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.     

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.     

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.     

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.     

一例15q11.2微重复患儿的临床及遗传学分析

目的明确1例发育迟缓、智力低下患儿遗传学病因及其来源,并对该家系下一胎行产前诊断。方法采集患儿及其父母外周血进行常规G显带核型分析及单核苷酸多态性微阵列芯片(single nucleotide polymorphism array,SNP array)检测;并对该孕妇行产前诊断,进行羊水细胞染色体核型分析及SNP array检测。结果患儿及其父母染色体核型未见异常。SNP array检测结果显示患儿15号染色体15q11.2区段存在855.3 kb重复,该重复遗传至表型正常的母亲,父亲检测结果未见异常。孕妇羊水细胞染色体核型及SNP array检测结果均未见异常。结论15q11.2微重复可能与体格/智力发育障碍相关,CYFIP1可能是其候选基因,但该重复仅可增加其发病风险,外显率较低,在临床咨询中应引起重视。     

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.     

Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

We identified a novel homozygous 15q13.3 microdeletion in a young boy, with a complex neurodevelopmental disorder characterized by severe cerebral visual impairment with additional signs of congenital stationary night blindness, congenital hypotonia with areflexia, profound intellectual disability, and refractory epilepsy. The mechanisms by which the genes in the deleted region exert their effect are unclear. In this paper, we probed the role of downstream effects of the deletions as a contributing mechanism to the molecular basis of the observed phenotype. We analyzed gene expression of lymphoblastoid cells derived from peripheral blood of the proband and his relatives to ascertain the relative effects of the homozygous and heterozygous deletions. We identified 267 genes with apparent differential expression between the proband with the homozygous deletion and 3 age- and sex-matched typically developing controls. Several of the differentially expressed genes are known to influence neurodevelopment and muscular function, and thus may contribute to the observed cognitive impairment and hypotonia. We further investigated the role of CHRNA7 by measuring TNFα modulation (a potentially important pathway in regulating synaptic plasticity). We found that the cell line with the homozygous deletion lost the ability to inhibit the activation of tumor necrosis factor-α secretion. Our findings suggest downstream genes that may have been altered by the 15q13.3 homozygous deletion, and thus contributed to the severe developmental encephalopathy of the proband. Furthermore, we show that a potentially important pathway in learning and development is affected by the deletion of CHRNA7.     

A heterozygous,intragenic deletion of CNOT2 recapitulates the phenotype of 12q15 deletion syndrome

Only a few individuals with 12q15 deletion have been described, presenting with a disorder characterized by learning disability, developmental delay, nasal speech, and hypothyroidism. The smallest region of overlap for this syndrome was included in a genomic segment spanning CNOT2, KCNMB4, and PTPRB genes. We report on an additional patient harboring a 12q15 microdeletion encompassing only part of CNOT2 gene, presenting with a spectrum of clinical features overlapping the 12q15 deletion syndrome phenotype. We propose CNOT2 as the phenocritical gene for 12q15 deletion syndrome and its haploinsufficiency being associated with an autosomal dominant disorder, presenting with developmental delay, hypotonia, feeding problems, learning difficulties, nasal speech, skeletal anomalies, and facial dysmorphisms.     

Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder

Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.     

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.     

Case of 15q26-qter deletion associated with a Prader-Willi phenotype

Prader-Willi syndrome (PWS) is one of the common neurogenetic disorders associated with intellectual disability. PWS involves a complex inheritance pattern and is caused by an absence of gene expression on the paternally inherited 15q11.2-q13 region, either due to deletion, maternal uniparental disomy or imprinting defect. The syndrome is characterized principally by severe neonatal hypotonia, a weak suck in infancy that is later followed by hyperphagia and obesity, developmental delay, intellectual disability and short stature. In the case of the chromosome 15q26-qter deletion syndrome or Drayer's syndrome, very few reports have been published. Its characteristics include intrauterine growth restriction, postnatal growth failure, varying degrees of intellectual disability, developmental delay, typical facial appearance and diaphragmatic hernia. The present paper describes a female patient in whom clinical findings were suggestive of PWS and deletion in the 15q26-qter region. Both karyotyping and methylation-specific polymerase chain reaction were shown to be normal. Nevertheless, fluorescence in situ hybridization showed a 15qter deletion that was later mapped by single nucleotide polymorphism (SNP)-array. The deleted genomic region involves the insulin-like growth factor-1 receptor (IGF1R) gene, which is related to short stature, developmental delay and intellectual disability. This case had various clinical characteristics in common with the cases of 15q26-qter deletionand characteristics compatible with PWS.     

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 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features

Array-CGH analysis using 244k Agilent oligoarray revealed a de novo 17q21.31 microduplication in a 10-year-old girl with severe psychomotor developmental delay, facial dysmorphism, microcephaly, abnormal digits and hirsutism. The duplication encompassed the MAPT and CRHR1 genes and was reciprocal to the recently described 17q21.31 microdeletion, associated with a recognizable clinical phenotype. Genotyping showed that the duplication was derived from non-allelic homologous recombination of paternal H1 and H2 haplotypes. To our knowledge this is the first report of a patient with a 17q21.31 microduplication.     

Identification of single gene deletions at 15q13.3: further evidence that CHRNA7 causes the 15q13.3 microdeletion syndrome phenotype

The 15q13.3 microdeletion syndrome (OMIM #612001) is characterized by a wide range of phenotypic features, including intellectual disability, seizures, autism, and psychiatric conditions. This deletion is inherited in approximately 75% of cases and has been found in mildly affected and normal parents, consistent with variable expressivity and incomplete penetrance. The common deletion is approximately 2 Mb and contains several genes; however, the gene(s) responsible for the resulting clinical features have not been clearly defined. Recently, four probands were reported with small deletions including only the CHRNA7 gene. These patients showed a wide range of phenotypic features similar to those associated with the larger 15q13.3 microdeletion. To further correlate genotype and phenotype, we queried our database of >15,000 patients tested in the Mayo Clinic Cytogenetics Laboratory from 2008 to 2011 and identified 19 individuals (10 probands and 9 family members) with isolated heterozygous CHRNA7 gene deletions. All but two infants displayed multiple features consistent with 15q13.3 microdeletion syndrome. We also identified the first de novo deletion confined to CHRNA7 as well as the second known case with homozygous deletion of CHRNA7 only. These results provide further evidence implicating CHRNA7 as the gene responsible for the clinical findings associated with 15q13.3 microdeletion.     

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.     

1.5 Mb microdeletion in 15q24 in a patient with mild OAVS phenotype

We report on a boy presenting with features of OAVS (Oculoauriculovertebral spectrum) and carrying a 1.5 Mb microdeletion in 15q24.1q24.2. This recurrent deletion usually leads to a broad clinical spectrum but has never been found associated with features of OAVS such as ear agenesis. This observation is in accordance with OAVS being a genetically heterogeneous disorder, and points out the importance of array-CGH screening in this disorder.     

Phenotypic heterogeneity in a family with a small atypical microduplication of chromosome 22q11.2 involving TBX1

The chromosome 22q11.2 region is commonly involved in non-allelic homologous recombination (NAHR) events. Microduplications of 22q11.2, usually involving a 3 Mb or 1.5 Mb region constitute the 22q11 microduplication syndrome. Both microdeletions and microduplications of 22q11.21 are reported to share several phenotypic characteristics, including dysmorphic facial features, velopharyngeal insufficiency, congenital heart disease, urogenital abnormalities, and immunologic defects. We report a child who presented at 8 months of age for evaluation of microcephaly and mild motor delay. Head circumference at birth, at 8 months, and at 19 months of age was below the 3rd centile. Other findings included left-sided cryptorchidism and developmental dysplasia of the left hip. In addition, echocardiography revealed a restrictive patent ductus arteriosus. Chromosomal microarray analysis using Affymetrix Genome-Wide Human SNP Array 6.0 revealed a novel 437 kb interstitial duplication at 22q11.21, involving TBX1, whose breakpoints did not coincide with known low copy repeat (LCR) regions. The same duplication was confirmed by fluorescent in situ hybridization (FISH) in the patient's mother and an older sister. The mother has a history of anxiety disorder and depression. The sister had a history of delayed motor milestones. None of the three duplication carriers has any documented renal anomalies or other significant medical problems. This report demonstrates the clinical heterogeneity associated with microduplications of 22q11.2 and illustrates the difficulties related to providing prognostic information and accurate genetic counseling to families when this finding is detected. The described microduplication is the smallest in this genomic region reported to date and further implicates abnormal gene dosage of TBX1 in disorders resulting from 22q11.2 rearrangements.     

Duplication of 8q12 encompassing CHD7 is associated with a distinct phenotype but without duane anomaly

Interstitial duplications of 8q12 encompassing CHD7 have recently been described as a new microduplication syndrome. Three 8q12 duplications have been reported with shared recognizable phenotype: Duane anomaly, developmental delay and dysmorphic facial features. We identified a 2.7 Mb duplication on chromosome 8q12 with SNP-array in a patient with growth delay, congenital heart defects, ear anomalies and torticollis. To our knowledge, this is the smallest duplication reported to date. Our findings support the notion that increased copy number of CHD7 may underlie the phenotype of the 8q12 duplication. Our study together with previous studies suggest that the 8q12 duplication could be defined as a novel syndrome.     

3q29 interstitial microduplication: a new syndrome in a three-generation family

Microdeletion and microduplication genetic syndromes are known to be a significant cause of developmental delay and dysmorphology. Utilizing high-resolution chromosome analysis, array CGH and SNP technologies we identified a novel genomic syndrome comprising of an interstitial duplication of approximately 1.61 Mb at the distal end of chromosome 3 band q29. The imbalance was present in five individuals in a three generation family with clinical features including mild to moderate mental retardation and microcephaly. The duplicated segment overlaps with and is the genomic counterpart of the recently described microdeletion of 3q29. Both syndromes are proposed to occur by non-allelic homologous recombination between regions of low copy repeats present around the breakpoints.