Precise mapping of a de novo duplication 18(q21→q22) utilizing cytogenetic, biochemical, and molecular techniques

Wolff, Daynna J.; Schwartz, Marcia; Cohen, Maimon M.; Schwartz, Stuart

doi:10.1002/ajmg.1320460512

Cited by 15 publications

(11 citation statements)

References 16 publications

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“…Attempts at karyotype-phenotype correlations based on a limited number of unrelated patients with (almost) similar chromosomal imbalances have often been unsuccessful and therefore must be viewed with caution (Wilson et al 1990). Triplicated chromosomal segments appear not to be autonomous in producing the phenotypic manifestations (Wilson et al 1990;Mewar et al 1993;Wolff et al 1993;Boghosian-Sell et al 1994). To our knowledge, only seven patients with duplications of the proximal region of the long arm of chromosome 18 have been reported.…”

Section: Discussionmentioning

confidence: 94%

Noonan-like phenotype in monozygotic twins with a duplication-deficiency of the long arm of chromosome 18 resulting from a maternal paracentric inversion

et al. 1998

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We report on newborn monozygotic twins with a Noonan-like phenotype, and multiple congenital anomalies due to a monocentric recombinant chromosome 18. The mother carried a paracentric inversion of the long arm of chromosome 18, inv(18)(q21.1q22.3). Cytogenetic, fluorescent in situ hybridization, comparative genomic hybridization and DNA marker analyses allowed the delineation of the deleted (18q22.3-qter) and duplicated (18q12.1-q21.1) chromosomal regions in the recombinant chromosome 18, and suggest that this duplication-deletion chromosome 18 resulted from breakage of a dicentric recombinant chromosome 18 with subsequent reconstitution of telomeric sequences on the long arm. Marked variability is observed in the phenotypic expression of the same chromosomal anomaly in these monozygotic twins. The clinical findings of these patients are compared with those reported in proximal 18q-duplication and distal 18q-deletion patients. The clinical features of both infants are compatible with Noonan syndrome, suggesting that a locus for this syndrome may be located on the long arm of chromosome 18.

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Section: Discussionmentioning

confidence: 94%

Noonan-like phenotype in monozygotic twins with a duplication-deficiency of the long arm of chromosome 18 resulting from a maternal paracentric inversion

et al. 1998

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“…In these cases patients display manifestations ranging from a relatively mild to a severe phenotype. Genotype-phenotype correlations have suggested that duplication of regions (18)(q12.1q21.2) is critical for the trisomy 18 phenotype [9,10], while the relationship between duplication of the other 18q regions and mental retardation, growth delay, and dysmorphism is less clear. Our patient displayed only mild dysmorphic features and speech delay.…”

Section: Discussionmentioning

confidence: 99%

The use of array-CGH in a cohort of Greek children with developmental delay

Manolakos

Vetro

Kefalas³

et al. 2010

Mol Cytogenet

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BackgroundThe genetic diagnosis of mental retardation (MR) is difficult to establish and at present many cases remain undiagnosed and unexplained. Standard karyotyping has been used as one of the routine techniques for the last decades. The implementation of Array Comparative Genomic Hybridization (array-CGH) has enabled the analysis of copy number variants (CNVs) with high resolution. Major cohort studies attribute 11% of patients with unexplained mental retardation to clinically significant CNVs. Here we report the use of array-CGH for the first time in a Greek cohort. A total of 82 children of Greek origin with mean age 4.9 years were analysed in the present study. Patients with visible cytogenetic abnormalities ascertained by standard karyotyping as well as those with subtelomeric abnormalities determined by Multiplex Ligation-dependent Probe Amplification (MLPA) or subtelomeric FISH had been excluded.ResultsFourteen CNVs were detected in the studied patients. In nine patients (11%) the chromosomal aberrations were inherited from one of the parents. One patients showed two duplications, a 550 kb duplication in 3p14.1 inherited from the father and a ~1.1 Mb duplication in (22)(q13.1q13.2) inherited from the mother. Although both parents were phenotypically normal, it cannot be excluded that the dual duplication is causative for the patient's clinical profile including dysmorphic features and severe developmental delay. Furthermore, three de novo clinically significant CNVs were detected (3.7%). There was a ~6 Mb triplication of 18q21.1 in a girl 5 years of age with moderate MR and mild dysmorphic features and a ~4.8 Mb duplication at (10)(q11.1q11.21) in a 2 years old boy with severe MR, multiple congenital anomalies, severe central hypotonia, and ataxia. Finally, in a 3 year-old girl with microcephaly and severe hypotonia a deletion in (2)(q31.2q31.3) of about ~3.9 Mb was discovered. All CNVs were confirmed by Fluorescence in situ hybridization (FISH). For the remaining 9 patients the detected CNVs (inherited duplications or deletions of 80 kb to 800 kb in size) were probably not associated with the clinical findings.ConclusionsGenomic microarrays have within the recent years proven to be a highly useful tool in the investigation of unexplained MR. The cohorts reported so far agree on an around 11% diagnostic yield of clinically significant CNVs in patients with unexplained MR. Various publicly available databases have been created for the interpretation of identified CNVs and parents are analyzed in case a rare CNV is identified in the child. We have conducted a study of Greek patients with unexplained MR and confirmed the high diagnostic value of the previous studies. It is important that the technique becomes available also in less developed countries when the cost of consumables will be reduced.

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“…Duplications of 18q21 ! 18q22 give rise to a mild phenotype [Wolf et al, 1993] in comparison to other 18q duplications [Erlich et al, 1983]. To this date, no duplication of 18q has been reported involving only 18q23 !…”

Section: Introductionmentioning

confidence: 97%

Array‐based comparative genomic hybridization facilitates identification of breakpoints of a novel der(1)t(1;18)(p36.3;q23)dn in a child presenting with mental retardation

Lennon

Cooper

Curtis

et al. 2006

American J of Med Genetics Pt A

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Monosomy of distal 1p36 represents the most common terminal deletion in humans and results in one of the most frequently diagnosed mental retardation syndromes. This deletion is considered a contiguous gene deletion syndrome, and has been shown to vary in deletion sizes that contribute to the spectrum of phenotypic anomalies seen in patients with monosomy 1p36. We report on an 8-year-old female with characteristics of the monosomy 1p36 syndrome who demonstrated a novel der(1)t(1;18)(p36.3;q23). Initial G-banded karyotype analysis revealed a deleted chromosome 1, with a breakpoint within 1p36.3. Subsequent FISH and array-based comparative genomic hybridization not only confirmed and partially characterized the deletion of chromosome 1p36.3, but also uncovered distal trisomy for 18q23. In this patient, the duplicated 18q23 is translocated onto the deleted 1p36.3 region, suggesting telomere capture. Molecular characterization of this novel der(1)t(1;18)(p36.3;q23), guided by our clinical array-comparative genomic hybridization, demonstrated a 3.2 Mb terminal deletion of chromosome 1p36.3 and a 200 kb duplication of 18q23 onto the deleted 1p36.3, presumably stabilizing the deleted chromosome 1. DNA sequence analysis around the breakpoints demonstrated no homology, and therefore this telomere capture of distal 18q is apparently the result of a non-homologous recombination. Partial trisomy for 18q23 has not been previously reported. The importance of mapping the breakpoints of all balanced and unbalanced translocations found in the clinical laboratory, when phenotypic abnormalities are found, is discussed.

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Precise mapping of a de novo duplication 18(q21→q22) utilizing cytogenetic, biochemical, and molecular techniques

Cited by 15 publications

References 16 publications

Noonan-like phenotype in monozygotic twins with a duplication-deficiency of the long arm of chromosome 18 resulting from a maternal paracentric inversion

Noonan-like phenotype in monozygotic twins with a duplication-deficiency of the long arm of chromosome 18 resulting from a maternal paracentric inversion

The use of array-CGH in a cohort of Greek children with developmental delay

Array‐based comparative genomic hybridization facilitates identification of breakpoints of a novel der(1)t(1;18)(p36.3;q23)dn in a child presenting with mental retardation

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