Reassessment of the 12q15 deletion syndrome critical region

Interstitial deletions of the long arm of chromosome 12 are rare and only few cases have been reported in literature so far, with different phenotypic features related to size and gene content of deleted regions. Five patients reported a 12q15-q21 deletion, sharing a 1.3 Mb small region of overlap (SRO) and presenting with developmental delay, nasal speech and mild dysmorphic features.We identified by microarray analysis a new case of 12q15 deletion. Our patient clinical features allow the refinement of the SRO to CNOT2, KCNMB4, and PTPRB genes, improving genotype-phenotype correlations.     

Polycystic kidneys and del (4)(q21.1q21.3): further delineation of a distinct phenotype

A three year-old boy was evaluated because of growth and developmental delay, hypotonia and dysmorphic features. G-banding analysis revealed a small interstitial deletion of the long arm of chromosome four described as 46,XY,del (4)(q21.1q21.3). This patient's findings on physical exam included relative macrocephaly, frontal bossing, short fingers with clinodactyly and were consistent with the phenotypes of previously reported deletions involving the 4q21--> 4q22 band region (Am. J. Med. Genet. 68 (1997) 400-405). To date there are 10 reported live-born cases with such deletions and similar features. The case reported here delimits a minimal critical region for this phenotype to chromosomal region 4q21. Our patient was also found to have cysts in both his kidneys. The gene for type II polycystic kidney disease (PKD2) has been mapped to chromosomal region 4q21--> 4q23. FISH analysis, with a probe including the PKD2 gene, demonstrated hemizygosity at this locus. Thus the absence of one of the PKD2 alleles in the case reported here is associated with early bilateral cyst development. Kidney ultrasound/autopsy studies were reported in seven of the patients with the characteristic phenotype, and were positive for cysts in four cases including the one presented here (Clin. Genet. 31 (1987) 199-205; Am. J. Med. Genet. 68 (1997) 400-405; Am. J. Med. Genet. 40 (1991) 77-790. Our report supports the presence of a distinct phenotype associated with a deleted chromosomal region within 4q21. Hemizygosity for the PKD2 gene is likely in such deletions and may lead to renal cyst formation.     

16q21 is critical for 16q deletion syndrome

A 1-year-old girl with an interstitial deletion of the long arm of chromosome 16 is reported. She was characterized by a distinct craniofacial dysmorphism, meningoencephalocele, mild hydrocephalus, short neck, broad great toes and abnormally positioned toes. High resolution GTG and RBG banding analyses revealed a karyotype: 46,XX,del(16) (q13q22) de novo. An analysis of the smallest region of overlap revealed that the critical band region for 16q deletion syndrome is 16q21.     

Deletion of chromosome 3q proximal region gives rise to a variable phenotype

We report two new cases with interstitial deletions of chromosome 3. Both had breakpoints established as q 12q21. Despite an apparently identical abnormal karyotype, their phenotypes were different although hypotonia, severe developmental delay, lack of speech, high arched palate and pointed chin were common features. One patient had corpus cajlosum agenesis (ACC), also present in two of the only four previously reported cases with a deletion in this region.     

Identification of a previously unrecognized microdeletion syndrome of 16q11.2q12.2

We report the identification of microdeletions of 16q11.2q12.2 by microarray-based comparative genomic hybridization (aCGH) in two individuals. The clinical features of these two individuals include hypotonia, gastroesophageal reflux, ear anomalies, and toe deformities. Other features include developmental delay, mental retardation, hypothyroidism, and seizures. The identification of common clinical features in these two individuals and those of one other report suggests microdeletion of 16q12.1q12.2 is a rare, emerging syndrome. These results illustrate that aCGH is particularly suited to identify rare chromosome abnormalities in patients with apparently non-syndromic idiopathic mental retardation and birth defects.     

Novel deletions of 14q11.2 associated with developmental delay, cognitive impairment and similar minor anomalies in three children

METHODS AND RESULTS: We identified de novo submicroscopic chromosome 14q11.2 deletions in two children with idiopathic developmental delay and cognitive impairment. Vancouver patient 5566 has a approximately 200 kb deletion and Vancouver patient 8326 has a approximately 1.6 Mb deletion. The Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER) revealed a third patient with idiopathic developmental delay and cognitive impairment, DECIPHER patient 126, who has a approximately 1.1 Mb deletion of 14q11.2. The deletion of patient 5566 overlaps that of patient 126 and both of these deletions lie entirely within that of patient 8326. All three children have similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip and similar auricular anomalies. CONCLUSION: The minimal common deletion region on chromosome 14q11.2 is only approximately 35 kb (from 20.897 to 20.932, University of California at Santa Cruz (UCSC) Genome Browser; build hg18, March 2006) and includes only two genes, SUPT16H and CHD8, which are good candidate genes for the phenotypes. The non-recurrent breakpoints of these patients, the presence of normal copy number variants in the region and the local genomic structure support the notion that this region has reduced stability.     

The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype

Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith–Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett''s syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems.     

Segregation of a familial balanced (12;10) insertion resulting in dup(10)(q21.2q22.1) and del(10)(q21.2q22.1) in first cousins

An interchromosomal insertion in 3 generations of a family was ascertained through two developmentally delayed first cousins. Cytogenetic analysis using G-banding and chromosome painting showed an apparently balanced direct insertion of chromosome 10 material into chromosome 12, ins(12;10)(q15;q21.2q22.1), in the mothers and grandfather of these children. The proposita inherited only the derivative 10 chromosome, resulting in deletion of 10q21.2 → 22.1 while her cousin inherited only the derivative 12, resulting in duplication of 10q21.2 → 22.1. A comparison of the proposita with published deletion cases suggests a pattern of anomalies attributable to deletion of the 10q21 → q22 region: developmental delay, hypotonia, a heart murmur, telecanthus, broad nasal root and ear abnormalities. This is the first report of a nontandem duplication of the 10q21 → q22 region. The phenotype of the cousin with the duplication does not overlap greatly with published tandem 10q duplications. Finally, this report reaffirms the importance of obtaining family studies of patients with interstitial chromosomal abnormalities. Am J. Med. Genet. 69:188–193, 1997. © 1997 Wiley-Liss, Inc.     

15q24.1 BP4-BP1 microdeletion unmasking paternally inherited functional polymorphisms combined with distal 15q24.2q24.3 duplication in a patient with epilepsy,psychomotor delay,overweight, ventricular arrhythmia

15q24 microdeletion and microduplication syndromes are genetic disorders caused by non-allelic homologous recombination between low-copy repeats (LCRs) in the 15q24 chromosome region. Individuals with 15q24 microdeletion and microduplication syndromes share a common 1.2 Mb critical interval, spanning from LCR15q24B to LCR15q24C. Patients with 15q24 microdeletion syndrome exhibit distinct dysmorphic features, microcephaly, variable developmental delay, multiples congenital anomalies while individuals with reciprocal 15q24 microduplication syndrome show mild developmental delay, facial dysmorphism associated with skeletal and genital abnormalities. We report the first case of a 10 year-old girl presenting mild developmental delay, psychomotor retardation, epilepsy, ventricular arrhythmia, overweight and idiopathic central precocious puberty. 180K array-CGH analysis identified a 1.38 Mb heterozygous interstitial 15q24.1 BP4-BP1 microdeletion including HCN4 combined with a concomitant 2.6 Mb heterozygous distal 15q24.2q24.3 microduplication. FISH analysis showed that both deletion and duplication occurred de novo in the proband. Of note, both copy number imbalances did not involve the 1.2 Mb minimal deletion/duplication critical interval of the 15q24.1q24.2 chromosome region (74.3–75.5 Mb). Sequencing of candidate genes for epilepsy and obesity showed that the proband was hemizygous for paternal A-at risk allele of BBS4 rs7178130 and NPTN rs7171755 predisposing to obesity, epilepsy and intellectual deficits. Our study highlights the complex interaction of functional polymorphisms and/or genetic variants leading to variable clinical manifestations in patients with submicroscopic chromosomal aberrations.     

Omphalocele in trisomy 3q: further delineation of phenotype

We report a case of a patient with omphalocele, dysmorphic features, and mild developmental delay associated with a chromosomal aberration. Chromosome studies showed that the propositus carries a maternally derived unbalanced translocation der(4)t(3;4)(q27.3;q32.3), resulting in trisomy for region 3q27.3→qter and monosomy for 4q32.3→qter. Because the association between dup3q and omphalocele has been reported in several cases, we analyzed the data on 93 previously reported patients with partial trisomy of the long arm of chromosome 3 and compared the clinical features between the cases. The imbalance of chromosome 3 in the patient was further defined by fluorescence in situ hybridization (FISH) studies using bacterial artificial chromosome (BAC) clones. BAC clone RP11-171N2 was identified as a breakpoint-spanning clone in the patient and his mother. Based on our comparative analysis, we have delineated that the smallest region of overlap (SRO) associated with omphalocele is from BAC 171N2 to 3qter. We hypothesize that the SRO contains a gene(s) important in normal abdominal wall development and is of potential interest for further investigation.     

Multigeneration family with short stature,developmental delay,and dysmorphic features due to 4q27-q28.1 microdeletion

Deletions of the long arm of chromosome 4 are rare but have been previously reported to be associated with craniofacial anomalies, digital anomalies, developmental delay, growth failure, and cardiovascular anomalies [1], [2], [3], [4], [5], [6]. Strehle et al. [1] previously presented 20 patients with 4q deletions and began to construct a phenotype–genotype map for chromosome 4q. This report follows up on that work by providing clinical and molecular cytogenetic data on a three generation pedigree including seven patients with short stature, dysmorphic features, and developmental delay identified to have a 4q27-q28.1 microdeletion of approximately 5.68 Mb by oligonucleotide chromosomal microarray. This family represents a rare report of an inherited interstitial deletion of the long arm of chromosome 4. To our knowledge, only two cases have been previously reported [7], [8]. The contribution of candidate genes in the region is discussed.     

16q22.1 microdeletion and anticipatory guidance

The widespread availability of comparative genomic hybridization (CGH) array analysis has led to the discovery of several genomic microdeletion‐associated syndromes and has identified possible genetic causes for patients with previously unexplained clinical features. We report the case of four unrelated patients who share common clinical characteristics, namely failure to thrive, developmental delay, dysmorphic features, and congenital anomalies. CGH array analysis revealed that all four patients had a de novo microdeletion at 16q22.1. In this case report, we describe the clinical features of these patients and offer possible explanations for how their 16q22.1 microdeletion may account for their symptoms. We also suggest guidelines for the management of 16q22.1 microdeletion based on the phenotypes seen in our patients and the function of the genes affected by this microdeletion.     

Interstitial deletions of chromosome 6q: genotype-phenotype correlation utilizing array CGH

Interstitial deletions of the long arm of chromosome 6 are relatively rare, with fewer than 100 cases reported. Phenotypic variation is in large part due to differences in size and location of the segmental aneuploidy. We report three new patients with interstitial deletions of chromosome 6q defined at the molecular level by array comparative genomic hybridization (array CGH). In two of three cases, the molecular breakpoints differed from those indicated by conventional karyotyping, demonstrating the enhanced resolution of array CGH. Two patients had minimal deletions of 6 and 8.8 Mb involving 6q16.2-->q21, and the third patient had a deletion of 11.3 Mb spanning 6q15-->q21. All three had developmental delay, craniofacial dysmorphology, and functional eye disorders, suggesting that genes affecting brain and craniofacial development are located in 6q16.2-->q21, the deleted region common to all three patients. Furthermore, gene(s) for discordant phenotypic features, such as central diabetes insipidus, may reside at 6q15, the monosomic region unique to patient 3. All three cases described here showed loss of paternal alleles within the deleted segment, providing further evidence of the predominantly paternal origin for 6q deletions and rearrangements.     

Refining critical regions in 15q24 microdeletion syndrome pertaining to autism

Chromosome 15q24 microdeletion syndrome is characterized by developmental delay, facial dysmorphism, hearing loss, hypotonia, recurrent infection, and other congenital malformations including microcephaly, scoliosis, joint laxity, digital anomalies, as well as sometimes having autism spectrum disorder (ASD) and attention deficit hyperactivity disorder. Here, we report a boy with a 2.58‐Mb de novo deletion at chromosome 15q24. He is diagnosed with ASD and having multiple phenotypes similar to those reported in cases having 15q24 microdeletion syndrome. To delineate the critical genes and region that might be responsible for these phenotypes, we reviewed all previously published cases. We observe a potential minimum critical region of 650 kb (LCR15q24A‐B) affecting NEO1 among other genes that might pertinent to individuals with ASD carrying this deletion. In contrast, a previously defined minimum critical region downstream of the 650‐kb interval (LCR15q24B‐D) is more likely associated with the developmental delay, facial dysmorphism, recurrent infection, and other congenital malformations. As a result, the ASD phenotype in this individual is potentially attributed by genes particularly NEO1 within the newly proposed critical region.     

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.     

De novo interstitial deletion 16(q12. 1q13) of paternal origin in a 10-year-old boy

A 10-year-old boy with a de novo del(16)(q12.1q13) and many features of the deletion 16q phenotype is described. The deletion occurred in a paternal chromosome as demonstrated by DNA studies with polymorphic (AC)n microsatellite repeat markers. Comparison with published cases suggests that deletion of either of two regions (q13 and q22.1) on the long arm of chromosome 16 is associated with an apparently identical phenotype. No parental imprinting of this region was demonstrated.     

Interstitial deletion of 14q24.3-q32.2 in a male patient with plagiocephaly, BPES features, developmental delay, and congenital heart defects

Distal interstitial deletions of chromosome 14 involving the 14q24‐q23.2 region are rare, and only been reported so far in 20 patients. Ten of these patients were analyzed both clinically and genetically. Here we present a de novo interstitial deletion of chromosome 14q24.3‐q32.2 in a male patient with developmental delay, language impairment, plagiocephaly, BPES features (blepharophimosis, ptosis, epicanthus), and congenital heart defect. The deletion breakpoints were fine mapped using fluorescence in situ hybridization (FISH) and the size of the deletion is estimated to be approximately 23 Mb. Based on genotype–phenotype comparisons of the 10 previously published patients and the present case, we suggest that the shortest regions for deletion overlap may include candidate genes for speech impairment, mental retardation, and hypotonia. © 2010 Wiley‐Liss, Inc.     

SALL4 and NFATC2: Two major actors of interstitial 20q13.2 duplication

Interstitial duplication within the long arm of chromosome 20 is an uncommon chromosome structural abnormality. We report here the clinical and molecular characterization associated with pure 20q13.2 duplication in three unrelated patients. The most frequent clinical features were developmental delay, facial dysmorphism, cardiac malformation and skeletal anomalies. All DNA gains occurred de novo, ranging from 1.1 Mb to 11.5 Mb. Compared with previously reported conventional cytogenetic analyses, oligonucleotides array CGH allowed us to refine breakpoints and determine the genes of interest in the region. Involvement of SALL4 in cardiac malformations and NFATC2 gene disruption in both cardiac and skeletal anomalies are discussed.     

3q29 microduplication syndrome: Description of two new cases and delineation of the minimal critical region

Heterogeneous clinical and neuropsychological features, such as intellectual disability, developmental and language delay, hypotonia, and, to a lesser extent, microcephaly that is present in about the half of the reported patients, characterize the 3q29 microduplication syndrome with usually a milder phenotype compared with the corresponding 3q29 microdeletion syndrome. The duplications described so far range from 2.3?Mb to 1.6?Mb, spanning from TFRC to BDH1 genes. Here we report on two patients with overlapping interstitial duplications of the 3q29 region differing in size. Patient 1 harboured a common-seized 3q29 microduplication spanning ～1.6?Mb, while patient 2 carried a very small 3q29 microduplication of 448.8?Kb encompassing only two genes, DLG1 and BDH1. Both patients presented clinical characteristics similar to those reported in the literature in 3q29 microduplication syndrome. Interestingly, heterotopic gray matter nodules were found along the right lateral ventricle on brain MRI in patient 1, thus expanding the neuroradiological phenotype in 3q29 microduplication syndrome, while patient 2 allowed us to define with more precision the smallest region of overlap (SRO). Gene content analysis of the duplicated region suggests that gain-of-dosage of DLG1 and BDH1 may be a good candidate for the main clinical features of this syndrome.     

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.