmorphic features, bilateral hearing loss and heart defect. Review of reported cases with genomic findings noted one case with proximal deletion involving the NOG gene and a case series with distal recurrent microdeletions involving the TBX2 and TBX4 genes. Our case presented a unique deletion partially overlapped with the above deletions but not including the NOG, TBX2, and TBX4 genes. A genomic map for deletions in this 17q22-q23.1 region was constructed to further define the common deletion intervals for potential haplo-insufficient genes.     

Genotype–phenotype analysis of 18q12.1-q12.2 copy number variation in autism

Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions characterized by delays in social interactions and communication as well as displays of restrictive/repetitive interests. DNA copy number variants have been identified as a genomic susceptibility factor in ASDs and imply significant genetic heterogeneity. We report a 7-year-old female with ADOS-G and ADI-R confirmed autistic disorder harbouring a de novo 4 Mb duplication (18q12.1). Our subject displays severely deficient expressive language, stereotypic and repetitive behaviours, mild intellectual disability (ID), focal epilepsy, short stature and absence of significant dysmorphic features. Search of the PubMed literature and DECIPHER database identified 4 additional cases involving 18q12.1 associated with autism and/or ID that overlap our case: one duplication, two deletions and one balanced translocation. Notably, autism and ID are seen with genomic gain or loss at 18q12.1, plus epilepsy and short stature in duplication cases, and hypotonia and tall stature in deletion cases. No consistent dysmorphic features were noted amongst the reviewed cases. We review prospective ASD/ID candidate genes integral to 18q12.1, including those coding for the desmocollin/desmoglein cluster, ring finger proteins 125 and 138, trafficking protein particle complex 8 and dystrobrevin-alpha. The collective clinical and molecular features common to microduplication 18q12.1 suggest that dosage-sensitive, position or contiguous gene effects may be associated in the etiopathogenesis of this autism-ID-epilepsy syndrome.     

No evidence for submicroscopic 22qter deletions in patients with features suggestive for Angelman syndrome

Patients with monosomy 22q13.3 --> qter have, in addition to (usually severe) developmental delay, hypotonia, severe expressive language delay leading to absence of speech, pervasive developmental abnormalities, and subtle facial anomalies. Thus far, it has been one of the more common submicroscopic telomere deletions seen in patients with mental retardation. Due to the phenotypic overlap between monosomy 22q13.3 and Angelman syndrome (AS), 44 patients with AS features but without one of the characteristic molecular 15q abnormalities were tested for 22qter deletions. In the study group, 31/44 (70%) were heterozygous for locus D22S163 with probe cMS607 (distance 0.125 Mb from telomere). The remaining 13/44 (30%) patients were heterozygous for one or more of four microsatellite markers centromeric from D22S163 in the 22qter region (distances 1.5-4.3 Mb from telomere). Based on the present study, there is no evidence that patients with an "Angelman-like" phenotype are more likely to have a 22qter deletion than other individuals with mental retardation.     

Multigene deletions on chromosome 20q13.13-q13.2 including SALL4 result in an expanded phenotype of Okihiro syndrome plus developmental delay

Okihiro syndrome results from truncating mutations in the SALL4 locus on the chromosome 20q13.13-q13.2. Deletions of the whole SALL4 coding region as well as single exon deletions are also a common cause of Okihiro syndrome and indicate haploinsufficiency as the disease causing mechanism. The phenotypes caused by SALL4 deletions are not different from those caused by point mutations. No multigene deletion including SALL4 has been documented to date. Here we report the detection and molecular characterization of four novel, overlapping microdeletions, all spanning SALL4 and flanking genes, in four unrelated cases with features of Okihiro syndrome and variable degrees of psychomotor delay. All deletions were first identified and mapped by quantitative Real Time PCR. Subsequently, three of four deletions were mapped in further detail by high-resolution array CGH (244k oligo-arrays). All cases had larger deletions of varying size (1.76-1.78 Mb, 2.01-2.05 Mb, 2.16-2.17 Mb, and 1.3-2.8 Mb, respectively), which included SALL4 plus 3 to 7 additional functional genes. While three cases with largely overlapping deletions are mildly developmentally delayed, the only patient with a more centromeric deletion is clearly mentally retarded. In this patient, four genes (MOCS3, DPM1, ADNP, BCAS4) are deleted, which were not affected in the other three cases, suggesting that the deletion of one or more of these genes contributes to the mental retardation. Since two of the four cases presented with choanal atresia, large deletions including SALL4 should be considered in the differential diagnosis of children with suspected CHARGE syndrome but without detectable CHD7 mutations.     

Molecular cytogenetic analysis of a de novo interstitial chromosome 10q22 deletion

Interstitial deletions of 10q are rare, and only one patient with a deletion confined to chromosome band 10q22 has been reported so far. We report on a 2 6/12-year-old girl with a constitutional interstitial deletion of one homologue of 10q [karyotype: 46,XX,del(10)(q22.2q22.3)de novo]. Our patient had muscular hypotonia, developmental delay, growth retardation, mild facial dysmorphism, and hypoplastic labia minora. The precise location and extent (3.6 Mb) of the deletion was determined by fluorescence in situ hybridization (FISH) using 16 YAC and BAC clones. The clinical features in our patient are remarkably similar to the previously reported patient with a 10q22.2 deletion.     

Unexpected identification of two interstitial deletions in a patient with a pericentric inversion of a chromosome 4 and an abnormal phenotype

Interstitial deletions and pericentric inversions of chromosome 4 appear to be unusual phenomena. Here, we report the case of a 14-year-old boy with severe psychomotor retardation with a de novo 46,XY,der(4)del(p15.2p15.31)inv(4)(p15.2q13.3)del(4)(q13.2q13.2) karyotype. We used FISH analysis with YAC and BAC clones to characterise the inversion's breakpoints. A complex event with six breakpoints was found, characterised by a pericentric inversion and two deletions, the first on the short arm of chromosome 4 (4p) and the second on the long arm of chromosome 4 (4q). The deletion events had removed two segments, one of approximately 5 Mb, from 4p, outside the inversion, and the other 2 Mb from 4q, inside the inversion. These rearrangements were not found in the parents. Microsatellite marker analysis showed that the inversion carrying chromosome 4 was derived from the father. Bioinformatic analysis of the human genome sequence allowed us to identify several hemizygotic genes in the patient, which might be involved in the pathogenesis of this clinical phenotype.     

Five patients with novel overlapping interstitial deletions in 8q22.2q22.3

High‐resolution microarray technology has facilitated the detection of submicroscopic chromosome aberrations and characterization of new microdeletion syndromes. We present clinical and molecular data of five patients with previously undescribed overlapping interstitial deletions involving 8q22.2q22.3. All deletions differ in size and breakpoints. Patients 1–4 carry deletions between 5.25 and 6.44 Mb in size, resulting in a minimal deletion overlap of 3.87 Mb (from 100.69 to 104.56 Mb; hg18) comprising at least 25 genes. These patients share similar facial dysmorphisms with blepharophimosis, telecanthus, epicanthus, flat malar region, thin upper lip vermillion, down‐turned corners of the mouth, and a poor facial movement/little facial expression. They have a moderate to severe developmental delay (4/4), absent speech (3/4), microcephaly (3/4), a history of seizures (3/4), postnatal short stature (2/4), and a diaphragmatic or hiatal hernia (2/4). Patient 5 was diagnosed with a smaller deletion of about 1.92 Mb (containing nine genes) localized within the deletion overlap of the other four patients. Patient 5 shows a different facial phenotype and a less severe mental retardation. In Patients 1–4, COH1 is involved in the deletion (in total or in part), but none of them showed clinical features of Cohen syndrome. In two patients (Patients 2 and 4), ZFPM2 (also called FOG2, a candidate gene for congenital diaphragmatic hernias) was partly deleted. We suggest that patients with a microdeletion of 8q22.2q22.3 may represent a clinically recognizable condition characterized particularly by the facial phenotype and developmental delay. More patients have to be evaluated to establish a phenotype–genotype correlation. © 2011 Wiley‐Liss, Inc.     

Chromosome 4q deletion syndrome: narrowing the cardiovascular critical region to 4q32.2-q34.3

The 4q deletion syndrome is a rare chromosome deletion syndrome with a wide range of clinical phenotypes. There is limited clinical phenotype and molecular correlation for congenital heart defects (CHDs) reported so far for this region primarily because many cases are large deletions, often terminal, and because high-resolution array has not been reported in the evaluation of this group of patients. CHDs are reported in about 60% of patients with 4q deletion syndrome, occurring in the presence or absence of dHAND deletion, implying the existence of additional genes in 4q whose dosage influences cardiac development. We report an 8-month-old patient with a large mid-muscular to outlet ventricular septal defect (VSD), moderate-sized secundum-type atrial septal defect (ASD), thickened, dysplastic pulmonary valve with mild stenosis and moderate pulmonic regurgitation, and patent ductus arteriosus (PDA). Illumina CytoSNP array analysis disclosed a de novo, heterozygous, interstitial deletion of 11.6?Mb of genomic material from the long arm of chromosome 4, at 4q32.3-q34.3 (Chr4:167236114-178816031; hg18). The deleted region affects 37 RefSeq genes (hg18), including two provisional microRNA stemloops. Three genes in this region, namely TLL1 (Tolloid-like-1), HPGD (15-hydroxyprostaglandin dehydrogenase), and HAND2 (Heart and neural crest derivatives-expressed protein 2), are known to be involved in cardiac morphogenesis. This report narrows the critical region responsible for CHDs seen in 4q deletion syndrome.     

Characterization of an interstitial deletion 6q13-q14.1 in a female with mild mental retardation, language delay and minor dysmorphisms

Chromosomal imbalances, recognized as the major cause of mental retardation (MR), are often due to submicroscopic deletions or duplications not evidenced by conventional cytogenetic methods. Array-based comparative genomic hybridization (array-CGH) improves considerably the detection rate of submicroscopic chromosomal abnormalities and has proven to be an effective tool for detection of submicroscopic chromosome abnormalities in children with MR and/or multiple congenital defects. Observations of array-CGH deletions in defined chromosomal regions linked to a clinical phenotype will more and more allow to define genotype-phenotype correlations. We report here the case of a 10-year-old female with a de novo 7.8 Mb deletion in the 6q13-6q14.1 ascertained by array-CGH. The clinical features of this patient include psychomotor and language delay associated with minor dysmorphic features.     

Genotype-phenotype mapping of chromosome 18q deletions by high-resolution array CGH: an update of the phenotypic map

Partial deletions of the long arm of chromosome 18 lead to variable phenotypes. Common clinical features include a characteristic face, short stature, congenital aural atresia (CAA), abnormalities of the feet, and mental retardation (MR). The presence or absence of these clinical features may depend on the size and position of the deleted region. Conversely, it is also known that patients whose breakpoints are localized within the same chromosome band may exhibit distinct phenotypes. New molecular techniques such as array CGH allow for a more precise determination of breakpoints in cytogenetic syndromes, thus leading to better-defined genotype-phenotype correlations. In order to update the phenotypic map for chromosome 18q deletions, we applied a tiling resolution chromosome 18 array to determine the exact breakpoints in 29 patients with such deletions. Subsequently, we linked the genotype to the patient's phenotype and integrated our results with those previously published. Using this approach, we were able to refine the critical regions for microcephaly (18q21.33), short stature (18q12.1-q12.3, 18q21.1-q21.33, and 18q22.3-q23), white matter disorders and delayed myelination (18q22.3-q23), growth hormone insufficiency (18q22.3-q23), and CAA (18q22.3). Additionally, the overall level of MR appeared to be mild in patients with deletions distal to 18q21.33 and severe in patients with deletions proximal to 18q21.31. The critical region for the 'typical' 18q-phenotype is a region of 4.3 Mb located within 18q22.3-q23. Molecular characterization of more patients will ultimately lead to a further delineation of the critical regions and thus to the identification of candidate genes for these specific traits.