Duplication 16q12.1-q22.1 characterized by array CGH in a girl with spina bifida

We report a 7-year-old girl with spina bifida carrying a complex chromosome abnormality resulting in duplication 16q12.1-q22.1. An abnormal karyotype was identified involving the long arm of chromosome 11 and fluorescent in situ hybridization (FISH) to metaphase chromosomes revealed an insertion of part of chromosome 16 on chromosome 11. A detailed mapping of the chromosome abnormality using whole genome array based comparative genomic hybridization (CGH) of the patient DNA revealed a duplication 16q12.1-q22.1 corresponding to gain of 19.8Mb of DNA without any detectable loss of genetic material on chromosome 11. The karyotype is defined as 46,XX,der(11)ins(11;16)(q13;q12.1q22.1). We present here the clinical findings and a fine mapping of the associated structural chromosome abnormalities. We suggest that a gene dosage imbalance of 16q12.1-q22.1 is associated with spina bifida in the patient.     

Delineation of 15q13.3 microdeletions

Masurel‐Paulet A, Andrieux J, Callier P, Cuisset JM, Le Caignec C, Holder M, Thauvin‐Robinet C, Doray B, Flori E, Alex‐Cordier MP, Beri M, Boute O, Delobel B, Dieux A, Vallee L, Jaillard S, Odent S, Isidor B, Beneteau C, Vigneron J, Bilan F, Gilbert‐Dussardier B, Dubourg C, Labalme A, Gautier A, Pernes P, Bidon C, Pinoit JM, Huet F, Mugneret F, Aral B, Jonveaux P, Sanlaville D, Faivre L. Delineation of 15q13.3 microdeletions. The increasing use of array‐comparative genomic hybridization (array‐CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4–BP5 microdeletion out of a series of 4625 patients screened by array‐CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical ～1.5 Mb BP4–BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.     

Clinical report: AN INTERSTITIAL deletion of 16p13.11 detected by array CGH in a patient with infantile spasms

Chromosome 16p13.11 has recently been reported as a region of recurrent microdeletion/duplication, which may contribute to a specific clinical phenotype of epilepsy, significant learning difficulties and distinct facial dysmorphism. The 16p13.11 microdeletion syndrome is associated with schizophrenia, developmental delay and idiopathic generalised epilepsy. Haploinsufficiency of genes in 16p13.11 has been suggested as contributing to the pathogenicity of this microdeletion syndrome. We report a three-year-old boy with the 16p13.11 microdeletion syndrome, identified on array CGH, and describe his clinical phenotype, thereby adding to the existing literature on this newly-described microdeletion syndrome. We discuss the function and potential relevance of the genes in this region with regards to the features described in this condition.     

Nasal speech and hypothyroidism are common hallmarks of 12q15 microdeletions

The introduction of array CGH in clinical diagnostics has led to the discovery of many new microdeletion/microduplication syndromes. Most of them are rare and often present with a variable range of clinical anomalies. In this study we report three patients with a de novo overlapping microdeletion of chromosome bands 12q15q21.1. The deletions are ～2.5 Mb in size, with a 1.34-Mb common deleted region containing six RefSeq genes. All three patients present with learning disability or developmental delay, nasal speech and hypothyroidism. In this paper we will further elaborate on the genotype-phenotype correlation associated with this deletion and compare our patients with previously reported cases.     

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.     

Microdeletion at 4q21.3 is associated with intellectual disability, dysmorphic facies, hypotonia, and short stature

Chromosomal imbalances are a major cause of intellectual disability (ID) and multiple congenital anomalies. We have clinically and molecularly characterized two patients with chromosome translocations and ID. Using whole genome array CGH analysis, we identified a microdeletion involving 4q21.3, unrelated to the translocations in both patients. We confirmed the 4q21.3 microdeletions using fluorescence in situ hybridization and quantitative genomic PCR. The corresponding deletion boundaries in the patients were further mapped and compared to previously reported 4q21 deletions and the associated clinical features. We determined a common region of deletion overlap that appears unique to ID, short stature, hypotonia, and dysmorphic facial features.     

Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome

The clinical use of array comparative genomic hybridization in the evaluation of patients with multiple congenital anomalies and/or mental retardation has recently led to the discovery of a number of novel microdeletion and microduplication syndromes. We present four male patients with overlapping molecularly defined de novo microdeletions of 16q24.3. The clinical features observed in these patients include facial dysmorphisms comprising prominent forehead, large ears, smooth philtrum, pointed chin and wide mouth, variable cognitive impairment, autism spectrum disorder, structural anomalies of the brain, seizures and neonatal thrombocytopenia. Although deletions vary in size, the common region of overlap is only 90 kb and comprises two known genes, Ankyrin Repeat Domain 11 (ANKRD11) (MIM 611192) and Zinc Finger 778 (ZNF778), and is located approximately 10 kb distally to Cadherin 15 (CDH15) (MIM 114019). This region is not found as a copy number variation in controls. We propose that these patients represent a novel and distinctive microdeletion syndrome, characterized by autism spectrum disorder, variable cognitive impairment, facial dysmorphisms and brain abnormalities. We suggest that haploinsufficiency of ANKRD11 and/or ZNF778 contribute to this phenotype and speculate that further investigation of non-deletion patients who have features suggestive of this 16q24.3 microdeletion syndrome might uncover other mutations in one or both of these genes.     

17q21.31 microdeletion in a patient with pituitary stalk interruption syndrome

We report the case of a 26-month-old boy with mental retardation, facial dysmorphism, childhood feeding difficulties, short stature, bilateral cryptorchidism, micropenis, and heart defect. Endocrinal evaluation revealed complete growth hormone deficiency (GHD) and gonadotropic deficiency, and pituitary magnetic resonance imaging showed partial pituitary stalk interruption syndrome (PSIS). A de novo 493 kb microdeletion on chromosome 17q21.31 was identified using array comparative genomic hybridization (array-CGH) analysis. This is the first report of PSIS in the phenotypical spectrum of 17q21.31 microdeletion syndrome, although other midline abnormalities have previously been described. Our report suggests that GHD should be investigated in patients with 17q21.31 microdeletion syndrome and short stature, defined by a body height below - 2 standard deviation scores (SDS) for age and sex. This finding also opens new avenues of research on the etiopathogenesis of PSIS, for which the genetic mechanisms remain unknown.     

A novel 800 kb microduplication of chromosome 16q22.1 resulting in learning disability and epilepsy may explain phenotypic variability in a family with 15q13 microdeletion

The phenotype of 15q13.3 microdeletion is variable and can be non-penetrant. Recently, "second-hit hypothesis" has been proposed as a possible explanation for some variability in recurrent microdeletion syndromes. We present a family with a 1.9 Mb 15q13.3 deletion and a novel 800 kb 16q22.1 duplication. We show that the 16q22.1 duplication may be a phenotypic modifier in this family and likely results in epilepsy and learning difficulties. We state the possible genes in this region that may be important in neurological development and function.     

A 15q24 microduplication, reciprocal to the recently described 15q24 microdeletion, in a boy sharing clinical features with 15q24 microdeletion syndrome patients

A 15q24 microduplication, reciprocal to the minimal critical region for the recently described 15q24 microdeletion syndrome, was found in a 2-year-old boy by 244k Agilent oligoarray CGH analysis. The boy had global developmental delay and dysmorphic facial features, digital and genital abnormalities. The duplication was inherited from a healthy father, but was considered clinically significant, as the patient shared clinical features with 15q24 microdeletion syndrome patients. To our knowledge this is the first report of a patient with a 15q24 microduplication.     

Distal duplication of chromosome 16q22.1q23.1 in a Vietnamese patient with midface hypoplasia and intellectual disability

The clinical presentation of distal duplications of the long arm of chromosome (chr) 16 is currently not well described. Only one case of microduplication of chr16q22.1 and another involving the chr16q22.1q23.1 region have been reported so far. Here, using array comparative genomic hybridization, we identified a second case of chr16q22.1q23.1 duplication in a Vietnamese boy, who shares significant clinical phenotype with the previously described case. Aside from developmental delay, intellectual disability and midface hypoplasia, our patient also displays a forked tongue, visual impairment and external ptosis. Our report further expands the clinical spectrum associated with duplication of this region.     

Refinement of the critical 7p22.1 deletion region: Haploinsufficiency of ACTB is the cause of the 7p22.1 microdeletion-related developmental disorders

Non-recurrent microdeletion (≤2?Mb in size) in 7p22.1 is a rarely described cytogenetic aberration, only recently reported in patients with developmental delay/intellectual disability, short stature and microcephaly. The size of the deletions ranged from 0.37 to 1.5?Mb, and reported genotype-phenotype correlations identified a minimum deleted region of 0.37?Mb involving the FBLX18, ACTB, FSCN1, RNF216 and ZNF815P genes. The authors suggested that deletion of ACTB, which encodes β-actin, an essential component of the cytoskeleton, could be responsible for the clinical features observed in the patients with a 7p22.1 microdeletion. Here, we describe a 23-month-old child displaying developmental delay, short stature, microcephaly and distinctive facial features. Chromosomal microarray analysis performed using high-resolution SNP-array platform revealed a de novo interstitial 60?Kb microdeletion in the 7p22.1 region (from 5,509,127 bp to 5,569,096 bp, hg19) encompassing only two genes: FBXL18 and ACTB. To the best of our knowledge, this is the smallest deletion at 7p22.1 to date reported in medical literature (Pubmed). Combining our data with phenotypic and genotypic data of cases from literature, we were able to narrow the minimal critical region, which contained only two genes, i.e., FBXL18 and ACTB. Our finding is useful to perform a more accurate genotype-phenotype correlation and strongly strengthen the hypothesis that haploinsufficiency of ACTB is the main cause of the clinical phenotype observed in the patients with 7p22.1 microdeletions, facilitating genetic diagnosis and counseling.     

1.6 Mb deletion in chromosome band 3q29 associated with eye abnormalities

We report on a patient with a de novo microdeletion 3q29 detected by molecular karyotyping using array CGH analysis. The girl displayed microphthalmia and cataract, hyperplastic pyloric stenosis, mild dysmorphic facial features, and developmental delay. Array CGH analysis uncovered a 1.6 Mb deletion within chromosome band 3q29, which overlaps with the commonly deleted region in 3q29 microdeletion syndrome. According to published data, none of the patients with deletion 3q29 showed either congenital cataract and microphthalmia, or other ocular features. Our report expands the phenotypic spectrum of the 3q29 microdeletion syndrome by adding structural eye malformations.     

微阵列基因组杂交技术在22q11．21微缺失家系中的应用研究

目的了解反复孕育严重先天性心脏病儿、胎儿父亲患有原发性甲状旁腺功能低下家系的基因组拷贝数变化,确定其发病的遗传学原因。方法对常规染色体核型分析未见异常的法洛氏四联症胎儿及其整个家系中的7人采用微阵列基因组杂交（array—based comparative genomic hybridization,array—CGH）技术进行基因组拷贝数变化的检测分析（copy number variations,CNVs）。结果经过array—CGH分析,在胎儿及其父亲的22q11．21均发现存在2．52Mb的致病性缺失片段,位于18,919,942—21,440,514区段。家系中其他成员未发现同样的片段异常。结论22q11．21微缺失是导致其父亲患原发性甲状旁腺功能减退的遗传学原因,也是该家系多次孕育严重先天性心脏病患儿的原因,同时表明22q11．21微缺失表型多样,临床症状差异大。array—CGH是一种高通量、高分辨率及高准确性的遗传学分析技术,能够发现染色体片段上的亚微结构异常,是临床遗传学研究的重要工具。     

1.3 Mb de novo deletion in chromosome band 3q29 associated with normal intelligence in a child

We report on a 6 and 9/12 year-old male patient with a de novo chromosome 3q29 microdeletion identified by BAC array comparative genomic hybridization assay (aCGH), with accompanying normal 46,XY high-resolution chromosome analysis. The patient has language-based learning disabilities and behavioral features consistent with diagnoses of autism and attention deficit hyperactivity disorder (ADHD) of the inattentive type. He also displays some other features previously associated with chromosome 3q29 microdeletion such as an elongated face, long fingers, and joint laxity. Most notably our patient, per formal IQ testing, was not found to have frank mental retardation as has been previously reported among patients with chromosome 3q29 terminal deletion, but rather our patient has demonstrated an average full-scale IQ result. Our report further expands the phenotypic spectrum of the rare chromosome 3q29 microdeletion syndrome to include the possibility of normal intelligence as corroborated by formal, longitudinal psycho-educational testing.     

Subtelomeric monosomy 11q and trisomy 16q in siblings and an unrelated child: molecular characterization of two der(11)t(11;16)

We report here three children with a der(11)t(11;16), two sibs (patients 1 and 2) having inherited a recombinant chromosome from a maternal t(11;16)(q24.3;q23.2) and a third unrelated child with a de novo der(11)t(11;16)(q25;q22.1), leading to partial monosomy 11q and trisomy 16q. Fluorescent in situ hybridization (FISH) using bacterial artificial chromosome (BAC) clones and array‐CGH were performed to determine the breakpoints involved in the familial and the de novo rearrangements. The partial 11 monosomy extended from 11q24.3 to 11qter and measured 6.17–6.21 Mb in Patients 1 and 2 while the size of the partial 11q25‐>qter monosomy was estimated at 1.97–2.11 Mb for Patient 3. The partial 16 trisomy extended from 16q23.2 to 16qter and measured 8.93–8.95 Mb in Patients 1 and 2 while the size of the partial 16q22.1‐>qter trisomy was 20.82 Mb for Patient 3. Intraventricular hemorrhage and transitional thrombocytopenia were found in both sibs but not in the third patient. The FLI1 gene, which is the most relevant gene for thrombocytopenia in Jacobsen syndrome, was neither deleted in family A nor in Patient 3. We suggest that a positional effect could affect the FLI1 expression for these two sibs. Deafness of our three patients confirmed the association of this anomaly to 11q monosomy and tended to confirm the hypothetic role of DFNB20 in Jacobsen syndrome hearing loss. Both sibs shared most of the features commonly observed in Jacobsen syndrome, but not the third patient. This confirmed that terminal 11q trisomy spanning 1 to 1.97–2.11 Mb is not associated with a typical Jacobsen syndrome. © 2011 Wiley‐Liss, Inc.     

A novel microdeletion at chromosome 2q31.1-31.2 in a three-generation family presenting duplication of great toes with clinodactyly

HOXD gene cluster maps to chromosome 2q31 and plays a key role in embryonic limb morphogenesis. Mutations of the HOXD13 and HOXD10 genes have been found to be associated with digital and limb malformations. In addition, dysregulation of HOXD gene cluster has been proposed to account for the limb abnormalities in patients with chromosome 2q rearrangements. In this report, we investigated a three-generation family presenting clinical phenotypes of duplication of great toes, tapering fingers, and clinodactyly of the fifth finger in both hands, which were transmitted in a dominant fashion in this family. We identified and validated an interstitial microdeletion of ∼3.4 Mb at chromosome 2q31.1-31.2 by array-based comparative genomic hybridization, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction that cosegregates with the clinical phenotypes in this family. The microdeletion removes 30 labeled genes including the entire HOXD gene cluster, suggesting that the digital abnormalities of this family may be attributed to the haploinsufficiency of the HOXD gene cluster. The delineation of the microdeletion region may contribute to the genotype–phenotype correlation study in patients with genomic rearrangements of the long arm of chromosome 2 and helps to understand the pathogenesis of haploinsufficiency of the HOXD gene cluster.     

The 8q22.1 microdeletion syndrome or Nablus mask-like facial syndrome: Report on two patients and review of the literature

Nablus mask-like facial syndrome (NMFLS) is a rare microdeletion syndrome with a mask-like facial appearance as the most characteristic feature. In 2000, Teebi, was the first to report on a 4 years old boy affected with NMFLS. Since then two additional patients have been reported. Three years later, with the development of the array CGH technology, Shieh et al., elucidated the etiology of NMFLS by showing that the two patients studied share a ～4 Mb microdeletion in the long arm of chromosome 8 (q21.3–q22.1). Here we report on two NMFLS patients among which the first patient described by Teebi in 2000, and present newly described clinical findings including the common happy behaviour of the children. Array CGH analysis of these two patients permitted to reveal a deletion in the same region, 8q21.3–q22.1. Combining the available literature and our data, we were able to narrow the common deleted region to 2.78 Mb (93.56–96.34 Mb) in 8q22.1. Direct relations between the clinical findings with (one of) the genes in the critical region have to await further studies on NFMLS patients with overlapping or smaller deletions.     

Detection of single clone deletions using array CGH: identification of submicroscopic deletions in the 22q11.2 deletion syndrome as a model system

Constitutional submicroscopic DNA copy number alterations have been shown to cause numerous medical genetic syndromes, and are suspected to occur in a portion of cases for which the causal events remain undiscovered. Array comparative genomic hybridization (array CGH) allows high-throughput, high-resolution genome scanning for DNA dosage aberrations and thus offers an attractive approach for both clinical diagnosis and discovery efforts. Here we assess this capability by applying array CGH to the analysis of copy number alterations in 44 patients with a phenotype of the 22q11.2 deletion syndrome. Twenty-five patients had the deletion on chromosome 22 characteristic of this syndrome as determined by fluorescence in situ hybridization (FISH). The array measurements were in complete concordance with the FISH analysis, supporting their diagnostic utility. These data show that a genome-scanning microarray has the level of sensitivity and specificity required to prospectively interrogate and identify single copy number aberrations in a clinical setting. We demonstrate that such technology is ideally suited for microdeletion syndromes such as 22q11.2.     

A familial case of overgrowth syndrome caused by a 9q22.3 microdeletion in a mother and daughter

Microdeletions in the 9q22.3 chromosomal region can cause macrosomia with characteristic features, including prenatal-onset overgrowth, metopic craniosynostosis, hydrocephalus, developmental delay, and intellectual disability, in addition to manifestations of nevoid basal cell carcinoma syndrome (NBCCS). Haploinsufficiency of PTCH1 may be responsible for accelerated overgrowth, but the mechanism of macrosomia remains to be elucidated. We report a familial case with a 9q22.3 microdeletion, manifesting with prenatal-onset overgrowth in a mother and post-natal overgrowth in her daughter. Although both were clinically diagnosed with NBCCS, they had characteristic features of 9q22.3 microdeletion, especially the daughter. Microarray comparative genomic hybridization analysis revealed a 4.0 Mb deletion of chromosome 9q22.3 in both individuals. Among the 11 reported patients of overgrowth and/or macrosomia, a 550 Kb region encompassing PTCH1, C9orf3, FANCC, and 5 miRNAs is the most commonly deleted region. The let-7 family miRNAs, which are involved in diverse cellular processes including growth and tumor processes, were identified in the deleted regions in 10 of 11 patients. Characteristic features of 9q22.3 microdeletion might be associated with decreased expression of let-7.