Niels Tommerup - Academia.edu (original) (raw)

Papers by Niels Tommerup

Research paper thumbnail of Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes

Journal of medical genetics, 2014

Recently, a number of patients have been described with structural rearrangements at 3q13.31, del... more Recently, a number of patients have been described with structural rearrangements at 3q13.31, delineating a novel microdeletion syndrome with common clinical features including developmental delay and other neurodevelopmental disorders (NDD). A smallest region of overlapping deletions (SRO) involved five RefSeq genes, including the transcription factor gene ZBTB20 and the dopamine receptor gene DRD3, considered as candidate genes for the syndrome. We used array comparative genomic hybridization and next-generation mate-pair sequencing to identify key structural rearrangements involving ZBTB20 in two patients with NDD. In a patient with developmental delay, attention-deficit hyperactivity disorder, psychosis, Tourette's syndrome and autistic traits, a de novo balanced t(3;18) translocation truncated ZBTB20. The other breakpoint did not disrupt any gene. In a second patient with developmental delay and autism, we detected the first microdeletion at 3q13.31, which truncated ZBTB20 ...

Research paper thumbnail of Not para-, not peri-, but centric inversion of chromosome 12

Journal of Medical Genetics, 1998

Research paper thumbnail of New assignment of the adenosine deaminase gene locus to chromosome 20q13 X 11 by study of a patient with interstitial deletion 20q

Journal of Medical Genetics, 1987

Research paper thumbnail of Non-disjunction of chromosome 18

Human Molecular Genetics, 1998

We performed a molecular study with 21 microsatellites on a sample of 82 trisomy 13 conceptuses, ... more We performed a molecular study with 21 microsatellites on a sample of 82 trisomy 13 conceptuses, the largest number of cases studied to date. The parental origin was determined in every case and in 89% the extra chromosome 13 was of maternal origin with an almost equal number of maternal MI and MII errors. The latter finding is unique among human autosomal trisomies, where maternal MI (trisomies 15, 16, 21, 22) or MII (trisomy 18) errors dominate. Of the nine paternally derived cases five were of MII origin but none arose from MI errors. There was some evidence for elevated maternal age in cases with maternal meiotic origin for liveborn infants. Maternal and paternal ages were elevated in cases with paternal meiotic origin. This is in contrast to results from a similar study of non-disjunction of trisomy 21 where paternal but not maternal age was elevated. We find clear evidence for reduced recombination in both maternal MI and MII errors and the former is associated with a significant number of tetrads (33%) that are nullichiasmate, which do not appear to be a feature of normal chromosome 13 meiosis. This study supports the evidence for subtle chromosome-specific influences on the mechanisms that determine non-disjunction of human chromosomes, consistent with the diversity of findings for other trisomies.

Research paper thumbnail of Non-disjunction of chromosome 13

Human Molecular Genetics, 2007

Research paper thumbnail of Structural genomic variation in childhood epilepsies with complex phenotypes

European Journal of Human Genetics, 2013

Research paper thumbnail of Characterization of a t(5;8)(q31;q21) translocation in a patient with mental retardation and congenital heart disease: implications for involvement of RUNX1T1 in human brain and heart development

European Journal of Human Genetics, 2009

Research paper thumbnail of MECP2 mutations in Danish patients with Rett syndrome: High frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern

European Journal of Human Genetics, 2001

Research paper thumbnail of The strength of combined cytogenetic and mate-pair sequencing techniques illustrated by a germline chromothripsis rearrangement involving FOXP2

European Journal of Human Genetics, 2013

Next-generation mate-pair sequencing (MPS) has revealed that many constitutional complex chromoso... more Next-generation mate-pair sequencing (MPS) has revealed that many constitutional complex chromosomal rearrangements (CCRs) are associated with local shattering of chromosomal regions (chromothripsis). Although MPS promises to identify the molecular basis of the abnormal phenotypes associated with many CCRs, none of the reported mate-pair sequenced complex rearrangements have been simultaneously studied with state-of-the art molecular cytogenetic techniques. Here, we studied chromothripsis-associated CCR involving chromosomes 2, 5 and 7, associated with global developmental and psychomotor delay and severe speech disorder. We identified three truncated genes: CDH12, DGKB and FOXP2, confirming the role of FOXP2 in severe speech disorder, and suggestive roles of CDH12 and/or DGKB for the global developmental and psychomotor delay. Our study confirmes the power of MPS for detecting breakpoints and truncated genes at near nucleotide resolution in chromothripsis. However, only by combining MPS data with conventional G-banding and extensive fluorescence in situ hybridizations could we delineate the precise structure of the derivative chromosomes.

Research paper thumbnail of Identification of positional candidates for neurological disorders on chromosome 13q14→q22

Cytogenetic and Genome Research, 1997

In the course of a research project aimed at the molecular characterization of balanced chromosom... more In the course of a research project aimed at the molecular characterization of balanced chromosome rearrangements associated with mental retardation (MR), several YACs spanning MR-associated chromosomal rearrangements in the 13q14→q22 region were identified. To facilitate the search for relevant candidate genes, we have analyzed a total of 102 EST clones from this region. Sequence comparisons revealed that these 102 clones represent up to 72 distinct transcripts. When no physical mapping data were available, a minimal YAC contig was screened for each unique transcript by the polymerase chain reaction (PCR) or hybridization. Fifty-eight independent ESTs could be localized to YAC clones between the markers D13S1248 and DBS1201. Several ESTs are located on YAC clones detecting chromosomal rearrangements in MR patients. One EST was mapped within the critical region for Rieger syndrome type 2, and three transcripts were identified in the region for the nocturnal enuresis type 1. Some EST...

Research paper thumbnail of Search for late onset diseases among carriers of balanced chromosomal rearrangements

Research paper thumbnail of Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes

American journal of human genetics, Jun 17, 2018

The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected... more The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19.5% versus 8.3%, p = 0.04), which was increased to 26.8% upon clinical follow-up. Chromosomal microarray of 32 carriers revealed no pathogenic imbalances, illustrating a low prognostic value when fetal ultrasound scan is normal. In contrast, mate-pair sequencing revealed disrupted genes (ARID1B, NPAS3, CELF4), regulatory domains of known developmental genes (ZEB2, HOXC), and complex BCRs associated with adverse outcomes. Seven unmappable autosomal-autosomal BCRs ...

Research paper thumbnail of Wirth, J. et al. Systematic characterisation of disease associated balanced chromosome rearrangements by FISH: cytogenetically and genetically anchored YACs identify microdeletions and candidate regions for mental retardation genes. J. Med. Genet. 36, 271-278

Journal of Medical Genetics

Disease associated balanced chromosome rearrangements (DBCRs) have been instrumental in the isola... more Disease associated balanced chromosome rearrangements (DBCRs) have been instrumental in the isolation of many disease genes. To facilitate the molecular cytogenetic characterisation of DBCRs, we have generated a set of >1200 nonchimeric, cytogenetically and genetically anchored CEPH YACs, on average one per 3 cM, spaced over the entire human genome. By fluorescence in situ hybridisation (FISH), we have performed a systematic search for YACs spanning translocation breakpoints. Patients with DBCRs and either syndromic or nonsyndromic mental retardation (MR) were ascertained through the Mendelian Cytogenetics Network (MCN), a collaborative eVort of, at present, 270 cytogenetic laboratories throughout the world. In this pilot study, we have characterised 10 diVerent MR associated chromosome regions delineating candidate regions for MR. Five of these regions are narrowed to breakpoint spanning YACs, three of which are located on chromosomes 13q21, 13q22, and 13q32, respectively, one on chromosome 4p14, and one on 6q25. In two out of six DBCRs, we found cytogenetically cryptic deletions of 3-5 Mb on one or both translocation chromosomes. Thus, cryptic deletions may be an important cause of disease in seemingly balanced chromosome rearrangements that are associated with a disease phenotype. Our region specific FISH probes, which are available to MCN members, can be a powerful tool in clinical cytogenetics and positional cloning.

Research paper thumbnail of Dysregulation of FOXG1 by ring chromosome 14

Molecular Cytogenetics, 2015

In this study we performed molecular characterization of a patient with an extra ring chromosome ... more In this study we performed molecular characterization of a patient with an extra ring chromosome derived from chromosome 14, with severe intellectual disability, epilepsy, cerebral paresis, tetraplegia, osteoporosis and severe thoraco-lumbal scoliosis. Array CGH analysis did not show any genomic imbalance but conventional karyotyping and FISH analysis revealed the presence of an interstitial 14q12q24.3 deletion and an extra ring chromosome derived from the deleted material. The deletion and ring chromosome breakpoints were identified at base-pair level by mate-pair and Sanger sequencing. Both breakpoints disrupted putative long non-coding RNA genes (TCONS00022561;RP11-148E17.1) of unknown function. However, the proximal breakpoint was 225 kb downstream of the forkhead box G1 gene (FOXG1), within the known regulatory landscape of FOXG1. The patient represents the first case of a r(14) arising from an interstitial excision where the phenotype is compatible with dysregulation of FOXG1. In turn, the phenotypic overlap between the present case, the FOXG1 syndrome and the r(14) syndrome supports that dysregulation of FOXG1 may contribute to the classical r(14)-syndrome, likely mediated by dynamic mosaicism.

Research paper thumbnail of Subtelomeric study of 132 patients with mental retardation reveals 9 chromosomal anomalies and contributes to the delineation of submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter

BMC medical genetics, Jan 17, 2005

Cryptic chromosome imbalances are increasingly acknowledged as a cause for mental retardation and... more Cryptic chromosome imbalances are increasingly acknowledged as a cause for mental retardation and learning disability. New phenotypes associated with specific rearrangements are also being recognized. Techniques for screening for subtelomeric rearrangements are commercially available, allowing the implementation in a diagnostic service laboratory. We report the diagnostic yield in a series of 132 subjects with mental retardation, and the associated clinical phenotypes. We applied commercially available subtelomeric fluorescence in situ hybridization (FISH). All patients referred for subtelomeric screening in a 5-year period were reviewed and abnormal cases were further characterized clinically and if possible molecularly. We identified nine chromosomal rearrangements (two of which were in sisters) corresponding to a diagnostic yield of approx. 7%. All had dysmorphic features. Five had imbalances leading to recognizable phenotypes. Subtelomeric screening is a useful adjunct to conven...

Research paper thumbnail of Sex dependent transmission of Beckwith-Wiedemann syndrome associated with a reciprocal translocation t(9;11)(p11.2;p15.5)

Journal of Medical Genetics, 1993

Beckwith-Wiedemann syndrome (BWS), a disorder associated with neonatal hypoglycaemia, increased g... more Beckwith-Wiedemann syndrome (BWS), a disorder associated with neonatal hypoglycaemia, increased growth potential, and predisposition to Wilms's tumour (WT) and other malignancies, has been mapped to llpl5. The association with llpl5 duplications of paternal origin, of balanced translocations and inversions with breakpoints within llpl5.4-pl5.5 of maternal origin, and the demonstration of uniparental paternal llpl5 isodisomy in some sporadic cases point towards the involvement of genomic imprinting. In agreement with this, we show the paternal origin of a de novo 9;11 translocation in a phenotypically normal mother, whose carrier daughter developed BWS. This supports the fact that BWS associated with balanced chromosome mutations is transmitted in the same sex dependent pattern as non-cytogenetic forms of familial BWS.

Research paper thumbnail of Pierre Robin sequence may be caused by dysregulation of SOX9 and KCNJ2

Journal of Medical Genetics, 2007

Research paper thumbnail of Early onset, non-progressive, mild cerebellar ataxia co-segregating with a familial balanced translocation t(8;20)(p22;q13)

Journal of Medical Genetics, 2004

Research paper thumbnail of A cytogenetic survey in Menkes disease: implications for the detection of chromosomal rearrangements in X linked disorders

Journal of Medical Genetics, 1993

Research paper thumbnail of Constitutional ring chromosomes and tumour suppressor genes

Journal of Medical Genetics, 1992

The types of malignancy reported in carriers of constitutional ring chromosomes r(1), r(l3), and ... more The types of malignancy reported in carriers of constitutional ring chromosomes r(1), r(l3), and r(22) are concordant with the chromosomal assignment of tumour suppressor loci associated with Wilms' tumour, retinoblastoma, and meningioma. It is suggested that the somatic instability of ring chromosomes may play a role in this association and that constitutional ring chromosomes may be a source for mapping of tumour suppressor loci with the potential for covering most or all of the human genome. The hypothesis predicts the presence of a locus on chromosome 10 associated with follicular carcinoma of the thyroid, in line with previous cytogenetic findings of rearrangements involving chromosome 10 in thyroid tumours, and a locus on chromosome 22 associated with testicular cancer. Development of neurofibromatoses (NF) that do not fulfil the clinical criteria of neurofibromatosis type 2 (NF2) in carriers with r(22) suggests either the presence of an additional NF locus on chromosome 22 or that ring chromosome mediated predisposition to somatic mutation of a specific tumour suppressor may be associated with atypical development of features usually associated with germline mutations.

Research paper thumbnail of Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes

Journal of medical genetics, 2014

Recently, a number of patients have been described with structural rearrangements at 3q13.31, del... more Recently, a number of patients have been described with structural rearrangements at 3q13.31, delineating a novel microdeletion syndrome with common clinical features including developmental delay and other neurodevelopmental disorders (NDD). A smallest region of overlapping deletions (SRO) involved five RefSeq genes, including the transcription factor gene ZBTB20 and the dopamine receptor gene DRD3, considered as candidate genes for the syndrome. We used array comparative genomic hybridization and next-generation mate-pair sequencing to identify key structural rearrangements involving ZBTB20 in two patients with NDD. In a patient with developmental delay, attention-deficit hyperactivity disorder, psychosis, Tourette's syndrome and autistic traits, a de novo balanced t(3;18) translocation truncated ZBTB20. The other breakpoint did not disrupt any gene. In a second patient with developmental delay and autism, we detected the first microdeletion at 3q13.31, which truncated ZBTB20 ...

Research paper thumbnail of Not para-, not peri-, but centric inversion of chromosome 12

Journal of Medical Genetics, 1998

Research paper thumbnail of New assignment of the adenosine deaminase gene locus to chromosome 20q13 X 11 by study of a patient with interstitial deletion 20q

Journal of Medical Genetics, 1987

Research paper thumbnail of Non-disjunction of chromosome 18

Human Molecular Genetics, 1998

We performed a molecular study with 21 microsatellites on a sample of 82 trisomy 13 conceptuses, ... more We performed a molecular study with 21 microsatellites on a sample of 82 trisomy 13 conceptuses, the largest number of cases studied to date. The parental origin was determined in every case and in 89% the extra chromosome 13 was of maternal origin with an almost equal number of maternal MI and MII errors. The latter finding is unique among human autosomal trisomies, where maternal MI (trisomies 15, 16, 21, 22) or MII (trisomy 18) errors dominate. Of the nine paternally derived cases five were of MII origin but none arose from MI errors. There was some evidence for elevated maternal age in cases with maternal meiotic origin for liveborn infants. Maternal and paternal ages were elevated in cases with paternal meiotic origin. This is in contrast to results from a similar study of non-disjunction of trisomy 21 where paternal but not maternal age was elevated. We find clear evidence for reduced recombination in both maternal MI and MII errors and the former is associated with a significant number of tetrads (33%) that are nullichiasmate, which do not appear to be a feature of normal chromosome 13 meiosis. This study supports the evidence for subtle chromosome-specific influences on the mechanisms that determine non-disjunction of human chromosomes, consistent with the diversity of findings for other trisomies.

Research paper thumbnail of Non-disjunction of chromosome 13

Human Molecular Genetics, 2007

Research paper thumbnail of Structural genomic variation in childhood epilepsies with complex phenotypes

European Journal of Human Genetics, 2013

Research paper thumbnail of Characterization of a t(5;8)(q31;q21) translocation in a patient with mental retardation and congenital heart disease: implications for involvement of RUNX1T1 in human brain and heart development

European Journal of Human Genetics, 2009

Research paper thumbnail of MECP2 mutations in Danish patients with Rett syndrome: High frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern

European Journal of Human Genetics, 2001

Research paper thumbnail of The strength of combined cytogenetic and mate-pair sequencing techniques illustrated by a germline chromothripsis rearrangement involving FOXP2

European Journal of Human Genetics, 2013

Next-generation mate-pair sequencing (MPS) has revealed that many constitutional complex chromoso... more Next-generation mate-pair sequencing (MPS) has revealed that many constitutional complex chromosomal rearrangements (CCRs) are associated with local shattering of chromosomal regions (chromothripsis). Although MPS promises to identify the molecular basis of the abnormal phenotypes associated with many CCRs, none of the reported mate-pair sequenced complex rearrangements have been simultaneously studied with state-of-the art molecular cytogenetic techniques. Here, we studied chromothripsis-associated CCR involving chromosomes 2, 5 and 7, associated with global developmental and psychomotor delay and severe speech disorder. We identified three truncated genes: CDH12, DGKB and FOXP2, confirming the role of FOXP2 in severe speech disorder, and suggestive roles of CDH12 and/or DGKB for the global developmental and psychomotor delay. Our study confirmes the power of MPS for detecting breakpoints and truncated genes at near nucleotide resolution in chromothripsis. However, only by combining MPS data with conventional G-banding and extensive fluorescence in situ hybridizations could we delineate the precise structure of the derivative chromosomes.

Research paper thumbnail of Identification of positional candidates for neurological disorders on chromosome 13q14→q22

Cytogenetic and Genome Research, 1997

In the course of a research project aimed at the molecular characterization of balanced chromosom... more In the course of a research project aimed at the molecular characterization of balanced chromosome rearrangements associated with mental retardation (MR), several YACs spanning MR-associated chromosomal rearrangements in the 13q14→q22 region were identified. To facilitate the search for relevant candidate genes, we have analyzed a total of 102 EST clones from this region. Sequence comparisons revealed that these 102 clones represent up to 72 distinct transcripts. When no physical mapping data were available, a minimal YAC contig was screened for each unique transcript by the polymerase chain reaction (PCR) or hybridization. Fifty-eight independent ESTs could be localized to YAC clones between the markers D13S1248 and DBS1201. Several ESTs are located on YAC clones detecting chromosomal rearrangements in MR patients. One EST was mapped within the critical region for Rieger syndrome type 2, and three transcripts were identified in the region for the nocturnal enuresis type 1. Some EST...

Research paper thumbnail of Search for late onset diseases among carriers of balanced chromosomal rearrangements

Research paper thumbnail of Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes

American journal of human genetics, Jun 17, 2018

The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected... more The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19.5% versus 8.3%, p = 0.04), which was increased to 26.8% upon clinical follow-up. Chromosomal microarray of 32 carriers revealed no pathogenic imbalances, illustrating a low prognostic value when fetal ultrasound scan is normal. In contrast, mate-pair sequencing revealed disrupted genes (ARID1B, NPAS3, CELF4), regulatory domains of known developmental genes (ZEB2, HOXC), and complex BCRs associated with adverse outcomes. Seven unmappable autosomal-autosomal BCRs ...

Research paper thumbnail of Wirth, J. et al. Systematic characterisation of disease associated balanced chromosome rearrangements by FISH: cytogenetically and genetically anchored YACs identify microdeletions and candidate regions for mental retardation genes. J. Med. Genet. 36, 271-278

Journal of Medical Genetics

Disease associated balanced chromosome rearrangements (DBCRs) have been instrumental in the isola... more Disease associated balanced chromosome rearrangements (DBCRs) have been instrumental in the isolation of many disease genes. To facilitate the molecular cytogenetic characterisation of DBCRs, we have generated a set of >1200 nonchimeric, cytogenetically and genetically anchored CEPH YACs, on average one per 3 cM, spaced over the entire human genome. By fluorescence in situ hybridisation (FISH), we have performed a systematic search for YACs spanning translocation breakpoints. Patients with DBCRs and either syndromic or nonsyndromic mental retardation (MR) were ascertained through the Mendelian Cytogenetics Network (MCN), a collaborative eVort of, at present, 270 cytogenetic laboratories throughout the world. In this pilot study, we have characterised 10 diVerent MR associated chromosome regions delineating candidate regions for MR. Five of these regions are narrowed to breakpoint spanning YACs, three of which are located on chromosomes 13q21, 13q22, and 13q32, respectively, one on chromosome 4p14, and one on 6q25. In two out of six DBCRs, we found cytogenetically cryptic deletions of 3-5 Mb on one or both translocation chromosomes. Thus, cryptic deletions may be an important cause of disease in seemingly balanced chromosome rearrangements that are associated with a disease phenotype. Our region specific FISH probes, which are available to MCN members, can be a powerful tool in clinical cytogenetics and positional cloning.

Research paper thumbnail of Dysregulation of FOXG1 by ring chromosome 14

Molecular Cytogenetics, 2015

In this study we performed molecular characterization of a patient with an extra ring chromosome ... more In this study we performed molecular characterization of a patient with an extra ring chromosome derived from chromosome 14, with severe intellectual disability, epilepsy, cerebral paresis, tetraplegia, osteoporosis and severe thoraco-lumbal scoliosis. Array CGH analysis did not show any genomic imbalance but conventional karyotyping and FISH analysis revealed the presence of an interstitial 14q12q24.3 deletion and an extra ring chromosome derived from the deleted material. The deletion and ring chromosome breakpoints were identified at base-pair level by mate-pair and Sanger sequencing. Both breakpoints disrupted putative long non-coding RNA genes (TCONS00022561;RP11-148E17.1) of unknown function. However, the proximal breakpoint was 225 kb downstream of the forkhead box G1 gene (FOXG1), within the known regulatory landscape of FOXG1. The patient represents the first case of a r(14) arising from an interstitial excision where the phenotype is compatible with dysregulation of FOXG1. In turn, the phenotypic overlap between the present case, the FOXG1 syndrome and the r(14) syndrome supports that dysregulation of FOXG1 may contribute to the classical r(14)-syndrome, likely mediated by dynamic mosaicism.

Research paper thumbnail of Subtelomeric study of 132 patients with mental retardation reveals 9 chromosomal anomalies and contributes to the delineation of submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter

BMC medical genetics, Jan 17, 2005

Cryptic chromosome imbalances are increasingly acknowledged as a cause for mental retardation and... more Cryptic chromosome imbalances are increasingly acknowledged as a cause for mental retardation and learning disability. New phenotypes associated with specific rearrangements are also being recognized. Techniques for screening for subtelomeric rearrangements are commercially available, allowing the implementation in a diagnostic service laboratory. We report the diagnostic yield in a series of 132 subjects with mental retardation, and the associated clinical phenotypes. We applied commercially available subtelomeric fluorescence in situ hybridization (FISH). All patients referred for subtelomeric screening in a 5-year period were reviewed and abnormal cases were further characterized clinically and if possible molecularly. We identified nine chromosomal rearrangements (two of which were in sisters) corresponding to a diagnostic yield of approx. 7%. All had dysmorphic features. Five had imbalances leading to recognizable phenotypes. Subtelomeric screening is a useful adjunct to conven...

Research paper thumbnail of Sex dependent transmission of Beckwith-Wiedemann syndrome associated with a reciprocal translocation t(9;11)(p11.2;p15.5)

Journal of Medical Genetics, 1993

Beckwith-Wiedemann syndrome (BWS), a disorder associated with neonatal hypoglycaemia, increased g... more Beckwith-Wiedemann syndrome (BWS), a disorder associated with neonatal hypoglycaemia, increased growth potential, and predisposition to Wilms's tumour (WT) and other malignancies, has been mapped to llpl5. The association with llpl5 duplications of paternal origin, of balanced translocations and inversions with breakpoints within llpl5.4-pl5.5 of maternal origin, and the demonstration of uniparental paternal llpl5 isodisomy in some sporadic cases point towards the involvement of genomic imprinting. In agreement with this, we show the paternal origin of a de novo 9;11 translocation in a phenotypically normal mother, whose carrier daughter developed BWS. This supports the fact that BWS associated with balanced chromosome mutations is transmitted in the same sex dependent pattern as non-cytogenetic forms of familial BWS.

Research paper thumbnail of Pierre Robin sequence may be caused by dysregulation of SOX9 and KCNJ2

Journal of Medical Genetics, 2007

Research paper thumbnail of Early onset, non-progressive, mild cerebellar ataxia co-segregating with a familial balanced translocation t(8;20)(p22;q13)

Journal of Medical Genetics, 2004

Research paper thumbnail of A cytogenetic survey in Menkes disease: implications for the detection of chromosomal rearrangements in X linked disorders

Journal of Medical Genetics, 1993

Research paper thumbnail of Constitutional ring chromosomes and tumour suppressor genes

Journal of Medical Genetics, 1992

The types of malignancy reported in carriers of constitutional ring chromosomes r(1), r(l3), and ... more The types of malignancy reported in carriers of constitutional ring chromosomes r(1), r(l3), and r(22) are concordant with the chromosomal assignment of tumour suppressor loci associated with Wilms' tumour, retinoblastoma, and meningioma. It is suggested that the somatic instability of ring chromosomes may play a role in this association and that constitutional ring chromosomes may be a source for mapping of tumour suppressor loci with the potential for covering most or all of the human genome. The hypothesis predicts the presence of a locus on chromosome 10 associated with follicular carcinoma of the thyroid, in line with previous cytogenetic findings of rearrangements involving chromosome 10 in thyroid tumours, and a locus on chromosome 22 associated with testicular cancer. Development of neurofibromatoses (NF) that do not fulfil the clinical criteria of neurofibromatosis type 2 (NF2) in carriers with r(22) suggests either the presence of an additional NF locus on chromosome 22 or that ring chromosome mediated predisposition to somatic mutation of a specific tumour suppressor may be associated with atypical development of features usually associated with germline mutations.