The implementation of high-throughput diagnostic sequencing has led to the generation of large am... more The implementation of high-throughput diagnostic sequencing has led to the generation of large amounts of mutational data, making their interpretation more complex and responsible for long delays. It has been important to prioritize certain analyses, particularly those of “actionable” genes in diagnostic situations, involving specific treatment and/or management. In our project, we carried out an objective assessment of the clinical actionability of genes involved in myopathies, for which only few data obtained methodologically exist to date. Using the ClinGen Actionability criteria, we scored the clinical actionability of all 199 genes implicated in myopathies published by FILNEMUS for the “National French consensus on gene Lists for the diagnosis of myopathies using next generation sequencing”. We objectified that 63 myopathy genes were actionable with currently available data. Among the 36 myopathy genes with highest actionability scores, only 8 had been scored to date by ClinGen...
Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H). Few cases hav... more Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H). Few cases have been described to date, but this gene is not systematically analysed due to the absence of specific signs and difficulties in protein analysis. By using high-throughput mutation screening techniques, we identified mutations in TRIM32 in two patients presenting nonspecific progressive LGMD. We report the first case of total inactivation by homozygous deletion of the entire TRIM32 gene. Of interest, the deletion removes part of the ASTN2 gene, a large gene in which TRIM32 is nested. Despite the total TRIM32 gene inactivation, the patient does not present a more severe phenotype. However, he developed a mild progressive cognitive impairment that may be related to the loss of function of ASTN2 since association between ASTN2 heterozygous deletions and neurobehavioral disorders was previously reported. Regarding genomic characteristics at breakpoint of the deleted regions of TRIM32, we found a high density of repeated elements, suggesting a possible hotspot. These observations illustrate the importance of high-throughput technologies for identifying molecular defects in LGMD, confirm that total loss of function of TRIM32 is not associated with a specific phenotype and that ASTN2 inactivation could be associated with cognitive impairment.
Proceedings of the National Academy of Sciences, 1997
Friedreich’s ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases... more Friedreich’s ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for ≈17% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the majo...
We report on a rare homozygous intragenic deletion encompassing exons 1-6 of the SMN1 gene in a p... more We report on a rare homozygous intragenic deletion encompassing exons 1-6 of the SMN1 gene in a patient with spinal muscular atrophy (SMA) born into a consanguineous family. This exceptional configuration induced misinterpretation of the molecular defect involved in this patient, who was first reported as having a classic SMN1 exon 7 deletion. This case points out the possible pitfalls in molecular diagnosis of SMA in affected patients and their relatives: exploration of the SMN1 exon 7 (c.840C/T alleles) may be disturbed by several non-pathological or pathological variants around the SMN1 exon 7. In order to accurately describe the molecular defect in an SMA-affected patient, we propose to apply the Human Genome Variation Society nomenclature. This widely accepted nomenclature would improve the reporting of the molecular defect observed in SMA patients and thus would avoid the commonly used but imprecise terminology "absence of SMN1 exon 7."
Spinal and bulbar muscular atrophy (SBMA) is an X-linked, late-onset neuro-endocrine disorder res... more Spinal and bulbar muscular atrophy (SBMA) is an X-linked, late-onset neuro-endocrine disorder resulting from an expansion of a CAG repeat in the androgen receptor gene. Material and method. We report the detailed phenotypic study in a series of 12 SBMA patients evaluated in four kindreds. Clinical phenotypic spectrum varied considerably, ranging from childhood-onset weakness and atrophy mimicking limb-girdle myopathy in patients with 53 CAG repeats to isolated hyperCKemia in an adult with 42 CAG repeats. All male patients had gynecomastia. Two female carriers presented with paresthesias and hand action tremor. Homozygous deletions of SMN1 and SMN2 genes were not found in any patients. This report demonstrates that SBMA may present with a wider clinical spectrum than previously described and suggests that clinical phenotype severity in SBMA is partially linked to the number of CAG repeats. It also suggests that SMN1 and SMN2 genes do not act as modifying genes in SBMA.
Until recently, Bardet-Biedl syndrome was considered as a classic autosomal recessive condition. ... more Until recently, Bardet-Biedl syndrome was considered as a classic autosomal recessive condition. The disorder is defined by the association of the following clinical features: retinitis pigmentosa, polydactyly, obesity, hypogonadism, and possible mental retardation. This syndrome leads to multiple handicaps (visual impairment, complications of obesity, kidney failure, endocrine dysfunction). This condition, apparently clearly defined from a clinical point of view, appears to be genetically heterogenous. To date, six different genes have been identified: BBS1, BBS2, BBS4, BBS6, BBS7 and BBS8. Interestingly, this condition has recently been linked to a failure of cellular ciliogenesis. Moreover, this disorder is characterized by an additional degree of complexity, as it is the first example of triallelic inheritance described in human beings. However, this new finding appears to be less frequent than expected in this syndrome.
The implementation of high-throughput diagnostic sequencing has led to the generation of large am... more The implementation of high-throughput diagnostic sequencing has led to the generation of large amounts of mutational data, making their interpretation more complex and responsible for long delays. It has been important to prioritize certain analyses, particularly those of “actionable” genes in diagnostic situations, involving specific treatment and/or management. In our project, we carried out an objective assessment of the clinical actionability of genes involved in myopathies, for which only few data obtained methodologically exist to date. Using the ClinGen Actionability criteria, we scored the clinical actionability of all 199 genes implicated in myopathies published by FILNEMUS for the “National French consensus on gene Lists for the diagnosis of myopathies using next generation sequencing”. We objectified that 63 myopathy genes were actionable with currently available data. Among the 36 myopathy genes with highest actionability scores, only 8 had been scored to date by ClinGen...
Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H). Few cases hav... more Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H). Few cases have been described to date, but this gene is not systematically analysed due to the absence of specific signs and difficulties in protein analysis. By using high-throughput mutation screening techniques, we identified mutations in TRIM32 in two patients presenting nonspecific progressive LGMD. We report the first case of total inactivation by homozygous deletion of the entire TRIM32 gene. Of interest, the deletion removes part of the ASTN2 gene, a large gene in which TRIM32 is nested. Despite the total TRIM32 gene inactivation, the patient does not present a more severe phenotype. However, he developed a mild progressive cognitive impairment that may be related to the loss of function of ASTN2 since association between ASTN2 heterozygous deletions and neurobehavioral disorders was previously reported. Regarding genomic characteristics at breakpoint of the deleted regions of TRIM32, we found a high density of repeated elements, suggesting a possible hotspot. These observations illustrate the importance of high-throughput technologies for identifying molecular defects in LGMD, confirm that total loss of function of TRIM32 is not associated with a specific phenotype and that ASTN2 inactivation could be associated with cognitive impairment.
Proceedings of the National Academy of Sciences, 1997
Friedreich’s ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases... more Friedreich’s ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for ≈17% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the majo...
We report on a rare homozygous intragenic deletion encompassing exons 1-6 of the SMN1 gene in a p... more We report on a rare homozygous intragenic deletion encompassing exons 1-6 of the SMN1 gene in a patient with spinal muscular atrophy (SMA) born into a consanguineous family. This exceptional configuration induced misinterpretation of the molecular defect involved in this patient, who was first reported as having a classic SMN1 exon 7 deletion. This case points out the possible pitfalls in molecular diagnosis of SMA in affected patients and their relatives: exploration of the SMN1 exon 7 (c.840C/T alleles) may be disturbed by several non-pathological or pathological variants around the SMN1 exon 7. In order to accurately describe the molecular defect in an SMA-affected patient, we propose to apply the Human Genome Variation Society nomenclature. This widely accepted nomenclature would improve the reporting of the molecular defect observed in SMA patients and thus would avoid the commonly used but imprecise terminology "absence of SMN1 exon 7."
Spinal and bulbar muscular atrophy (SBMA) is an X-linked, late-onset neuro-endocrine disorder res... more Spinal and bulbar muscular atrophy (SBMA) is an X-linked, late-onset neuro-endocrine disorder resulting from an expansion of a CAG repeat in the androgen receptor gene. Material and method. We report the detailed phenotypic study in a series of 12 SBMA patients evaluated in four kindreds. Clinical phenotypic spectrum varied considerably, ranging from childhood-onset weakness and atrophy mimicking limb-girdle myopathy in patients with 53 CAG repeats to isolated hyperCKemia in an adult with 42 CAG repeats. All male patients had gynecomastia. Two female carriers presented with paresthesias and hand action tremor. Homozygous deletions of SMN1 and SMN2 genes were not found in any patients. This report demonstrates that SBMA may present with a wider clinical spectrum than previously described and suggests that clinical phenotype severity in SBMA is partially linked to the number of CAG repeats. It also suggests that SMN1 and SMN2 genes do not act as modifying genes in SBMA.
Until recently, Bardet-Biedl syndrome was considered as a classic autosomal recessive condition. ... more Until recently, Bardet-Biedl syndrome was considered as a classic autosomal recessive condition. The disorder is defined by the association of the following clinical features: retinitis pigmentosa, polydactyly, obesity, hypogonadism, and possible mental retardation. This syndrome leads to multiple handicaps (visual impairment, complications of obesity, kidney failure, endocrine dysfunction). This condition, apparently clearly defined from a clinical point of view, appears to be genetically heterogenous. To date, six different genes have been identified: BBS1, BBS2, BBS4, BBS6, BBS7 and BBS8. Interestingly, this condition has recently been linked to a failure of cellular ciliogenesis. Moreover, this disorder is characterized by an additional degree of complexity, as it is the first example of triallelic inheritance described in human beings. However, this new finding appears to be less frequent than expected in this syndrome.
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Papers by M. Cossée