CACNA1C haploinsufficiency accounts for the common features of interstitial 12p13.33 deletion carriers
Catia MioNadia PassonFederica BaldanElisa BregantElisabetta MonacoLoretta Ilaria ManciniEliana DemoriGiuseppe Damante
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Keywords:
Haploinsufficiency
Proband
Comparative genomic hybridization
Speech delay
Global developmental delay
Human genetics
Monosomy
Haploinsufficiency
Microcephaly
Speech delay
Microdeletion syndrome
Angelman Syndrome
Global developmental delay
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Purpose To determine genetic features of a pediatric uveal melanoma in a 6-year-old girl by array-based comparative genomic hybridization (a-CGH) and assess prognosis, and to search for constitutional copy number variations (CNVs) encompassing oncosuppressor genes. Methods High-resolution a-CGH was performed on genomic DNA from cancer cells and from peripheral blood cells. Histopathology and clinical staging of the tumor were simultaneously assessed. Results Array-based CGH revealed no CNVs on tumor cells associated with poor prognosis; namely, no monosomy 3, losses of 1p, 6q, or 8p, and no gains of 8q. A unique genomic profile was observed, consisting mainly of partial terminal duplications affecting chromosomes 1, 4, 5, 9, 10, 11, 16, and 19, and complete trisomy of chromosomes 6, 7, and 20. The nonmetastatic tumor had predominantly epithelioid histology. No constitutional CNVs encompassing oncosuppressor genes were detected. Conclusions We report a very rare uveal melanoma characterized by low-risk genomic profile and poor prognostic histologic and clinical features. The child is relapse-free at 1-year follow-up. The unusual CNVs detected by a-CGH suggest specific pathogenic mechanisms.
Comparative genomic hybridization
Monosomy
Histopathology
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Monosomy
Comparative genomic hybridization
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We report a two-generation family with four females harboring an 8.5Mb heterozygous deletion of 5q15-q21.2 who present with dysmorphic craniofacial features and speech delay. We hypothesize haploinsufficiency of CHD1 to be contributing to the clinical features observed in this family.
Haploinsufficiency
Facial dysmorphism
Speech delay
Gene deletion
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Haploinsufficiency
Speech delay
Global developmental delay
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Haploinsufficiency
Monosomy
Hypoparathyroidism
DiGeorge syndrome
Chromosomal region
Human genetics
Aplasia
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Eleven uveal melanomas were analyzed using comparative genomic hybridization (CGH). The most abundant genetic changes were loss of chromosome 3, overrepresentation of 6p, loss of 6q, and multiplication of 8q. The smallest overrepresented regions on 6p and 8q were 6pter-->p21 and 8q24-->qter, respectively. Several additional gains and losses of chromosome segments were repeatedly observed, the most frequent one being loss of 9p (three cases). Monosomy 3 appeared to be a marker for ciliary body involvement. CGH data were compared with the results of chromosome banding. Some alterations, e.g., gains of 6p and losses of 6q, were observed with higher frequencies after CGH, while others, e.g., 9p deletions, were detected only by CGH. The data suggest some similarities of cytogenetic alterations between cutaneous and uveal melanoma. In particular, the 9p deletions are of interest due to recent reports about the location of a putative tumor-suppressor gene for cutaneous malignant melanoma in this region.
Comparative genomic hybridization
Monosomy
Chromosome 3
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Comparative genomic hybridization
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Partial monosomy 10p is a rare chromosomal condition and a significant proportion of patients show features of DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). A critical haploinsufficiency region for DGS/VCFS was defined on 10p (DGCR2). We performed molecular deletion analysis of two further patients with partial monosomy 10p, who showed hypoparathyroidism, deafness, and renal dysplasia or renal insufficiency, but no cardiac defect, cleft palate, or reduced T cell levels. Previously, the combination of hypoparathyroidism, deafness, and renal dysplasia has been proposed to represent a specific syndrome (MIM 146255) under the acronym HDR. In addition to the two patients in this report, at least four published cases with partial monosomy 10p show the triad of HDR and 14 other patients present with at least two of the three features. We therefore conclude that HDR syndrome can be associated with partial monosomy 10p. Based on molecular deletion analysis and the clinical data, we suggest that the DGS/VCFS phenotype associated with 10p deletion can be considered as a contiguous gene syndrome owing to haploinsufficiency of two different regions. Hemizygosity of the proximal region, designatedDGCR2, can cause cardiac defect and T cell deficiency. Hemizygosity of the distal region, designatedHDR1, can cause hypoparathyroidism and in addition sensorineuronal deafness and renal dysplasia/insufficiency or a subset of this triad.
Haploinsufficiency
DiGeorge syndrome
Monosomy
Hypoparathyroidism
Renal dysplasia
Hypertelorism
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Comparative genomic hybridization
Monosomy
Falx cerebri
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