Microduplication Syndrome Research Articles

Potocki-Lupski Syndrome: A Microduplication Syndrome Associated with Oropharyngeal Dysphagia and Failure to Thrive

Failure to thrive (FTT) is a feature of children with Potocki-Lupski syndrome (PTLS) [duplication 17p11.2]. This study was designed to describe the growth characteristics of 24 subjects with PTLS from birth through age 5 years in conjunction with relevant physical features and swallow function studies. We evaluated 24 individuals with PTLS who were ascertained by chromosome analysis and/or array comparative genome hybridization. Clinical assessments included review of medical records, physical examination, otolaryngological examination, and swallow function studies. Measures of height and weight were converted to Z-scores. The mean weight-for-age and weight-for-length Z-scores at birth were lower (P < .01) than the reference standard and did not change with age. A history of poor feeding, hypotonia, and FTT were reported in 92%, 88%, and 71%, respectively. Individuals with hypotonia had lower weight-for-age and body mass index-for-age Z-scores (P = .01). Swallow function studies demonstrated at least one abnormality in all subjects. FTT is common in children with PTLS. We hypothesize that oropharyngeal dysphagia and hypotonia likely contribute to FTT in patients with PTLS and recommend that once a diagnosis is established, the individual be assessed for feeding and growth issues and be availed of oromotor therapy and nutritional services.

Further evidence for the pathogenicity of 15q24 microduplications distal to the minimal critical regions

DNA copy number alterations in 15q24 have repeatedly been reported in patients exhibiting mild to moderate developmental delay and dysmorphic features. To date, mainly microdeletions have been described, and comparison of overlapping regions allowed the definition of minimal critical regions (MCRs) for microdeletions as well as microduplications. These MCRs are associated with distinct phenotypes. Recently, a family with a new microduplication distal to these MCRs was reported. However, for this alteration the typical phenotypical consequences could not yet be determined. Here we present another family with a nearly identical microduplication exhibiting a broad clinical spectrum including developmental delay, autistic traits and dysmorphic features. Our data suggest that microduplications adjacent and distal to the known MCRs are variable in expressivity and are associated with distinct features. They might represent a novel and recurrent microduplication syndrome.

Clinical application of array-based comparative genomic hybridization by two-stage screening for 536 patients with mental retardation and multiple congenital anomalies

Recent advances in the analysis of patients with congenital abnormalities using array-based comparative genome hybridization (aCGH) have uncovered two types of genomic copy-number variants (CNVs); pathogenic CNVs (pCNVs) relevant to congenital disorders and benign CNVs observed also in healthy populations, complicating the screening of disease-associated alterations by aCGH. To apply the aCGH technique to the diagnosis as well as investigation of multiple congenital anomalies and mental retardation (MCA/MR), we constructed a consortium with 23 medical institutes and hospitals in Japan, and recruited 536 patients with clinically uncharacterized MCA/MR, whose karyotypes were normal according to conventional cytogenetics, for two-stage screening using two types of bacterial artificial chromosome-based microarray. The first screening using a targeted array detected pCNV in 54 of 536 cases (10.1%), whereas the second screening of the 349 cases negative in the first screening using a genome-wide high-density array at intervals of approximately 0.7 Mb detected pCNVs in 48 cases (13.8%), including pCNVs relevant to recently established microdeletion or microduplication syndromes, CNVs containing pathogenic genes and recurrent CNVs containing the same region among different patients. The results show the efficient application of aCGH in the clinical setting.

Clinical characterization of a girl with trisomy 20q13.2qter and monosomy 13q33.1qter: Delineating phenotype–genotype correlations

Array comparative genomic hybridization (aCGH) is a techniqueenabling high-resolution, genome-wide screeningof genomic seg-mentalcopynumbervariations(CNVs)[Solinas-Toldoetal.,1997;Pinkeletal.,1998].Itisbecominganessentialandaroutineclinicaldiagnostic tool and is gradually replacing cytogenetic methods.Most of the clinically available aCGH platforms are designed todetectaneuploidies,well-characterizedmicrodeletion/microdupli-cation syndromes and subtelomeric or other unbalanced chromo-somal rearrangements [Ballif et al., 2006; Shinawi and Cheung,2008]. The aim of the present paper is to present the clinical andmolecular description of a patient with a submicroscopic rear-rangement resulting in trisomy 20q and monosomy 13q andtherebytodelineatethephenotypeassociatedtoaspecificchromo-somal region.Thepatient,a6-year-oldgirl,istheproductofthefirstpregnancyofhealthy,nonconsanguineousparents,aged45years(mother)and51 years (father). The pregnancy was complicated by reduced fetalmovement and vaginal infection.Intrauterine diagnosis at the 7th month of pregnancy showedhypoplasia of the corpus callosum during the final month severeIUGR was diagnosed.Thepatientwasdeliveredat38weeksgestationviainducedlabor.The weight was 1,400g (<10th centile), length 45.5cm (10thcentile), and the OFC was 30cm (3rd centile). Examinationsimmediately after birth revealed that the patient had hyporeflexia,hypoactivity, and flattened occiput. The cerebral ultrasoundshowedthatshehadhypogenesisofthecorpuscallosum.Echocar-diographyand subsequent cardiac catheterization showed an osti-um secundum atrial septal defect and branch pulmonary stenosis.Congenital tracheal stenosis was diagnosed by a bronchoscopy.Fundus and evoked potentials were both normal.Significant psychomotor developmental delay was observed ininfancyandattheageof6years,shewasstillunabletostandalone.Vocalizations began at 4 years and at 6 years she said disyllabicnon-referentialwordsandcommunicatedwithsimplegestures.Shehad no developmental regression Since 3 years of age, she hasexperiencedsporadicseizures(5or6episodes)andreceivedfurthertreatment with valproic acid or clonazepam. No deterioration wasseeninassociationwiththeepisodes.Shehadslowweightgainandlongitudinal growth.Amongtheillnesshad,shewasadmittedat22monthsoldduetoan episode of acute gastroenteritis with severe hypernatremicdehydration and prerenal acute renal failure. In addition, she hashad several urinary tract infections with normal renal findings onsonogram.

Evidence-based information guides to rare chromosome disorders for families and professionals

The purpose of this project is to develop reliable, relevant, accurate leaflets for affected families and health (and other) professionals that fill an information gap about rare chromosome disorders. In 2003 Unique surveyed information materials published in the UK about specific rare chromosome disorders: for over 93% of members, no accessible disorder-specific information was available. Unique asked families what they most wanted to know at diagnosis and what questions remained unanswered. Unique prioritised 66 disorders according to frequency on its database (7,140 member families at February 2010) and absence of existing information accessible to families. Information was compiled from the medical literature, from Unique’s database and from detailed surveys sent to member families. Draft texts were reviewed for accuracy by Unique’s medical adviser and by medical and genetics professional experts in the specific disorders. Photographically illustrated draft leaflets were vetted for content by families. By early 2010, leaflets have been developed on 113 rare chromosome disorders including numerical and structural disorders, subtelomere deletions, mosaic disorders, emerging microdeletion and microduplication syndromes and a broad range of less common diagnoses. Twenty-one leaflets have been translated into at least one European language. Many more leaflets are in preparation or planned. Leaflets are available free to families and the professionals who work with them either in print format or online from Unique’s website at http://www.rarechromo.org. The leaflets improve families’ understanding and acceptance of a rare chromosome disorder and help diminish the acute stress and anxiety associated with diagnosis. They are also proving to be a useful resource for professionals, including health professionals in clinic.

Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment

Genome-wide high-resolution array analysis is rapidly becoming a reliable method of diagnostic investigation in individuals with mental retardation and congenital anomalies, leading to the identification of several novel microdeletion and microduplication syndromes. We have identified seven individuals with duplication on chromosome 14q11.2q13.1, who exhibited idiopathic developmental delay and cognitive impairment, severe speech delay, and developmental epilepsy. Among these cases, the minimal common duplicated region on chromosome 14q11.2q13.1 includes only three genes, FOXG1, C14orf23, and PRKD1. We propose that increased dosage of Forkhead Box G1 (FOXG1) is the best candidate to explain the abnormal neurodevelopmental phenotypes observed in our patients. Deletions and inactivating mutations of FOXG1 have been associated with a Rett-like syndrome characterized by hypotonia, irritability, developmental delay, hand stereotypies, and deceleration of head growth. FOXG1, encoding a brain-specific transcription factor, has an important role in the developing brain. In fact, in vivo studies in chicken brain demonstrated that overexpression of FOXG1 results in thickening of the neuroepithelium and outgrowth of the telencephalon and mesencephalum, secondary to a reduction in neuroepithelial cell apoptosis.

A novel microdeletion/microduplication syndrome of 19p13.13

PurposeWhole genome interrogation by array-based comparative genomic hybridization has led to a rapidly increasing number of discoveries of novel microdeletion and/or microduplication syndromes. We here describe the clinical and cytogenomic correlates of a novel microdeletion/microduplication of 19p13.13. MethodsAmong patients referred to the Cytogenetics laboratory for array-based comparative genomic hybridization analysis, we identified four with a deletion and one with a duplication within 19p13.13. Confirmatory fluorescence in situ hybridization and parental studies were performed. Detailed clinical findings and array profiles were reviewed and compared. ResultsPatients with deletions of 19p13.13 share a unique constellation of phenotypic abnormalities. In addition to developmental disabilities, the microdeletion manifested in overgrowth, macrocephaly, and ophthalmologic and gastrointestinal findings; in contrast, the single microduplication manifested in growth delay and microcephaly. ConclusionThe consistent constellation of clinical findings associated with copy number variation of this region warrants the designation of microdeletion/microduplication syndrome of 19p13.13. An approximately 311–340 Kb smallest region of overlap encompassing 16 genes was identified. Candidate genes include MAST1, NFIX, and CALR. Identification of this syndrome has led to recommendations for diagnostic work-up and follow-up of patients with this copy number variant. Integration of detailed clinical and array data is critical for advancing both patient care and human genomic research.

The molecular genetics of congenital heart disease: a review of recent developments

Our understanding of the interactions of genes and pathways during heart development continues to expand with our knowledge of the genetic basis of congenital heart disease. Along with the discovery of specific genes that cause lesions, recent research has focused on the interactions of some previously identified genes. This review focuses on the progress made during the last year. T-box, NK, and GATA transcription factors have known associations with a variety of syndromic and isolated congenital heart defects. Discovery of novel interactions of GATA and T-box transcription factors highlights the direction of recent research. In addition, the critical yet somewhat redundant roles of nkx2.5 and nkx2.7, along with the interaction of nkx2.7 with tbx20, have been elucidated. The contributions of still other transcription factor classes are being elucidated. Further understanding of 22q11.2 deletion and microduplication syndromes and their genetic interactions has also been studied. Recent work also highlights PTPN11 and NOTCH1 in Noonan syndrome. The recent developments in the genetics of congenital heart disease are reviewed. In many cases, it is the novel interactions of previously known genes that highlight this year's developments. These interactions will ultimately lead to better understanding of downstream transcriptional or signaling pathways.

Common recurrent microduplication syndromes: Diagnosis and management in clinical practice

Details on the phenotypic consequences of genomic microdeletions and microduplications are rapidly emerging in the wake of increased utilization of high-resolution methods for the detection of genomic copy number variants (CNVs). Due to their recent discovery, the complete phenotypic characterization of these syndromes is still in progress. For practicing clinicians, this unprecedented molecular diagnostic capability has in many cases outpaced our ability to convey conclusive information regarding these conditions to patients and family members. In particular, genomic microduplication syndromes are frequently associated with variable phenotypes and incomplete penetrance, leading to difficulty in counseling regarding the potential future consequences of a given microduplication. In this review, we have attempted to provide an initial set of recommendations for the management of patients with recurrent microduplication syndromes. We summarize the clinical information for microduplications of 14 different genomic regions and provide a framework for clinical evaluation and anticipatory guidance in these conditions. It is our expectation that these preliminary guidelines will be revised further for each microduplication syndrome as more information becomes available.

22q11.2 Microduplication in Two Patients with Bladder Exstrophy and Hearing Impairment

Purpose Bladder exstrophy is a congenital malformation of the bladder occurring in about 1 in 35 000 newborns. A few cases of bladder exstrophy patients have been described to carry chromosomal aberrations and in addition the recurrence risk in higher among relatives of bladder exstrophy cases than in the general population. This speaks in favour of a genetic contribution to the pathogenesis of bladder exstrophy. Material and Methods We have performed array-CGH analysis of 36 Swedish bladder exstrophy patients in order to look for submicroscopic chromosomal aberrations. Results The analysis revealed a 22q11.21 microduplication in two unrelated cases with bladder exstrophy and hearing impairment consistent with the recently described 22q11.2 microduplication syndrome. This finding was confirmed by multiplex ligation-dependent probe amplification (MLPA) and FISH analysis. Subsequent MLPA analysis of this chromosomal region in 33 bladder exstrophy patients did not reveal any deletion/duplication within this region. MLPA analysis of 171 anonymous control individuals revealed one individual carrying this microduplication. Conclusions Chromosomal rearrangements of 22q11.2 are implicated in several genomic disorders i.e. DiGeorge/velocardiofacial- and cat-eye syndrome. Deletions within this chromosomal region are relatively common while duplications of 22q11.2 are much less frequently observed. An increasing number of reports of microduplications of this region describe a highly variable phenotype. This is the first report of 22q11.2 microduplication associated with bladder exstrophy and hearing impairment. The finding of one carrier among a cohort of normal controls further highlights the variable phenotype linked to this microduplication syndrome.

Cognitive and Behavioral Characterization of the Potocki-Lupski Syndrome (Duplication 17p11.2)

To describe the cognitive and behavioral phenotypic features of the Potocki-Lupski syndrome (duplication 17p11.2), a recently recognized syndrome with multiple congenital anomalies and developmental delays. Fifteen subjects were enrolled in an extensive multidisciplinary clinical protocol. Cognitive and behavior evaluations included a parent-report medical and psychological history form, intellectual assessment and assessments of adaptive behavior, executive functioning, and maladaptive behavior and emotions. Eight of the families completed an Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule-Generic. The majority of patients (13 of 15) presented with intellectual disability. Moreover, the majority of patients also had moderate to severe behavioral difficulties, including atypicality, withdrawal, anxiety, and inattention. Many patients characterized also presented with autistic symptom pictures, some of whom (10 of 15) met diagnostic criteria for an autistic spectrum disorder, namely autistic disorder or pervasive developmental disorder not otherwise specified. This work expands on the behavioral phenotype of duplication 17p11.2 (Potocki-Lupski syndrome). Further phenotypic analysis will aid in clinical diagnosis, counseling, and management of this newly characterized microduplication syndrome. The association between this syndrome and autistic spectrum disorder may contribute to further understanding the etiology of the pervasive developmental disorders.

22q11.2 microduplication in two patients with bladder exstrophy and hearing impairment

Bladder exstrophy is a congenital malformation of the bladder and urethra. The genetic basis of this malformation is unknown however it is well known that chromosomal aberrations can lead to defects in organ development. A few bladder exstrophy patients have been described to carry chromosomal aberrations. Chromosomal rearrangements of 22q11.2 are implicated in several genomic disorders i.e. DiGeorge/velocardiofacial- and cat-eye syndrome. Deletions within this chromosomal region are relatively common while duplications of 22q11.2 are much less frequently observed. An increasing number of reports of microduplications of this region describe a highly variable phenotype. We have performed array-CGH analysis of 36 Swedish bladder exstrophy patients. The analysis revealed a similar and approximately 3 Mb duplication, consistent with the recently described 22q11.2 microduplication syndrome, in two unrelated cases with bladder exstrophy and hearing impairment. This finding was confirmed by multiplex ligation-dependent probe amplification (MLPA) and FISH analysis. Subsequent MLPA analysis of this chromosomal region in 33 bladder exstrophy patients did not reveal any deletion/duplication within this region. MLPA analysis of 171 anonymous control individuals revealed one individual carrying this microduplication. This is the first report of 22q11.2 microduplication associated with bladder exstrophy and hearing impairment. Furthermore the finding of one carrier among a cohort of normal controls further highlights the variable phenotype linked to this microduplication syndrome.

Prenatal study of common submicroscopic “genomic disorders” using MLPA with subtelomeric/microdeletion syndrome probe mixes, among gestations with ultrasound abnormalities in the first trimester

Purpose The present study aims to investigate the presence of common submicroscopic chromosomal rearrangements in fetuses with ultrasound abnormalities or positive screening in the first trimester and normal karyotype. We used the multiplex ligation-dependent probe amplification (MLPA) technique with subtelomeric (SALSA P036B) and microdeletion syndrome (SALSA P064B/P096) probe mixes as a screening method to measure copy number changes on the tested probes in chorionic villus sampling. MLPA with P036B and P064/P096 probe mixes was performed on 49 chorionic villi DNA samples obtained between the 11th and 13th week of gestation. Results The MLPA analyses did not detect any diminished or increased intensity for all the tested probes in the samples. Conclusions Our results suggest that the common submicroscopic “genomic disorders” (microdeletion and microduplication syndromes) would not be frequently detected in the first trimester anomalies screening.

Goldenhar phenotype in a child with distal 22q11.2 deletion and intracranial atypical teratoid rhabdoid tumor

Chromosome-specific low copy repeats (LCRs) are implicated in several clinically significant microdeletion and microduplication syndromes. The well-recognized phenotype of DiGeorge/velocardiofacial syndrome (DG/VCF) results from deletions of the long arm of chromosome 22 (22q11.2) mediated by the proximal LCRs in this region. More recent evidence suggests that the distal LCRs within 22q11.2 are also implicated in microdeletions and microduplications with less characterized phenotypes. Here we report on an infant diagnosed with Goldenhar syndrome (GS) phenotype who developed an atypical teratoid rhabdoid tumor (AT/RT) of the brain due to a distal deletion of the chromosome 22q11.2 region encompassing the INI1/SMARCB1 tumor suppressor. We also discuss the phenotype of patients with germline deletions of this region and the possible implication of the 22q11.2 region in the GS.

High resolution array analysis: diagnosing pregnancies with abnormal ultrasound findings

Background:Genome-wide high resolution array analysis is becoming established as a diagnostic test in the investigation of individuals with learning disability and congenital anomalies; many novel microdeletion and microduplication syndromes have...

Impact of genotype-first diagnosis: the detection of microdeletion and microduplication syndromes with cancer predisposition by aCGH

BackgroundThe use of microarray-based comparative genomic hybridization has allowed the genetic diagnosis of some conditions before their full clinical presentation. This “genotype-first” diagnosis has the most clinical implications for genomic alterations that confer an elevated risk of cancer. In these cases, diagnosis before the manifestation of the patient's full phenotype dramatically impacts genetic counseling, clinical management, and eventual prognosis and survivability. MethodsUsing microarray-based comparative genomic hybridization, we tested 18,437 individuals with indications such as developmental disabilities and congenital anomalies. ResultsWe identified 34 (0.18%) individuals with DNA copy number gains or losses that encompassed gene regions associated with recognized genetic conditions with an increased risk for cancer. Three of the 34 individuals (8.8%) had a previously abnormal cytogenetic study which microarray-based comparative genomic hybridization confirmed and/or further characterized. Seven of the 34 individuals (20.6%) either had the correct disease specified in the clinical indication for study or had clinical features highly indicative of that syndrome. The remaining 24 patients (70.6%) had indications for study that were not specific to the diagnosed syndrome, such as “developmental delay” or “dysmorphic features.” ConclusionsThe ability of microarray-based comparative genomic hybridization to rapidly and objectively interrogate the genome for chromosomal imbalances has led to the opportunity to optimize medical management and outcome. This has an even more profound impact and clinical utility in conditions associated with cancer predisposition syndromes.

Extending the phenotype of recurrent rearrangements of 16p11.2: Deletions in mentally retarded patients without autism and in normal individuals

Array CGH (comparative genomic hybridization) screening of large patient cohorts with mental retardation and/or multiple congenital anomalies (MR/MCA) has led to the identification of a number of new microdeletion and microduplication syndromes. Recently, a recurrent copy number variant (CNV) at chromosome 16p11.2 was reported to occur in up to 1% of autistic patients in three large autism studies. In the screening of 4284 patients with MR/MCA with various array platforms, we detected 22 individuals (14 index patients and 8 family members) with deletions in 16p11.2, which are genomically identical to those identified in the autism studies. Though some patients shared a facial resemblance and a tendency to overweight, there was no evidence for a recognizable phenotype. Autism was not the presenting feature in our series. The assembled evidence indicates that recurrent 16p11.2 deletions are associated with variable clinical outcome, most likely arising from haploinsufficiency of one or more genes. The phenotypical spectrum ranges from MR and/or MCA, autism, learning and speech problems, to a normal phenotype.

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

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

Epimutation at human chromosome 14q32.2 in a boy with a upd(14)mat‐like clinical phenotype

Recently, three reports described deletions and epimutations affecting the imprinted region at chromosome 14q32.2 in individuals with a phenotype typical for maternal uniparental disomy of chromosome 14 [upd(14)mat]. In this study, we describe another patient with upd(14)mat-like phenotype including low birth weight, neonatal feeding problems, muscular hypotonia, motor and developmental delay, small hands and feet, and truncal obesity. Conventional cytogenetic analyses, fluorescence in situ hybridization subtelomere screening, multiplex ligation-dependent probe amplification analysis of common microdeletion and microduplication syndromes, and methylation analysis of SNRPN all gave normal results. Methylation analysis at 14q32.2 revealed a gross hypomethylation of the differentially methylated regions (intergenic DMR and MEG3-DMR). Further molecular studies excluded full or segmental upd(14)mat as well as a microdeletion within this region. Evidently, the upd(14)mat-like clinical phenotype is caused by an epimutation at 14q32.2. The clinical and molecular features of this novel case are discussed with respect to the recently published cases.

Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice

Background:Microarray genome analysis is realising its promise for improving detection of genetic abnormalities in individuals with mental retardation and congenital abnormality. Copy number variations (CNVs) are now readily detectable using...