A girl with duplication 17p10-p12 associated with a dicentric chromosome (original) (raw)
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American Journal of Medical Genetics Part A, 2008
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. ß de Martinville B. 2008. The clinical spectrum associated with a chromosome 17 short arm proximal duplication (dup 17p11.2) in three patients. Am J Med Genet Part A 146A:917-924.
The phenotypic manifestations of chromosome 17p11.2 duplication
Brain, 1997
nerve acrodystrophic changes in several members. Concurrent focal peripheral nerve lesions were seen with both the CMT biopsies were carried out on 61 patients shown to have and Roussy-Lévy phenotypes, in seven patients. Upper limb a chromosome 17p11.2 duplication (hereditary motor and motor nerve conduction velocity was 19.9 m/s Ϯ 1.3 (SEM), sensory neuropathy-HMSN Ia). Of these, 50 showed a range 5-34 m/s. This corresponds to values previously Charcot-Marie-Tooth (CMT) phenotype and eight could be obtained for autosomal dominant HMSN I. This series classified as having the Roussy-Lévy syndrome. Of the consisted mainly of older patients with more advanced patients with a CMT phenotype, three had associated disease. In contrast to the findings in younger patients, in pyramidal signs and of these one had 'complicated' HMSN their nerve biopsies, myelin thickness tended to be relatively and also signs of cerebellar and bulbar involvement. reduced for axon size, indicating remyelination and/or Diaphragmatic weakness was present in three severely hypomyelination; there was also regression of the onion affected cases, one of whom also had denervation of the bulbs. It is concluded that the possession of two copies of anal sphincter associated with faecal incontinence. One the peripheral myelin protein 22 gene within the duplicated unusual case presented in middle life with incapacitating region on chromosome 17p gives rise to a range of phenotypes muscle cramps associated with calf hypertrophy and only and not solely to a CMT syndrome, and that the pattern of mild clinical signs of neuropathy. Prominent distal sensory histological change in the peripheral nerves alters with loss was a consistent feature in one family, resulting in advance of the disease. Keywords: Charcot-Marie-Tooth disease; hereditary motor and sensory neuropathy; hypertrophic neuropathy; peripheral myelin protein 22; Roussy-Lévy syndrome Abbreviations: CIDP ϭ chronic inflammatory demyelinating polyneuropathy; CMT ϭ Charcot-Marie-Tooth disease; HMSN ϭ hereditary motor and sensory neuropathy; HNPPϭ hereditary neuropathy with liability to pressure palsies; MNCV ϭ motor nerve conduction velocity; PMP22 ϭ peripheral myelin protein 22; SAP ϭ sensory nerve action potential
PubMed, 1991
We undertook clinical evaluation (32 cases) and molecular evaluation (31 cases) of unrelated patients affected with Smith-Magenis syndrome (SMS) associated with an interstitial deletion of band p11.2 of chromosome 17. Patients were evaluated both clinically and electrophysiologically for peripheral neuropathy, since markers showing close linkage to one form of Charcot-Marie-Tooth disease (CMT1A) map to this chromosomal region. The common clinical findings were broad flat midface with brachycephaly, broad nasal bridge, brachydactyly, speech delay, and hoarse, deep voice. Fifty-five percent of the patients showed clinical signs (e.g., decreased or absent deep tendon reflexes, pes planus or pes cavus, decreased sensitivity to pain, and decreased leg muscle mass) suggestive of peripheral neuropathy. However, unlike patients with CMT1A, these patients demonstrated normal nerve conduction velocities. Self-destructive behaviors, primarily onychotillomania and polyembolokoilamania, were observed in 67% of the patients, and significant symptoms of sleep disturbance were observed in 62%. The absence of REM sleep was demonstrated by polysomnography in two patients. Southern analysis indicated that most patients were deleted for five 17p11.2 markers--FG1 (D17S446), 1516 (D17S258), pYNM67-R5 (D17S29), pA10-41 (D17S71), and pS6.1-HB2 (D17S445)--thus defining a region which appears to be critical to SMS. The deletion was determined to be of paternal origin in nine patients and of maternal origin in six patients. The apparent random parental origin of deletion documented in 15 patients suggests that genomic imprinting does not play a role in the expression of the SMS clinical phenotype. Our findings suggest that SMS is likely a contiguous-gene deletion syndrome which comprises characteristic clinical features, developmental delay, clinical signs of peripheral neuropathy, abnormal sleep function, and specific behavioral anomalies.
2002
Charcot-Marie-Tooth (CMT) disease is a typical example of a clinically and genetically heterogeneous disorder and, in most cases, is dominantly inherited and caused by a 1.5 megabase duplication on chromosome 17p11.2 containing the PMP22 gene. This is a non-lethal disease with a wide spectrum of severity, from asymptomatism to severe motor and sensory disability. Unpredictable degree of disability is usually the reason why prenatal diagnosis is required and must be addressed. Molecular procedures such as the use of polymorphic non microsatellite STRs, allowing very fast and reliable results even when requiring a gene dosage interpretation are now available and have been recently validated in post-natal diagnosis. Our results indicate that this approach is also the best-adapted method in case of prenatal diagnosis. Nevertheless, ethical considerations raised by prenatal diagnosis in CMT and more generally in non-lethal disorders remain to be actively considered. Here, we present our experience in genetic counselling, and address the psychological issues for 7 CMT at risk pregnancies. In five cases, a CMT1A duplication was evidenced; pregnancy was terminated in four of these cases and the parents from one affected foetus decided to pursue the pregnancy.
The duplication in Charcot-Marie-Tooth disease type 1a spans at least 1100 kb on chromosome 17p11.2
Human Genetics, 1991
Recently, it has been shown that Charcot-Marie-Tooth disease type la (CMTla) is linked with a duplication of a DNA segment that is detected by probe VAW409R3, and that is located on chromosome 17p11.2. Here, we show that this duplication also contains VAW412R3a, but not A10-41 and EW503. Accounting for the duplication in recombination analysis, we found recombinants between CMTla and EW301 and EW502, but not with A10-41, VAW409R3, and VAW412R3. Using pulsed-field gel electrophoresis analysis, we estimated the minimal size of the duplicated region in CMTla patients to be 1100 kb.
Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients
American Journal of Human Genetics, 1996
Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (i) FISH analysis, (ii) PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (iii) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17pll.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17pll.1-17pll.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS.
Inheritance of CMT1A duplication from a mosaic father
Journal of Medical Genetics, 1995
We describe a case with molecular duplication of chromosome 17 (pll.2-pl2) whose duplicated chromosome was inherited from a mosaic father. The patient has clinical manifestations consistent with Charcot-Marie-Tooth disease type 1A (CMT1A), while the mosaic father has minmal findings of CMT1A. The father was found to be homozygous with DNA markers VAW409R3A (D17S122) and p132G8RI (PMP-22) which are duplicated in CMT1A cases. Fluorescence in situ hybridisation (FISH) analysis with YAC clone 49H7 confirmed the duplication in the affected patient and diagnosed the mosaicism in his father. These findings based on clinical diagnosis and FISH analysis suggest that the mosaicism may have occurred early in embryogenesis leading to the disease in the father. This is the only reported case ofCMT1A with transmission from a mildly affected mosaic father.
Non-radioactive detection of 17p11.2 duplication in CMT1A: a study of 78 patients
Journal of Medical Genetics, 1994
Charcot-Marie-Tooth disease type 1 (CMT1) is a peripheral neuropathy characterised by progressive distal muscular atrophy and sensory loss with markedly decreased nerve conduction velocity, mostly inherited as an autosomal dominant trait. The most common form, type 1A, is associated with a 1.5Mb DNA duplication in region p11.2-p12 of chromosome 17 in many patients. In this study a non-radioactive test for detection of the CMT1A duplication based on an RM11-GT microsatellite polymorphism is presented. Although different methods have been devised for this purpose, the present method has the advantage of being rapid, informative, economical, easily interpretable, and, therefore, it represents a very useful tool for diagnosis of CMT1A, especially before clear manifestation of clinical symptoms. Seventy-eight patients diagnosed clinically as having CMT and evaluated by electrophysiological methods were tested with an RM11-GT microsatellite and with probe pVAW409R3. The CMT1A duplication was found in 76% of the 56 unrelated patients. RM11-GT was the most informative marker with a heterozygosity of 89%.