Proximal Duplication Research Articles

CORR Insights ®: Are copy number variants associated with adolescent idiopathic scoliosis?

A dolescent idiopathic scoliosis (AIS) is a genetically heterogeneous complex condition that affects approximately 3% of the population. Although genome-wide association studies have pointed us towards candidate loci for genetic causes of this condition, it is evident that these loci do not constitute the majority of AIS heritability. Since copy number variation has been associated with the presence of birth defects, neuropsychiatric disabilities, congenital heart disease, and skeletal disorders such as clubfoot, Buchan et al. theorized that rare copy number variants contribute to the pathogenesis of scoliosis. In their study, Buchan et al. identified clinically significant copy number variation with a size of 125kb or greater having at least 50 markers using the Affymetrix Genome wide SNP array 6.0 in nine of 143 (6.3%) patients with AIS. These included proximal duplications of 1q21.1 (Thrombocytopenia Absent Radius syndrome region); 2q13, 15q11.2, and 16p11.2 deletions. Trisomy X was identified in two of 114 (1.8%) females with AIS. The 1q21.1 variant appeared to have reduced penetrance. These rare and novel copy number variations were observed with a greater frequency in the AIS population compared to a control population derived from 1079 individuals of European-American ancestry, which included individuals with bipolar disorder and idiopathic clubfoot. It is noteworthy that three of the observed copy number variations are associated with bone phenotypes including 1q21.1 (radial abnormalities), 15q11.2 duplications (hemivertebrae), and Trisomy X (scoliosis).

Antegrade Venography Identifies Parallel Venous Duplications in the Majority of Adolescents with Varicocele

We performed intraoperative antegrade venography to assess the prevalence of internal spermatic venous malformations in adolescents with varicocele. During a 2-year period 58 adolescent males with visible or palpable varicocele underwent antegrade venography before varicocele surgery. Antegrade venography was performed through a scrotal incision. A vein within the pampiniform plexus was cannulated and up to 1.75 mg/kg iohexol 300 mg/ml was injected to outline the entire length of the internal spermatic vein. The radiographs were reviewed and classified according to Bähren and Murray criteria. Of the patients 43 (74.1%) demonstrated parallel duplications (Murray classification type P) of the internal spermatic vein. This rate is higher than the 2% reported based on retrograde venography. Of the patients with parallel duplications 21 (48.8%) showed duplications arising superior to the iliac crest (subtype A) and 22 (51.2%) had a combination of proximal duplications (subtypes B and C). Ten patients (17.2%) had a single internal spermatic vein, 2 (3.4%) had lumbar collaterals and 3 (5.2%) had renal collaterals. Parallel duplication of the internal spermatic vein is a common finding on antegrade venography. The various levels of duplication need to be identified before treatment of varicocele to maximize the success of the procedure.

Proximal 10q duplication in a child with severe central hypotonia characterized by array-comparative genomic hybridization: A case report and review of the literature

Proximal 10q duplication is a well-defined but rare genetic syndrome. Duplication of proximal segments of the long arm of chromosome 10 results in a pattern of malformations, which are distinct from those of the more common distal 10q trisomy syndrome. The present study describes the case of a boy with phenotypic abnormalities (severe central hypotonia, mild ataxia, moderate developmental delay and mild dysmorphic features), due to duplication of chromosome region, 10q11.21→q11.22, which was characterized by the array-comparative genomic hybridization (CGH) technique. The phenotypic findings were compared with those in eight additional similar published cases. Major similarities have emerged, suggesting a likely minimal critical region. However, only detailed characterization of additional cases may provide firm conclusions.

Tandem Duplication of Exons 1-7 Neither Impairs ATP7A Expression Nor Causes a Menkes Disease Phenotype.

ATP7A duplications are estimated to represent the molecular cause of Menkes disease in 4-10% of affected patients. We identified a novel duplication of ATP7A exons 1-7 discovered in the context of a challenging prenatal diagnostic situation. All other reported ATP7A duplications (n = 24) involved intragenic tandem duplications, predicted to disrupt the normal translational reading frame and produce nonfunctional ATP7A proteins. In contrast, the exon 1-7 duplication occurred at the 5' end of the ATP7A gene rather than within the gene and did not correspond to any known copy number variants. We hypothesized that, if the exon 1-7 duplication was in tandem, functional ATP7A molecules could be generated depending on promoter selection, mRNA splicing, and the proximal and distal duplication breakpoints and that Menkes disease would be averted. Here, we present detailed molecular characterization of this novel duplication, as well as 2-year postnatal clinical and biochemical correlations. The case highlights the ongoing need for cautious interpretation of prenatal genetic test results.

Oculo‐auriculo‐vertebral spectrum, cat eye, and distal 22q11 microdeletion syndromes: A unique double rearrangement

An array-CGH on 19-year-old male showed a proximal 1.11 Mb duplication and a distal 1.7 Mb deletion of 22q11.2 regions flanking the Velocardiofacial/DiGeorge syndrome region that remained intact. FISH analyses revealed both abnormalities to be on the same homolog 22. This double rearrangement lead to the co-existence of two syndromes: Cat eye and distal 22q11.2 microdeletion syndromes with a rare associated phenotype of oculo-auriculo-vertebral spectrum (OAVS). A review of the literature indicates that this is the second report of a proximal duplication and the fifth report of a distal deletion and OAVS suggestive of a possible OAVS candidate gene in this region.

Estimates of penetrance for recurrent pathogenic copy-number variations.

Purpose:Although an increasing number of copy-number variations are being identified as susceptibility loci for a variety of pediatric diseases, the penetrance of these copy-number variations remains mostly unknown. This poses challenges for counseling, both for recurrence risks and prenatal diagnosis. We sought to provide empiric estimates for penetrance for some of these recurrent, disease-susceptibility loci.Methods:We conducted a Bayesian analysis, based on the copy-number variation frequencies in control populations (n = 22,246) and in our database of >48,000 postnatal microarray-based comparative genomic hybridization samples. The background risk for congenital anomalies/developmental delay/intellectual disability was assumed to be ~5%. Copy-number variations studied were 1q21.1 proximal duplications, 1q21.1 distal deletions and duplications, 15q11.2 deletions, 16p13.11 deletions, 16p12.1 deletions, 16p11.2 proximal and distal deletions and duplications, 17q12 deletions and duplications, and 22q11.21 duplications.Results:Estimates for the risk of an abnormal phenotype ranged from 10.4% for 15q11.2 deletions to 62.4% for distal 16p11.2 deletions.Conclusion:This model can be used to provide more precise estimates for the chance of an abnormal phenotype for many copy-number variations encountered in the prenatal setting. By providing the penetrance, additional, critical information can be given to prospective parents in the genetic counseling session.

Mosaic marker chromosome 16 resulting in 16q11.2–q12.1 gain in a child with intellectual disability, microcephaly, and cerebellar cortical dysplasia

Proximal duplications of the long arm of chromosome 16 are rare and only a few patients have been reported. Clinically, the patients do not have a distinctive syndromic appearance; however they all show some degree of intellectual disability and most have severely delayed speech development. We report on a child presenting with mild-to-moderate intellectual disability, microcephaly, language dyspraxia, and mild dysmorphisms who was found to have a mosaic gain of chromosome 16q (16q11.2-16q12.1). Magnetic resonance imaging done at the age of 4 years demonstrated cerebellar cortical dysplasia involving the vermis and hemispheres. This is the first report of cerebellar anomalies in a patient with partial trisomy 16q. The genes ZNF423 and CBLN1 found in the duplicated region play a role in the development of the cerebellum and may be responsible for the cerebellar cortical dysplasia.

Clinical, cytogenetic and molecular-cytogenetic characterization of a patient with a de novo tandem proximal-intermediate duplication of 16q and review of the literature

Partial trisomy 16 is rare and most of the reported cases are secondary to chromosome rearrangements resulting in concurrent monosomies or trisomies of a second chromosome. Only a few patients survive the neonatal period and the duplication of the long arm seems to be mainly responsible for the prenatal lethality of the full trisomy 16. The reported patients with a partial 16q trisomy have a wide spectrum of congenital anomalies that include dysmorphic features, central nervous system malformations, failure to thrive, and club feet. The patients with duplications of proximal 16q frequently have short stature, developmental delay, speech delay, learning difficulties, and mild to severe behavioral problems. Here we describe a patient with an inverted de novo tandem duplication of 16q with breakpoints evaluated in detail by molecular-cytogenetic techniques. Main clinical features include postural, motor and speech delay with severe learning difficulties and behavioral problems, obesity, microcephaly, and mild dysmorphic features. In the report we attempt to classify the few reported patients with pure partial duplications of 16q in more narrow and homogeneous groups: proximal, proximal-intermediate, intermediate, and intermediate-distal duplications. Moreover, we emphasize the importance of proper cytogenetic investigation and complete molecular cytogenetic refinement in all cases with a suspected chromosomal anomaly.

Xq26.2-q26.3 microduplication in two brothers with intellectual disabilities: clinical and molecular characterization

Partial duplications involving the long arm of the X chromosome are associated with mental retardation, short stature, microcephaly, hypopituitarism and a wide range of physical findings. We identified an inherited Xq26.2-Xq26.3 duplication in two brothers with severe mental retardation, hypotonia, growth delay, craniofacial disproportion and dental malocclusion. Chromosome analysis was normal and multiplex ligation-dependent probe amplification analysis detected duplication on Xq26. Further characterization by array comparative genomic hybridization and quantitative PCR helped to determine proximal and distal duplication breakpoints giving a size of approximately 2.8 Mb. The duplication encompasses 24 known genes, including the X-linked mental retardation genes ARHGEF6, PHF6, HPRT1 and SLC9A6. Clinical and molecular characterization of Xq duplications will shed more light into the phenotypic implication of functional disomy of X-chromosome genes.

A duplex scan-based morphologic study of the femoral vein: Incidence and patterns of duplication

The presence of femoral vein (FV) duplicity has potential influence in the misdiagnosis of deep vein thrombosis. Also, FVs are suitable vascular substitutes, especially in the substitution of infected prosthetic grafts. The objective of this study was to describe the prevalence, anatomic patterns and characteristics of FV duplicity in adult individuals by duplex scan examination. A total of 174 adult individuals were submitted to duplex-scan examinations of both lower limbs. Individuals with duplex signs of present or previous DVT or with poor quality duplex images were excluded from the investigation. The remaining group consisted of 157 individuals (94 females), with a total of 314 limbs studied. Along with the conventional duplex investigation sequence, the FV was scanned both in transversal and longitudinal views. The number, extension and diameter of FVs were documented. It was found that 173 limbs (55.1%) had duplicated FV. Duplicity in the whole femoral extension was noted in 82 (26.1%) limbs, and out of these only 28 (8.9% of the overall number) had accessory veins with a diameter approximate to (at least 75%) the main FV. Partial (distal or proximal) duplications were seen in 89 (28.3%) limbs. A third FV was present in 28 limbs. As a possible vascular substitute, 99.0% of the main FVs and 25.4% of the accessory veins presented diameters superior to 6 mm, a suitable value for iliac substitution. In conclusion, FV duplicity is frequent, and occurred in 55% of all limbs studied. However, complete extension duplicated veins with similar diameters was an uncommon condition, noticed in fewer than 10% of limbs.

Congenital diaphragmatic hernia with a pure duplication of chromosome 1q: report of the first surviving case

Congenital diaphragmatic hernia (CDH) occurs in multiple malformation syndromes and associations, and has been associated with cytogenetic aberrations on almost every chromosome arm. However, CDH with a duplication of chromosome 1q is very rare in the literature, and all previously reported cases with detailed clinical courses died soon after birth. We present the first surviving case of CDH with a duplication of 1q12-q23, who had arthrogryposis multiplex congenita and hypertrophic cardiomyopathy. CDH patients with a proximal duplication of chromosome 1q may have a chance for survival, and CDH with a duplication of chromosome 1q is not necessarily a lethal association.

Webbed Penis Associated With Urethral Duplication: A Case Report

An 18-month-old boy was admitted to our hospital due to the abnormal appearance of the external genitalia. The boy was born at full term after an uneventful pregnancy, and weighed 3400 g with a length of 51 cm and a head circumference of 35 cm. The patient’s history showed that his mother first noticed the abnormal external genitalia at birth, and this was confirmed by his father. After a period of time, his general practitioner referred him to our hospital for surgical treatment. The mother’s pregnancy was uncomplicated and there was no exposure to drugs, alcohol, or other known toxins. Physical examination showed a web of skin between the scrotum and the urethral surface of the penis, and proximal incomplete urethral duplication (Figs. 1A, B). There was no chordee. The excretory urography showed Type I incomplete urethral duplication (Fig. 2A). The results of micturating cystourethrography (MCU) (Fig. 2B) and other laboratory tests were normal. In the operation, the web was incised transversely and sutured vertically. Urethroplasty was performed to repair the incomplete urethral duplication. Circumcision was also performed. He had no problems in the 15 months following the operation.

The clinical spectrum associated with a chromosome 17 short arm proximal duplication (dup 17p11.2) in three patients

The p11.2-p12 region of human chromosome 17 is gene rich and composed of at least two genomically unstable domains: the Smith-Magenis syndrome region (17p11.2) and the Charcot-Marie-Tooth region (17p12), both of which are flanked by several low-copy repeat sequences. Homologous recombination between these flanking repeats results in either deletion- or duplication-associated phenotypes caused by a gene dosage effect. We report on the clinical phenotype of three patients presenting with either a 17p11.2 or 17p11.2p12 duplication, revealed by chromosome analysis and confirmed by fluorescent in situ hybridization analysis, high resolution genomic analysis of the 17p region using oligonucleotide array comparative genomic hybridization, and molecular studies with microsatellite markers. Two patients carry the 17p11.2 duplication, while the third one shows a larger duplication including the 17p12 region. The facial features observed in our patients include triangular face, full cheeks, smooth philtrum, thin upper lip, dental malocclusion, irregular eyebrows, and sparse hair, all of which are consistent with the pure proximal dup 17p phenotype. The patients' other clinical features are compared with previously published cases.

Prader–Willi syndrome phenocopy due to duplication of Xq21.1–q21.31, with array CGH of the critical region

We report on a 4-year-old male with an interstitial tandem duplication of Xq21.1-q21.31 who presented with clinical features of Prader-Willi syndrome (PWS). The duplication was maternally inherited. Abnormalities of the X chromosome have previously been reported in association with a PWS phenotype, but to date, specific duplications of Xq21.1-q21.31 have not. We refined the chromosomal breakpoints seen on initial G-banded karyotyping in our case with comparative genomic hybridization by microarray (array CGH). The duplication was between 11.1 and 14.4 Mb in length and overlaps with three loci to which mental retardation with PWS-like features have been previously mapped, showing the utility of array CGH in helping to identify candidate genes. We conclude that duplication of chromosomal region Xq21.1-q21.31 potentially results in a PWS-like phenotype. Reviewing the literature on similar duplications, we further conclude that distal Xq duplications can result in features typically seen in infants with PWS, while proximal duplications can result in features typically seen in older children and adults with PWS. Duplications of chromosome Xq should be considered in the differential diagnosis of PWS, especially in males.

De novo proximal duplication of 1(q12q22) in a female infant with multiple congenital anomalies

Reports of small proximal 1q duplications are rare. We report a 1 month-old female who was referred to clinic because she was believed to have features suggestive of Turner syndrome. The patient's dysmorphic features included a prominent nose, low-set and crumpled ears, slightly high palate, short neck, high-pitched cry, mild micrognathia, hypoplastic labia majora, and somewhat deep palmar creases. Traditional G-band chromosome studies of the patient were interpreted as 46,XX,dup(1)(q12q21). To further evaluate the extent of the chromosome 1 duplication, Spectral Karyotyping and a series of six fluorescence in situ hybridization (FISH) probes were utilized. The FISH probes refined the extent of the duplication to involve the region 1(q12q22) indicating the duplicated segment was larger than interpreted by the G-banding studies. This first case of non-mosaic proximal duplication of 1q to be characterized by multiple locus specific FISH probes should allow a more refined delineation of the phenotypic findings and clinical significance associated with this rare chromosomal duplication.

A new case of de novo 11q duplication in a patient with normal development and intelligence and review of the literature

A new case of 11q interstitial duplication is reported in a patient with mild dysmorphic features but normal development. Chromosome analysis revealed a de novo 11q dup(11)(q14.1q21) on G banding and FISH studies. Additional molecular genetic studies revealed a similar but more distal duplication at the level of 11q21q23.1. Previous cases of isolated 11q duplication that overlapped with this case were associated with a wide variety of clinical findings and variable developmental disability. These cases all included additional material not duplicated in this patient. The current case represents the first de novo case of 11q duplication with normal development suggesting that the segment between 11q14.1 and 11q21 contains few genes that are dose sensitive. Review of other cases that have used conventional cytogenetic resolution studies suggests that the band 11q13.5 may contain genes contributing to the developmental disabilities in the cases previously reported with proximal 11q duplication. Differences between conventional cytogenetic techniques and newer molecular genetic studies are expected. These newer techniques will help refine prognosis and counseling for families in the future.

Duplication of 5q15‐q23.2: Case report and literature review

Pure partial trisomy of chromosome 5q is rare and cases have ranged over the entire region, making it difficult to describe a good phenotypic correlation to the cytogenetic duplication. We present a 4.5-year-old girl with a de novo direct duplication of chromosome 5q15-q23.2. She has moderate developmental delay with lack of speech, microcephaly, and subtle dysmorphic features including prominent forehead, bulbous nose, epicanthic folds, protruding tongue, and slightly posteriorly-rotated ears. A comparison is made with other similar duplication cases reported in the literature and a general description of a proximal 5q duplication phenotype is given, with lack of speech as the principal feature.

The euchromatic 9p+ polymorphism is a locus-specific amplification caused by repeated copies of a small DNA segment mapping within 9p12

A large duplication involving the proximal euchromatic region of chromosome 9p was detected by conventional cytogenetics in a healthy 33-year-old woman and in two unrelated foetuses; both of them received the rearrangement from their healthy father. The duplicated segment was R(RBG) and C(CBG)-negative and G(GTG)-positive and was also positive for a 9-specific painting probe. It was preliminarily interpreted as a pathological quantitative change of the genome in the foetuses. FISH analyses allowed us to characterise the chromosome boundaries of this polymorphism, being identified by the RP11-15E1 BAC clone, proximally, and by the RP11-402N8 clone, distally, both probes falling within the 9p12 region. The contiguous, distally, RP11-916H19 probe was not included in the amplification, and may represent the discriminating genetic locus between chromosome polymorphism and chromosome mutation. The 9p12 amplification was approximately 12, 7 and 8 Mb in the three different families and was stable through generations. Our observations confirm the already provided evidence that proximal 9p duplications represent a benign euchromatic polymorphism. However, we demonstrated that these variants are not a simple duplication of the region 9p11.2-p13.1, as already suggested, but that they result from a many-fold amplification of a segment mapping within 9p12. These results provide important insights both in the genetic counselling and in the prenatal diagnosis of rare euchromatic chromosome variants and in understanding the architecture of the human genome.

Trisomy 17p10‐p12 due to mosaic supernumerary marker chromosome: Delineation of molecular breakpoints and clinical phenotype, and comparison to other proximal 17p segmental duplications

The unstable, gene-rich chromosome region 17p11.2-p12 is associated with various structural aberrations including supernumerary marker chromosomes (SMCs). In some cases, SMC(17)s utilize the same substrates for recombination as the common recurrent 17p11.2 and 17p12 rearrangements. We report on a 9-year-old girl with a de novo mosaic SMC(17). The der(17) encompasses genetic material from 17p10-p11.2 and is present in 97% of peripheral blood lymphocytes and in 79% of buccal cells. The patient has few features similar to individuals with duplication 17p11.2 including mental retardation, language impairment, and sleep disturbances but has normal growth, and no structural abnormalities of the heart, kidneys, or brain. She has no substantial behavioral abnormalities or dysmorphic features. Molecular analyses determined that the der(17) contains RAI1 but not PMP22. We found one chromosome breakpoint within the centromere and the second breakpoint within the distal Smith-Magenis syndrome low-copy repeat (distal SMS-REP). Recently we characterized the breakpoints of three other marker chromosomes originating from the proximal short arm of chromosome 17. In all four cases, one breakpoint maps within the centromere and in three cases the second breakpoint maps within a low-copy repeat. We thus propose that genome architecture may play a significant role in the formation of marker chromosomes. We present the cytogenetic, molecular, and clinical data of this patient and compare our results with those of patients with dup(17)(p11.2p11.2) syndrome and other patients with SMC(17).

A new case of 2q duplication supports either a locus for orofacial clefting between markers D2S1897 and D2S2023 or a locus for cleft palate only on chromosome 2q13‐q21

We report on a pure duplication of the proximal chromosome 2q in a 6.5-year-old boy with V-shaped midline cleft palate and bifid uvula, posteriorly located tongue, and micrognathia (Pierre Robin sequence), celiac disease, failure to thrive, and developmental delay. Cytogenetic and FISH analysis indicated a duplication of chromosome 2q13-q22. In general, pure proximal duplication or triplication of 2q is rare. The clinical features and chromosomal breakpoints of the 10 previously reported patients varied, and no common phenotype or proximal duplication/triplication 2q syndrome could be defined to date. However, based on four previous patients with different orofacial clefts and our case, a locus for orofacial clefting may be located at proximal 2q. The duplication/triplication comprised chromosome 2q13 in all five affected individuals including our patient. Our patient and three previous cases (two with cleft palate only (CPO) and one with cleft lip/palate (CL/P)) showed a cytogenetic breakpoint at 2q13, which could support the presence of a critical dominant gene disrupted by a common breakpoint, however, the fifth case with CPO showed different breakpoints, advocating against the disruption of a critical dominant gene and supporting that the overexpression of a gene(s) on chromosome 2q13-q21 may cause cleft palate only (CPO) and Pierre Robin sequence. Hence, our findings support either the presence of one locus for orofacial clefting (CL/P, CPO, and Pierre Robin sequence) between markers D2S1897 (chromosome 2q12.2) and D2S2023 (chromosome 2q14.2), or alternatively the presence of a locus for CPO and Pierre Robin sequence on chromosome 2q13-q21.