Ludwine Messiaen | University of Alabama at Birmingham (original) (raw)
Papers by Ludwine Messiaen
Neurofibromatosis Type 1, 2012
Technical Tips Online, 1998
Acta Neuropathologica, 2012
The 2011 annual meeting of the Children's Tumor Foundation, the annual gathering of the neurofibr... more The 2011 annual meeting of the Children's Tumor Foundation, the annual gathering of the neurofibromatosis (NF) research and clinical communities, was attended by 330 participants who discussed integration of new signaling pathways into NF research, the appreciation for NF mutations in sporadic cancers, and an expanding pre-clinical and clinical agenda. NF1, NF2, and schwannomatosis collectively affect approximately 100,000 persons in US, and result from mutations in different genes. Benign tumors of NF1 (neurofibroma and optic pathway glioma) and NF2 (schwannoma, ependymoma, and meningioma) and schwannomatosis (schwannoma) can cause significant morbidity, and there are no proven drug treatments for any form of NF. Each disorder is associated with additional manifestations causing morbidity. The research presentations described in this review covered basic science, preclinical testing, and results from clinical M. Kalamarides Hôpital Beaujon, Inserm U674, Universite Paris 7,
Pathology - Research and Practice, 1987
Fischer rat cells before and after transfection with immortalizing and transforming genes produce... more Fischer rat cells before and after transfection with immortalizing and transforming genes produced tumours after s.c., i.p., or i.v. injection of cell suspensions and after s.c. implantation of cellular aggregates in the tail of syngeneic rats. Tumours were described histologically as fibrosarcoma-like. Virtually all tumours were considered macroscopically to be invasive because they adhered to the neighbouring tissues; in many tumours invasion was confirmed microscopically. All types of cells produced lung colonies (artificial metastases) after i.v. injection. Spontaneous metastases (from a primary tumour) were found with some tumours produced by cells before as well as after transfection. Differences in metastasis between various cell types could not be ascribed to variations in the periods of observation, in the minimum tumour-bearing periods, in the latency periods, or in the volume of primary tumours. We concluded that local invasion and spontaneous metastasis are usefull for the characterization of malignancy in experimental fibrosarcoma-like tumours. Since Fischer rat cells produced invasive and sometimes metastatic tumours before transfection, the present data do not show a rôle of immortalizing and transforming genes in the acquisition of invasiveness and metastatic capability.
Human Mutation, 2014
Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of t... more Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of the NF1 gene region. To date, only nine unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple café au lait spots (CALS), Lisch nodules, freckling, or neurofibromas, the hallmark signs of NF1. Here, we have characterized two novel NF1 duplications, one sporadic and one familial. Both index patients with NF1 duplications exhibited learning disabilities and atypical CALS. Additionally, patient R609021 had Lisch nodules, whereas patient R653070 exhibited two inguinal freckles. The mother and sister of patient R609021 also harbored the NF1 duplication and exhibited cognitive dysfunction but no CALS. The breakpoints of the nine NF1 duplications reported previously have not been identified and hence their underlying generative mechanisms have remained unclear. In this study, we performed high-resolution breakpoint analysis that indicated that the two duplications studied were mediated by nonallelic homologous recombination (NAHR) and that the duplication breakpoints were located within the NAHR hotspot paralogous recombination site 2 (PRS2), which also harbors the type-1 NF1 deletion breakpoints. Hence, our study indicates for the first time that NF1 duplications are reciprocal to type-1 NF1 deletions and originate from the same NAHR events.
American journal of medical genetics. Part A, Jan 14, 2015
We report a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris Syndrome (CS... more We report a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris Syndrome (CSS), and schwannomatosis. CSS is a rare congenital syndrome with characteristic clinical findings. This thirty-three-year-old man was diagnosed early in life with the constellation of moderate intellectual disability, hypotonia, mild microcephaly, coarse facies, wide mouth with full lips, hypoplasia of the digits, and general hirsutism. At age 26, he was found to have schwannomatosis after presenting with acute spinal cord compression. Blood and tissue analysis of multiple subsequent schwannoma resections revealed a germline missense mutation of SMARCB1, acquired loss of 22q including SMARCB1 and NF2 and mutation of the remaining NF2 wild-type allele-thus completing the four-hit, three-event mechanism associated with schwannomatosis. Variations in five genes have been associated with the Coffin-Siris phenotype: ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1. Of these genes, SMARCB1 has a w...
Human Mutation, 2014
Large NF1 deletions are mediated by nonallelic homologous recombination (NAHR). An in-depth analy... more Large NF1 deletions are mediated by nonallelic homologous recombination (NAHR). An in-depth analysis of gene conversion operating in the breakpoint-flanking regions of large NF1 deletions was performed to investigate whether the rate of discontinuous gene conversion during NAHR with crossover is increased, as has been previously noted in NAHR-mediated rearrangements. All 20 germline type-1 NF1 deletions analyzed were mediated by NAHR associated with continuous gene conversion within the breakpoint-flanking regions. Continuous gene conversion was also observed in 31/32 type-2 NF1 deletions investigated. In contrast to the meiotic type-1 NF1 deletions, type-2 NF1 deletions are predominantly of post-zygotic origin. Our findings therefore imply that the mitotic as well as the meiotic NAHR intermediates of large NF1 deletions are processed by long-patch mismatch repair (MMR), thereby ensuring gene conversion tract continuity instead of the discontinuous gene conversion that is characteristic of short-patch repair. However, the single type-2 NF1 deletion not exhibiting continuous gene conversion was processed without MMR, yielding two different deletion-bearing chromosomes, which were distinguishable in terms of their breakpoint positions. Our findings indicate that MMR failure during NAHR, followed by post-meiotic/mitotic segregation, has the potential to give rise to somatic mosaicism in human genomic rearrangements by generating breakpoint heterogeneity.
Human Mutation, 2012
Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number ... more Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number variation in the human genome. Although several disease-associated meiotic NAHR breakpoints have been analyzed in great detail, hotspots for mitotic NAHR are not well characterized. Type-2 NF1 microdeletions, which are predominantly of postzygotic origin, constitute a highly informative model with which to investigate the features of mitotic NAHR. Here, a custom-designed MLPA- and PCR-based approach was used to identify 23 novel NAHR-mediated type-2 NF1 deletions. Breakpoint analysis of these 23 type-2 deletions, together with 17 NAHR-mediated type-2 deletions identified previously, revealed that the breakpoints are nonuniformly distributed within the paralogous SUZ12 and SUZ12P sequences. Further, the analysis of this large group of type-2 deletions revealed breakpoint recurrence within short segments (ranging in size from 57 to 253-bp) as well as the existence of a novel NAHR hotspot of 1.9-kb (termed PRS4). This hotspot harbored 20% (8/40) of the type-2 deletion breakpoints and contains the 253-bp recurrent breakpoint region BR6 in which four independent type-2 deletion breakpoints were identified. Our findings indicate that a combination of an open chromatin conformation and short non-B DNA-forming repeats may predispose to recurrent mitotic NAHR events between SUZ12 and its pseudogene.
![Research paper thumbnail of Molecular characterization of a patient with an interstitial 1q deletion [del(1)(q24.1q25.3)] and distinctive skeletal abnormalities](https://attachments.academia-assets.com/42919475/thumbnails/1.jpg)
](American Journal of Medical Genetics Part A, 2008
Here we report on a patient with an interstitial deletion on the long(q) arm of chromosome 1 who ... more Here we report on a patient with an interstitial deletion on the long(q) arm of chromosome 1 who presents with a unique constellation of anomalies including brachydactyly type E, Müllerian agenesis, growth hormone deficiency, as well as other abnormalities. We present the clinical details of this patient's presentation, the skeletal findings, and provide characterization of the deletion at the molecular level. We postulate that these skeletal anomalies are distinctive to 1q deletions involving the 1q24q25 region. ß How to cite this article: Descartes M, Zenger Hain J, Conklin M, Franklin J, Mikhail FM, Lachman RS, Nolet S, Messiaen LM. 2008. Molecular characterization of a patient with an interstitial 1q deletion [del(1)(q24.1q25.3)]
American Journal of Medical Genetics Part A, 2011
Legius syndrome, is a recently identified autosomal dominant disorder caused by loss of function ... more Legius syndrome, is a recently identified autosomal dominant disorder caused by loss of function mutations in the SPRED1 gene, with individuals mainly presenting with multiple caf e-aulait macules (CALM), freckling and macrocephaly. So far, only SPRED1 point mutations have been identified as the cause of this syndrome. To determine if copy number changes (CNCs) are a cause of Legius syndrome, we have used a Multiplex Ligationdependent Probe Amplification (MLPA) assay covering all SPRED1 exons in a cohort of 510 NF1-negative patients presenting with multiple CALMs with or without freckling, but no other NF1 diagnostic signs. Four different deletions were identified by MLPA and confirmed by quantitative PCR, reverse transcriptase PCR and/or array CGH: a deletion of exon 1 and the SPRED1 promoter region in a proband and two first-degree relatives; a deletion of the entire SPRED1 gene in a sporadic patient; a deletion of exon 2-6 in a proband and her father; and an 6.6 Mb deletion on chromosome 15 that spans SPRED1 in a sporadic patient. Deletions account for 10% of the 40 detected SPRED1 mutations in this cohort of 510 individuals. These results indicate the need for dosage analysis to complement sequencingbased SPRED1 mutation analyses.
Human Mutation, 2014
Palindromic sequences can form hairpin structures or cruciform extrusions, which render them susc... more Palindromic sequences can form hairpin structures or cruciform extrusions, which render them susceptible to genomic rearrangements. A 197-bp long palindromic AT-rich repeat (PATRR17) is located within intron 40 of the neurofibromatosis type 1 (NF1) gene (17q11.2). Through comprehensive NF1 analysis, we identified six unrelated patients with a rearrangement involving intron 40 (five deletions and one reciprocal translocation t(14;17)(q32;q11.2)). We hypothesized that PATRR17 may be involved in these rearrangements thereby causing NF1. Breakpoint cloning revealed that PATRR17 was indeed involved in all of the rearrangements. As microhomology was present at all breakpoint junctions of the deletions identified, and PATRR17 partner breakpoints were located within 7.1 kb upstream of PATRR17, fork stalling and template switching/microhomology-mediated break-induced replication was the most likely rearrangement mechanism. For the reciprocal translocation case, a 51 bp insertion at the translocation breakpoints mapped to a short sequence within PATRR17, proximal to the breakpoint, suggesting a multiple stalling and rereplication process, in contrast to previous studies indicating a purely replicationindependent mechanism for PATRR-mediated translocations. In conclusion, we show evidence that PATRR17 is a hotspot for pathogenic intragenic deletions within the NF1 gene and suggest a novel replication-dependent mechanism for PATRR-mediated translocation. Hum Mutat 35:891-898, 2014. C 2014 Wiley Periodicals, Inc.
The American Journal of Human Genetics, 2015
Genomic rearrangements can cause both Mendelian and complex disorders. Currently, several major m... more Genomic rearrangements can cause both Mendelian and complex disorders. Currently, several major mechanisms causing genomic rearrangements, such as non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), fork stalling and template switching (FoSTeS), and microhomology-mediated break-induced replication (MMBIR), have been proposed. However, to what extent these mechanisms contribute to gene-specific pathogenic copy-number variations (CNVs) remains understudied. Furthermore, few studies have resolved these pathogenic alterations at the nucleotide-level. Accordingly, our aim was to explore which mechanisms contribute to a large, unique set of locus-specific non-recurrent genomic rearrangements causing the genetic neurocutaneous disorder neurofibromatosis type 1 (NF1). Through breakpoint-spanning PCR as well as array comparative genomic hybridization, we have identified the breakpoints in 85 unrelated individuals carrying an NF1 intragenic CNV. Furthermore, we characterized the likely rearrangement mechanisms of these 85 CNVs, along with those of two additional previously published NF1 intragenic CNVs. Unlike the most typical recurrent rearrangements mediated by flanking low-copy repeats (LCRs), NF1 intragenic rearrangements vary in size, location, and rearrangement mechanisms. We propose the DNA-replication-based mechanisms comprising both FoSTeS and/or MMBIR and serial replication stalling to be the predominant mechanisms leading to NF1 intragenic CNVs. In addition to the loop within a 197-bp palindrome located in intron 40, four Alu elements located in introns 1, 2, 3, and 50 were also identified as intragenic-rearrangement hotspots within NF1.
Journal of Pediatric Endocrinology and Metabolism, 2015
Although most hypocalcemia with hypomagenesemia in the neonatal period is due to transient neonat... more Although most hypocalcemia with hypomagenesemia in the neonatal period is due to transient neonatal hypoparathyroidism, magnesium channel defects should also be considered. We report a case of persistent hypomagnesemia in an 8-day-old Hispanic male who presented with generalized seizures. He was initially found to have hypomagnesemia, hypocalcemia, hyperphosphatemia and normal parathyroid hormone. Serum calcium normalized with administration of calcitriol and calcium carbonate. Serum magnesium improved with oral magnesium sulfate. However, 1 week after magnesium was discontinued, serum magnesium declined to 0.5 mg/dL. Magnesium supplementation was immediately restarted, and periodic seizure activity resolved after serum magnesium concentration was maintained above 0.9 mg/dL. The child was eventually weaned off oral calcium and calcitriol with persistent normocalemia. However, supraphysiologic oral magnesium doses were necessary to prevent seizures and maintain serum magnesium at the low limit of normal. As his clinical presentation suggested primary renal magnesium wastage, TRPM6 gene mutations were suspected; subsequent genetic testing revealed the child to be compound heterozygous for TRPM6 mutations. Two novel TRPM6 mutations are described with a new geographic and ethnic origin. This case highlights the importance of recognizing disorders of magnesium imbalance and describing new genetic mutations.
Bone, 2009
Edited by: B. Olsen Keywords: Neurofibromatosis type 1 Congenital pseudarthrosis of the tibia Mes... more Edited by: B. Olsen Keywords: Neurofibromatosis type 1 Congenital pseudarthrosis of the tibia Mesenchymal stem cell Osteoblast Skeletal Collagen Neurofibromin
Journal of Neurosurgery, 2010
Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder characterized by the develop... more Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder characterized by the development of benign tumors of the peripheral nervous system and the CNS, including schwannomas, meningiomas, and ependymomas. The gene responsible for the development of NF2 acts as a tumor suppressor gene. Stereotactic radiotherapy (SRT) or single-fraction stereotactic radiosurgery has been increasingly used in the past decades to treat benign tumors in patients with NF2. These radiotherapy methods are less invasive and can be potentially used to treat multiple tumors in a single session. The risk of inducing malignancy is unclear. Few reports exist of malignant peripheral nerve sheath tumors, meningiomas, or ependymomas occurring after SRT or stereotactic radiosurgery in patients with NF2. The authors present the first documented case of rhabdomyosarcoma following SRT for multiple NF2-associated schwannomas. Compared with patients with sporadic tumors, NF2 patients having a germline tumor suppressor gene defect may be more prone to secondary malignancies after treatment involving radiation therapy.
Journal of the American Academy of Dermatology, 2010
Background-Cafe-au-lait macules (CALMs) in NF1 are an early and accessible phenotype in NF1, but ... more Background-Cafe-au-lait macules (CALMs) in NF1 are an early and accessible phenotype in NF1, but have not been extensively studied.
Disease Markers, 1999
Since the identification of the BRCA1 and BRCA2 genes, several hundred different germline mutatio... more Since the identification of the BRCA1 and BRCA2 genes, several hundred different germline mutations in both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. As the mutational spectrum of the BRCA1 and BRCA2 genes in the Belgian patient population is largely unknown, we initiated mutation analysis for the complete coding sequence of both genes in Belgian families with multiple breast and/or ovarian cancer patients and in "sporadic" patients with early onset disease. We completed the analysis in 49 families and in 19 "sporadic" female patients with early onset breast and/or ovarian cancer. In 15 families we identified a mutation (12 mutations in BRCA1 and 3 mutations in BRCA2). In 5 apparently unrelated families the same splice site mutation was identified (BRCA1 IVS5+3A>G). Haplotype analysis revealed a common haplotype immediately flanking the mutation in all families suggesting that disease alleles are identical by descent. In none of the 19 sporadic patients was a mutation found.
Neurofibromatosis Type 1, 2012
Technical Tips Online, 1998
Acta Neuropathologica, 2012
The 2011 annual meeting of the Children's Tumor Foundation, the annual gathering of the neurofibr... more The 2011 annual meeting of the Children's Tumor Foundation, the annual gathering of the neurofibromatosis (NF) research and clinical communities, was attended by 330 participants who discussed integration of new signaling pathways into NF research, the appreciation for NF mutations in sporadic cancers, and an expanding pre-clinical and clinical agenda. NF1, NF2, and schwannomatosis collectively affect approximately 100,000 persons in US, and result from mutations in different genes. Benign tumors of NF1 (neurofibroma and optic pathway glioma) and NF2 (schwannoma, ependymoma, and meningioma) and schwannomatosis (schwannoma) can cause significant morbidity, and there are no proven drug treatments for any form of NF. Each disorder is associated with additional manifestations causing morbidity. The research presentations described in this review covered basic science, preclinical testing, and results from clinical M. Kalamarides Hôpital Beaujon, Inserm U674, Universite Paris 7,
Pathology - Research and Practice, 1987
Fischer rat cells before and after transfection with immortalizing and transforming genes produce... more Fischer rat cells before and after transfection with immortalizing and transforming genes produced tumours after s.c., i.p., or i.v. injection of cell suspensions and after s.c. implantation of cellular aggregates in the tail of syngeneic rats. Tumours were described histologically as fibrosarcoma-like. Virtually all tumours were considered macroscopically to be invasive because they adhered to the neighbouring tissues; in many tumours invasion was confirmed microscopically. All types of cells produced lung colonies (artificial metastases) after i.v. injection. Spontaneous metastases (from a primary tumour) were found with some tumours produced by cells before as well as after transfection. Differences in metastasis between various cell types could not be ascribed to variations in the periods of observation, in the minimum tumour-bearing periods, in the latency periods, or in the volume of primary tumours. We concluded that local invasion and spontaneous metastasis are usefull for the characterization of malignancy in experimental fibrosarcoma-like tumours. Since Fischer rat cells produced invasive and sometimes metastatic tumours before transfection, the present data do not show a rôle of immortalizing and transforming genes in the acquisition of invasiveness and metastatic capability.
Human Mutation, 2014
Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of t... more Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of the NF1 gene region. To date, only nine unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple café au lait spots (CALS), Lisch nodules, freckling, or neurofibromas, the hallmark signs of NF1. Here, we have characterized two novel NF1 duplications, one sporadic and one familial. Both index patients with NF1 duplications exhibited learning disabilities and atypical CALS. Additionally, patient R609021 had Lisch nodules, whereas patient R653070 exhibited two inguinal freckles. The mother and sister of patient R609021 also harbored the NF1 duplication and exhibited cognitive dysfunction but no CALS. The breakpoints of the nine NF1 duplications reported previously have not been identified and hence their underlying generative mechanisms have remained unclear. In this study, we performed high-resolution breakpoint analysis that indicated that the two duplications studied were mediated by nonallelic homologous recombination (NAHR) and that the duplication breakpoints were located within the NAHR hotspot paralogous recombination site 2 (PRS2), which also harbors the type-1 NF1 deletion breakpoints. Hence, our study indicates for the first time that NF1 duplications are reciprocal to type-1 NF1 deletions and originate from the same NAHR events.
American journal of medical genetics. Part A, Jan 14, 2015
We report a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris Syndrome (CS... more We report a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris Syndrome (CSS), and schwannomatosis. CSS is a rare congenital syndrome with characteristic clinical findings. This thirty-three-year-old man was diagnosed early in life with the constellation of moderate intellectual disability, hypotonia, mild microcephaly, coarse facies, wide mouth with full lips, hypoplasia of the digits, and general hirsutism. At age 26, he was found to have schwannomatosis after presenting with acute spinal cord compression. Blood and tissue analysis of multiple subsequent schwannoma resections revealed a germline missense mutation of SMARCB1, acquired loss of 22q including SMARCB1 and NF2 and mutation of the remaining NF2 wild-type allele-thus completing the four-hit, three-event mechanism associated with schwannomatosis. Variations in five genes have been associated with the Coffin-Siris phenotype: ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1. Of these genes, SMARCB1 has a w...
Human Mutation, 2014
Large NF1 deletions are mediated by nonallelic homologous recombination (NAHR). An in-depth analy... more Large NF1 deletions are mediated by nonallelic homologous recombination (NAHR). An in-depth analysis of gene conversion operating in the breakpoint-flanking regions of large NF1 deletions was performed to investigate whether the rate of discontinuous gene conversion during NAHR with crossover is increased, as has been previously noted in NAHR-mediated rearrangements. All 20 germline type-1 NF1 deletions analyzed were mediated by NAHR associated with continuous gene conversion within the breakpoint-flanking regions. Continuous gene conversion was also observed in 31/32 type-2 NF1 deletions investigated. In contrast to the meiotic type-1 NF1 deletions, type-2 NF1 deletions are predominantly of post-zygotic origin. Our findings therefore imply that the mitotic as well as the meiotic NAHR intermediates of large NF1 deletions are processed by long-patch mismatch repair (MMR), thereby ensuring gene conversion tract continuity instead of the discontinuous gene conversion that is characteristic of short-patch repair. However, the single type-2 NF1 deletion not exhibiting continuous gene conversion was processed without MMR, yielding two different deletion-bearing chromosomes, which were distinguishable in terms of their breakpoint positions. Our findings indicate that MMR failure during NAHR, followed by post-meiotic/mitotic segregation, has the potential to give rise to somatic mosaicism in human genomic rearrangements by generating breakpoint heterogeneity.
Human Mutation, 2012
Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number ... more Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number variation in the human genome. Although several disease-associated meiotic NAHR breakpoints have been analyzed in great detail, hotspots for mitotic NAHR are not well characterized. Type-2 NF1 microdeletions, which are predominantly of postzygotic origin, constitute a highly informative model with which to investigate the features of mitotic NAHR. Here, a custom-designed MLPA- and PCR-based approach was used to identify 23 novel NAHR-mediated type-2 NF1 deletions. Breakpoint analysis of these 23 type-2 deletions, together with 17 NAHR-mediated type-2 deletions identified previously, revealed that the breakpoints are nonuniformly distributed within the paralogous SUZ12 and SUZ12P sequences. Further, the analysis of this large group of type-2 deletions revealed breakpoint recurrence within short segments (ranging in size from 57 to 253-bp) as well as the existence of a novel NAHR hotspot of 1.9-kb (termed PRS4). This hotspot harbored 20% (8/40) of the type-2 deletion breakpoints and contains the 253-bp recurrent breakpoint region BR6 in which four independent type-2 deletion breakpoints were identified. Our findings indicate that a combination of an open chromatin conformation and short non-B DNA-forming repeats may predispose to recurrent mitotic NAHR events between SUZ12 and its pseudogene.
American Journal of Medical Genetics Part A, 2008
Here we report on a patient with an interstitial deletion on the long(q) arm of chromosome 1 who ... more Here we report on a patient with an interstitial deletion on the long(q) arm of chromosome 1 who presents with a unique constellation of anomalies including brachydactyly type E, Müllerian agenesis, growth hormone deficiency, as well as other abnormalities. We present the clinical details of this patient's presentation, the skeletal findings, and provide characterization of the deletion at the molecular level. We postulate that these skeletal anomalies are distinctive to 1q deletions involving the 1q24q25 region. ß How to cite this article: Descartes M, Zenger Hain J, Conklin M, Franklin J, Mikhail FM, Lachman RS, Nolet S, Messiaen LM. 2008. Molecular characterization of a patient with an interstitial 1q deletion [del(1)(q24.1q25.3)]
American Journal of Medical Genetics Part A, 2011
Legius syndrome, is a recently identified autosomal dominant disorder caused by loss of function ... more Legius syndrome, is a recently identified autosomal dominant disorder caused by loss of function mutations in the SPRED1 gene, with individuals mainly presenting with multiple caf e-aulait macules (CALM), freckling and macrocephaly. So far, only SPRED1 point mutations have been identified as the cause of this syndrome. To determine if copy number changes (CNCs) are a cause of Legius syndrome, we have used a Multiplex Ligationdependent Probe Amplification (MLPA) assay covering all SPRED1 exons in a cohort of 510 NF1-negative patients presenting with multiple CALMs with or without freckling, but no other NF1 diagnostic signs. Four different deletions were identified by MLPA and confirmed by quantitative PCR, reverse transcriptase PCR and/or array CGH: a deletion of exon 1 and the SPRED1 promoter region in a proband and two first-degree relatives; a deletion of the entire SPRED1 gene in a sporadic patient; a deletion of exon 2-6 in a proband and her father; and an 6.6 Mb deletion on chromosome 15 that spans SPRED1 in a sporadic patient. Deletions account for 10% of the 40 detected SPRED1 mutations in this cohort of 510 individuals. These results indicate the need for dosage analysis to complement sequencingbased SPRED1 mutation analyses.
Human Mutation, 2014
Palindromic sequences can form hairpin structures or cruciform extrusions, which render them susc... more Palindromic sequences can form hairpin structures or cruciform extrusions, which render them susceptible to genomic rearrangements. A 197-bp long palindromic AT-rich repeat (PATRR17) is located within intron 40 of the neurofibromatosis type 1 (NF1) gene (17q11.2). Through comprehensive NF1 analysis, we identified six unrelated patients with a rearrangement involving intron 40 (five deletions and one reciprocal translocation t(14;17)(q32;q11.2)). We hypothesized that PATRR17 may be involved in these rearrangements thereby causing NF1. Breakpoint cloning revealed that PATRR17 was indeed involved in all of the rearrangements. As microhomology was present at all breakpoint junctions of the deletions identified, and PATRR17 partner breakpoints were located within 7.1 kb upstream of PATRR17, fork stalling and template switching/microhomology-mediated break-induced replication was the most likely rearrangement mechanism. For the reciprocal translocation case, a 51 bp insertion at the translocation breakpoints mapped to a short sequence within PATRR17, proximal to the breakpoint, suggesting a multiple stalling and rereplication process, in contrast to previous studies indicating a purely replicationindependent mechanism for PATRR-mediated translocations. In conclusion, we show evidence that PATRR17 is a hotspot for pathogenic intragenic deletions within the NF1 gene and suggest a novel replication-dependent mechanism for PATRR-mediated translocation. Hum Mutat 35:891-898, 2014. C 2014 Wiley Periodicals, Inc.
The American Journal of Human Genetics, 2015
Genomic rearrangements can cause both Mendelian and complex disorders. Currently, several major m... more Genomic rearrangements can cause both Mendelian and complex disorders. Currently, several major mechanisms causing genomic rearrangements, such as non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), fork stalling and template switching (FoSTeS), and microhomology-mediated break-induced replication (MMBIR), have been proposed. However, to what extent these mechanisms contribute to gene-specific pathogenic copy-number variations (CNVs) remains understudied. Furthermore, few studies have resolved these pathogenic alterations at the nucleotide-level. Accordingly, our aim was to explore which mechanisms contribute to a large, unique set of locus-specific non-recurrent genomic rearrangements causing the genetic neurocutaneous disorder neurofibromatosis type 1 (NF1). Through breakpoint-spanning PCR as well as array comparative genomic hybridization, we have identified the breakpoints in 85 unrelated individuals carrying an NF1 intragenic CNV. Furthermore, we characterized the likely rearrangement mechanisms of these 85 CNVs, along with those of two additional previously published NF1 intragenic CNVs. Unlike the most typical recurrent rearrangements mediated by flanking low-copy repeats (LCRs), NF1 intragenic rearrangements vary in size, location, and rearrangement mechanisms. We propose the DNA-replication-based mechanisms comprising both FoSTeS and/or MMBIR and serial replication stalling to be the predominant mechanisms leading to NF1 intragenic CNVs. In addition to the loop within a 197-bp palindrome located in intron 40, four Alu elements located in introns 1, 2, 3, and 50 were also identified as intragenic-rearrangement hotspots within NF1.
Journal of Pediatric Endocrinology and Metabolism, 2015
Although most hypocalcemia with hypomagenesemia in the neonatal period is due to transient neonat... more Although most hypocalcemia with hypomagenesemia in the neonatal period is due to transient neonatal hypoparathyroidism, magnesium channel defects should also be considered. We report a case of persistent hypomagnesemia in an 8-day-old Hispanic male who presented with generalized seizures. He was initially found to have hypomagnesemia, hypocalcemia, hyperphosphatemia and normal parathyroid hormone. Serum calcium normalized with administration of calcitriol and calcium carbonate. Serum magnesium improved with oral magnesium sulfate. However, 1 week after magnesium was discontinued, serum magnesium declined to 0.5 mg/dL. Magnesium supplementation was immediately restarted, and periodic seizure activity resolved after serum magnesium concentration was maintained above 0.9 mg/dL. The child was eventually weaned off oral calcium and calcitriol with persistent normocalemia. However, supraphysiologic oral magnesium doses were necessary to prevent seizures and maintain serum magnesium at the low limit of normal. As his clinical presentation suggested primary renal magnesium wastage, TRPM6 gene mutations were suspected; subsequent genetic testing revealed the child to be compound heterozygous for TRPM6 mutations. Two novel TRPM6 mutations are described with a new geographic and ethnic origin. This case highlights the importance of recognizing disorders of magnesium imbalance and describing new genetic mutations.
Bone, 2009
Edited by: B. Olsen Keywords: Neurofibromatosis type 1 Congenital pseudarthrosis of the tibia Mes... more Edited by: B. Olsen Keywords: Neurofibromatosis type 1 Congenital pseudarthrosis of the tibia Mesenchymal stem cell Osteoblast Skeletal Collagen Neurofibromin
Journal of Neurosurgery, 2010
Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder characterized by the develop... more Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder characterized by the development of benign tumors of the peripheral nervous system and the CNS, including schwannomas, meningiomas, and ependymomas. The gene responsible for the development of NF2 acts as a tumor suppressor gene. Stereotactic radiotherapy (SRT) or single-fraction stereotactic radiosurgery has been increasingly used in the past decades to treat benign tumors in patients with NF2. These radiotherapy methods are less invasive and can be potentially used to treat multiple tumors in a single session. The risk of inducing malignancy is unclear. Few reports exist of malignant peripheral nerve sheath tumors, meningiomas, or ependymomas occurring after SRT or stereotactic radiosurgery in patients with NF2. The authors present the first documented case of rhabdomyosarcoma following SRT for multiple NF2-associated schwannomas. Compared with patients with sporadic tumors, NF2 patients having a germline tumor suppressor gene defect may be more prone to secondary malignancies after treatment involving radiation therapy.
Journal of the American Academy of Dermatology, 2010
Background-Cafe-au-lait macules (CALMs) in NF1 are an early and accessible phenotype in NF1, but ... more Background-Cafe-au-lait macules (CALMs) in NF1 are an early and accessible phenotype in NF1, but have not been extensively studied.
Disease Markers, 1999
Since the identification of the BRCA1 and BRCA2 genes, several hundred different germline mutatio... more Since the identification of the BRCA1 and BRCA2 genes, several hundred different germline mutations in both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. As the mutational spectrum of the BRCA1 and BRCA2 genes in the Belgian patient population is largely unknown, we initiated mutation analysis for the complete coding sequence of both genes in Belgian families with multiple breast and/or ovarian cancer patients and in "sporadic" patients with early onset disease. We completed the analysis in 49 families and in 19 "sporadic" female patients with early onset breast and/or ovarian cancer. In 15 families we identified a mutation (12 mutations in BRCA1 and 3 mutations in BRCA2). In 5 apparently unrelated families the same splice site mutation was identified (BRCA1 IVS5+3A>G). Haplotype analysis revealed a common haplotype immediately flanking the mutation in all families suggesting that disease alleles are identical by descent. In none of the 19 sporadic patients was a mutation found.