An interstitial deletion of about 12 Mb at 7q33eq36 was found in an adult female affected by auti... more An interstitial deletion of about 12 Mb at 7q33eq36 was found in an adult female affected by autism and primary amenorrhea. Two genes, CNTNAP2 and NOBOX, both contained within the deletion region, have been recently associated with autism susceptibility and premature ovarian failure, respectively. Our findings reinforce the hypothesis that haploinsufficiency of both these genes is sufficient for autism development and occurrence of primary amenorrhea, confirming a previous case in which CNTNAP2 had been disrupted by a chromosome inversion and possibly enlarging the phenotype of ovarian function disturbances already demonstrated for NOBOX mutations.
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
In situ hybridization of a telomeric (TTA-GGG)n sequence to metaphases from three cases of ring c... more In situ hybridization of a telomeric (TTA-GGG)n sequence to metaphases from three cases of ring chromosome, involving respectively chromosomes 4, 16, and 20, showed the presence of the cognate sequences in all three rings. To investigate whether these ring chromosomes originated by telomere-telomere fusion, we determined, by in situ hybridization, whether telomere-associated sequences and/or specific distal sequences were still present in the ring chromosomes. The finding that these sequences were preserved in all the ring chromosomes strongly indicates that they originated by telomere-telomere fusion. All three subjects carrying the ring chromosomes are affected by the so-called ring syndrome, with failure to thrive, minor dysmorphic signs and no major anomalies. The r(4) patient has the ring in mosaic form with a normal cell line and has normal intelligence. The r(16) and the r(20) patients have moderate mental retardation and suffer from seizures. We conclude that the ring syndrome, even in its more severe manifestation, is caused by ring chromosome instability.
cq-acid glycoprotein (ORM1) were found in a girl with a deletion 9q32-qter secondary to a materna... more cq-acid glycoprotein (ORM1) were found in a girl with a deletion 9q32-qter secondary to a maternal translocation (4@5; 9q32), thus excluding these loci from the deleted region. These results, and comparison with other informative data, map the locus for AK-1 to 9q32 and that for ORM1 to region 9q31-q32. The girl has several signs of the Goltz syndrome (focal dermal hypoplasia), which is listed in the McKusick catalog (no. 30560) as an X-linked dominant condition. Our finding indicates that the locus for Golz syndrome is autosomal and in region 9q32-qter or that there are two such conditions, one autosomal and one X-linked.
SOX9 is a widely expressed transcription factor playing several relevant functions during develop... more SOX9 is a widely expressed transcription factor playing several relevant functions during development and essential for testes differentiation. It is considered to be the direct target gene of the protein encoded by SRY and its overexpression in an XX murine gonad can lead to male development in the absence of Sry. Recently, a family was reported with a 178 kb duplication in the gene desert region ending about 500 kb upstream of SOX9 in which 46,XY duplicated persons were completely normal and fertile whereas the 46,XX ones were males who came to clinical attention because of infertility.
Background: Partial deletion of chromosome 21q is a very rare chromosomal abnormality associated ... more Background: Partial deletion of chromosome 21q is a very rare chromosomal abnormality associated with highly variable phenotypes, such as facial dysmorphic features, heart defects, seizures, psychomotor delay, and severe to mild intellectual disability, depending on the location and size of deletions. So far, three broad deletion regions of 21q have been correlated with the clinical phenotype. Results: We described the clinical and genetic features of three family members (father and two siblings) and other two unrelated patients with very wide range in age of diagnosis. All of them showed intellectual disability with very variable symptoms, from mild to severe, and carried 21q interstitial deletions with different sizes and position, as detected by conventional karyotype and array-CGH. Conclusions: Our study provided additional cases of partial 21q deletions, allowing to better delineate the genotypephenotype correlations. In contrast to previous observations, we showed that deletions of the 21q proximal region are not necessarily associated with severe phenotypes and, therefore, that mild phenotypes are not exclusively related to distal deletions. To the best of our knowledge, this is the first report showing 21q deletions in adult patients associated with mild phenotypes, mainly consisting of neurobehavioral abnormalities, such as obsessive-compulsive disorders, poor social interactions and vulnerability to psychosis.
Phelan-McDermid syndrome (PMS) is caused by SHANK3 haploinsufficiency. Its wide phenotypic variat... more Phelan-McDermid syndrome (PMS) is caused by SHANK3 haploinsufficiency. Its wide phenotypic variation is attributed partly to the type and size of 22q13 genomic lesion (deletion, unbalanced translocation, ring chromosome), partly to additional undefined factors. We investigated a child with severe global neurodevelopmental delay (NDD) compatible with her distal 22q13 deletion, complicated by bilateral perisylvian polymicrogyria (BPP) and urticarial rashes, unreported in PMS. Following the cytogenetic and array-comparative genomic hybridization (CGH) detection of a r(22) with SHANK3 deletion and two upstream duplications, whole-genome sequencing (WGS) in blood and whole-exome sequencing (WES) in blood and saliva were performed to highlight potential chromothripsis/chromoanagenesis events and any possible BPP-associated variants, even in low-level mosaicism. WGS confirmed the deletion and highlighted inversion and displaced order of eight fragments, three of them duplicated. The microh...
We describe a novel rearranged human Y chromosome consisting of an inverted duplication of the lo... more We describe a novel rearranged human Y chromosome consisting of an inverted duplication of the long arm heterochromatin and a small amount of euchromatin: rea(Y)(qter-q11.2::q11.2-qter). The normal centromere has been deleted and a neocentromere containing CENP-A,-C,-E and Mad2 but not CENP-B has formed close to the breakpoint. A 2.7 Mb yeast artificial chromosome contig spanning the breakpoint was constructed and the breakpoint was localised to a region of <120 kb close to the DAZ gene cluster. Combined immunofluorescence and fluorescence in situ hybridisation showed that the centromeric proteinbinding domain of the neocentromere was located near the breakpoint and within the DAZ cluster.
The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been r... more The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)-gene clusters are located close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms in the evolution and pathology of the human genome.
A 69,XXX female liveborn triploid survived 45 days. The phenotype was consistent with the average... more A 69,XXX female liveborn triploid survived 45 days. The phenotype was consistent with the average clinical picture of liveborn triploids. Autopsy revealed slight atrophy of cerebral cortex and corpus callosum and severe adrenal hypoplasia. Chromosome polymorphisms indicated that the origin of this triploid was dispermy. Replication studies of the X chromosome performed on lymphocytes and fibroblasts showed that the majority of cells had two late replicating X chromosomes. X chromosome inactivation in spontaneous abortuses and liveborn triploids is discussed. Nine enzymes encoded by autosomal genes were tested, five had normal, three increased, and one reduced levels of activity. The reduced activity of alpha-galactosidase, an X-linked enzyme, is in agreement with cytogenetic findings and demonstrated a gene dosage effect.
The Y chromosome plays a determinant rôle in human maleness. Studies on individuals with sex chro... more The Y chromosome plays a determinant rôle in human maleness. Studies on individuals with sex chromosome abnormalities indicate that a testis determining factor (TDF) is located on the short arm of the Y chromosome. A candidate gene, recently cloned, encodes a protein with multiple &quot;finger&quot; domains of a type known to bind DNA and control transcription. The puzzling finding that on the short arm of the X chromosome is located and homolog gene escaping X inactivation raises problems on the functional relationship of the two genes. The whole of the molecular studies using Y-specific probes have shown that XX males result from the transposition of TDF from the short arm of the Y to that of X chromosome; at least some XY females result from the same transposition, that leaves the Y chromosome without its distal short arm, TDF included. In XO males, the TDF is translocated to an autosome; according to the deletion of the latter, different malformation patterns may be present in these patients. If the presence or the absence of a critical segment of the Y chromosome do explain many instances of sex several, an outstanding problem is still represented by XX hermaphrodites since no Y-specific sequences have been found in their genome. Thus although the Y-chromosome testis- determining factor seems to play a pivotal rôle in sex determination, testicular tissue can be formed in the absence of it.
An interstitial deletion of about 12 Mb at 7q33eq36 was found in an adult female affected by auti... more An interstitial deletion of about 12 Mb at 7q33eq36 was found in an adult female affected by autism and primary amenorrhea. Two genes, CNTNAP2 and NOBOX, both contained within the deletion region, have been recently associated with autism susceptibility and premature ovarian failure, respectively. Our findings reinforce the hypothesis that haploinsufficiency of both these genes is sufficient for autism development and occurrence of primary amenorrhea, confirming a previous case in which CNTNAP2 had been disrupted by a chromosome inversion and possibly enlarging the phenotype of ovarian function disturbances already demonstrated for NOBOX mutations.
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
In situ hybridization of a telomeric (TTA-GGG)n sequence to metaphases from three cases of ring c... more In situ hybridization of a telomeric (TTA-GGG)n sequence to metaphases from three cases of ring chromosome, involving respectively chromosomes 4, 16, and 20, showed the presence of the cognate sequences in all three rings. To investigate whether these ring chromosomes originated by telomere-telomere fusion, we determined, by in situ hybridization, whether telomere-associated sequences and/or specific distal sequences were still present in the ring chromosomes. The finding that these sequences were preserved in all the ring chromosomes strongly indicates that they originated by telomere-telomere fusion. All three subjects carrying the ring chromosomes are affected by the so-called ring syndrome, with failure to thrive, minor dysmorphic signs and no major anomalies. The r(4) patient has the ring in mosaic form with a normal cell line and has normal intelligence. The r(16) and the r(20) patients have moderate mental retardation and suffer from seizures. We conclude that the ring syndrome, even in its more severe manifestation, is caused by ring chromosome instability.
cq-acid glycoprotein (ORM1) were found in a girl with a deletion 9q32-qter secondary to a materna... more cq-acid glycoprotein (ORM1) were found in a girl with a deletion 9q32-qter secondary to a maternal translocation (4@5; 9q32), thus excluding these loci from the deleted region. These results, and comparison with other informative data, map the locus for AK-1 to 9q32 and that for ORM1 to region 9q31-q32. The girl has several signs of the Goltz syndrome (focal dermal hypoplasia), which is listed in the McKusick catalog (no. 30560) as an X-linked dominant condition. Our finding indicates that the locus for Golz syndrome is autosomal and in region 9q32-qter or that there are two such conditions, one autosomal and one X-linked.
SOX9 is a widely expressed transcription factor playing several relevant functions during develop... more SOX9 is a widely expressed transcription factor playing several relevant functions during development and essential for testes differentiation. It is considered to be the direct target gene of the protein encoded by SRY and its overexpression in an XX murine gonad can lead to male development in the absence of Sry. Recently, a family was reported with a 178 kb duplication in the gene desert region ending about 500 kb upstream of SOX9 in which 46,XY duplicated persons were completely normal and fertile whereas the 46,XX ones were males who came to clinical attention because of infertility.
Background: Partial deletion of chromosome 21q is a very rare chromosomal abnormality associated ... more Background: Partial deletion of chromosome 21q is a very rare chromosomal abnormality associated with highly variable phenotypes, such as facial dysmorphic features, heart defects, seizures, psychomotor delay, and severe to mild intellectual disability, depending on the location and size of deletions. So far, three broad deletion regions of 21q have been correlated with the clinical phenotype. Results: We described the clinical and genetic features of three family members (father and two siblings) and other two unrelated patients with very wide range in age of diagnosis. All of them showed intellectual disability with very variable symptoms, from mild to severe, and carried 21q interstitial deletions with different sizes and position, as detected by conventional karyotype and array-CGH. Conclusions: Our study provided additional cases of partial 21q deletions, allowing to better delineate the genotypephenotype correlations. In contrast to previous observations, we showed that deletions of the 21q proximal region are not necessarily associated with severe phenotypes and, therefore, that mild phenotypes are not exclusively related to distal deletions. To the best of our knowledge, this is the first report showing 21q deletions in adult patients associated with mild phenotypes, mainly consisting of neurobehavioral abnormalities, such as obsessive-compulsive disorders, poor social interactions and vulnerability to psychosis.
Phelan-McDermid syndrome (PMS) is caused by SHANK3 haploinsufficiency. Its wide phenotypic variat... more Phelan-McDermid syndrome (PMS) is caused by SHANK3 haploinsufficiency. Its wide phenotypic variation is attributed partly to the type and size of 22q13 genomic lesion (deletion, unbalanced translocation, ring chromosome), partly to additional undefined factors. We investigated a child with severe global neurodevelopmental delay (NDD) compatible with her distal 22q13 deletion, complicated by bilateral perisylvian polymicrogyria (BPP) and urticarial rashes, unreported in PMS. Following the cytogenetic and array-comparative genomic hybridization (CGH) detection of a r(22) with SHANK3 deletion and two upstream duplications, whole-genome sequencing (WGS) in blood and whole-exome sequencing (WES) in blood and saliva were performed to highlight potential chromothripsis/chromoanagenesis events and any possible BPP-associated variants, even in low-level mosaicism. WGS confirmed the deletion and highlighted inversion and displaced order of eight fragments, three of them duplicated. The microh...
We describe a novel rearranged human Y chromosome consisting of an inverted duplication of the lo... more We describe a novel rearranged human Y chromosome consisting of an inverted duplication of the long arm heterochromatin and a small amount of euchromatin: rea(Y)(qter-q11.2::q11.2-qter). The normal centromere has been deleted and a neocentromere containing CENP-A,-C,-E and Mad2 but not CENP-B has formed close to the breakpoint. A 2.7 Mb yeast artificial chromosome contig spanning the breakpoint was constructed and the breakpoint was localised to a region of <120 kb close to the DAZ gene cluster. Combined immunofluorescence and fluorescence in situ hybridisation showed that the centromeric proteinbinding domain of the neocentromere was located near the breakpoint and within the DAZ cluster.
The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been r... more The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)-gene clusters are located close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms in the evolution and pathology of the human genome.
A 69,XXX female liveborn triploid survived 45 days. The phenotype was consistent with the average... more A 69,XXX female liveborn triploid survived 45 days. The phenotype was consistent with the average clinical picture of liveborn triploids. Autopsy revealed slight atrophy of cerebral cortex and corpus callosum and severe adrenal hypoplasia. Chromosome polymorphisms indicated that the origin of this triploid was dispermy. Replication studies of the X chromosome performed on lymphocytes and fibroblasts showed that the majority of cells had two late replicating X chromosomes. X chromosome inactivation in spontaneous abortuses and liveborn triploids is discussed. Nine enzymes encoded by autosomal genes were tested, five had normal, three increased, and one reduced levels of activity. The reduced activity of alpha-galactosidase, an X-linked enzyme, is in agreement with cytogenetic findings and demonstrated a gene dosage effect.
The Y chromosome plays a determinant rôle in human maleness. Studies on individuals with sex chro... more The Y chromosome plays a determinant rôle in human maleness. Studies on individuals with sex chromosome abnormalities indicate that a testis determining factor (TDF) is located on the short arm of the Y chromosome. A candidate gene, recently cloned, encodes a protein with multiple &quot;finger&quot; domains of a type known to bind DNA and control transcription. The puzzling finding that on the short arm of the X chromosome is located and homolog gene escaping X inactivation raises problems on the functional relationship of the two genes. The whole of the molecular studies using Y-specific probes have shown that XX males result from the transposition of TDF from the short arm of the Y to that of X chromosome; at least some XY females result from the same transposition, that leaves the Y chromosome without its distal short arm, TDF included. In XO males, the TDF is translocated to an autosome; according to the deletion of the latter, different malformation patterns may be present in these patients. If the presence or the absence of a critical segment of the Y chromosome do explain many instances of sex several, an outstanding problem is still represented by XX hermaphrodites since no Y-specific sequences have been found in their genome. Thus although the Y-chromosome testis- determining factor seems to play a pivotal rôle in sex determination, testicular tissue can be formed in the absence of it.
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