We report here four families with congenital contractural arachnodactyly (CCA) in which a wide ra... more We report here four families with congenital contractural arachnodactyly (CCA) in which a wide range of phenotypic expression is observed. In one family with a large number of affected individuals the condition is mildly expressed. These individuals usually have crumpled ears, camptodactyly with ulnar deviation of the fingers, adducted thumbs, limited elbow and/or knee extension, and hypoplasia of the calf muscles. Arachnodactyly is not a constant feature. No spinal deformities are present and only the proband has clubfoot deformities. With time, affecteds have experienced spontaneous improvement of their contractures and their condition in adulthood has not interfered with a normal lifestyle. Within this family there is little phenotypic variation between affected individuals. Those affected within each of the other families have had varying degrees of severity of the condition. A review of 29 other kindreds described in the literature with congenital contractural arachnodactyly shows that in this condition the most common features are abnormally formed ears, camptodactyly, arachnodactyly, adducted thumbs, limited movement of the elbows and knees, and underdevelopment of the calf muscles. Spontaneous improvement of the contractures with age is reported in 94% of cases. Kyphosis, scoliosis or kyphoscoliosis occurred in 50% and these defects were present in those who where more severely affected with CCA. No ocular problems have been reported in this syndrome, but congenital heart defects have occurred in 14.7%. Marfan syndrome is the most important condition to differentiate from congenital contractural arachnodactyly since these two conditions are similar phenotypically. However, in the former there are frequently serious ocular and cardiovascular problems which lead to significant morbidity and/or early death.
Habilidad Motriz Revista De Ciencias De La Actividad Fisica Y Del Deporte, 2004
Información del artículo Análisis de la actuación del entrenador de deporte escolar: un estudio e... more Información del artículo Análisis de la actuación del entrenador de deporte escolar: un estudio en voleibol.
, Summary of SMCHD1 mutations Table summarizing the mutation analysis in 60 FSHD2 families in all... more , Summary of SMCHD1 mutations Table summarizing the mutation analysis in 60 FSHD2 families in all protein-coding exons of SMCHD1 and their splice consensus sites. Mutations in SMCHD1 were identified in 51 families (85%), and for 9 families (15%) we could not find a mutation. Mutations that were identified in more families are highlighted in grey. The pathogenicity of the mutations was based on their segregation with D4Z4 hypomethylation, the absence in various SNP databases (dbSNP, the 1000 Genomes Project, the ESP Exome Variant Server, or in house databases) and nucleotide conservation (column 16). For missense mutations we evaluated the pathogenic effect of the point mutation by conservation analysis of the altered amino acid (column 17) and by checking the physicochemical difference between wild type and mutant amino acid (column 18). Further prediction whether an amino acid substitution affects protein function were done in columns 19-21 by Grantham difference, Align GVGD (Grantham Variation and Grantham Deviation) and SIFT (Sorting Intolerant from Tolerant). Column 1 shows the family number and column 2 the country of origin. In case the mutation was transmitted from the previous generation, column 3 shows from which parent it was inherited. The number of carriers and non-carriers identified are indicated in columns 4 and 5. The D4Z4 methylation, Delta 1 and Delta2 values for the index case or the average for families with multiple mutation carriers are shown in columns 7 and 8. Columns 9, 10, 11 and 12 show the position of the mutation with respect to genomic position, cDNA, protein and exon number, respectively. Mutation type categorization into Missense (M), Nonsense (N), Insertion/deletion (Indel) or Splicesite (5S or 3S) are shown in column 13. These mutation types can be further categorized into two main mutation types; D-ORF mutations (nonsense and splicing and indel frameshift mutations), which we predicted to result in reduced protein levels and P-ORF mutations (non-frame shifting; missense and in frame splicing mutations) that are interfering with the activity of the wild type allele (D-ORF and P-ORF in column 14). Mostly, these mutations can already be distinguished at the transcriptional level, as D-ORF mutations seem to be subjected to nonsense mediated mRNA decay (NMD) resulting in highly reduced levels of the mutant transcript, while P-ORF mutant transcripts can be found at levels similar to the wild type allele. Depending on the available material of SMCHD1 mutation carriers, we were able to study the effect of the mutation at the transcriptional level for 21 of these mutations and these results are summarized in column 15. For the other mutations in column 15, the transcriptional outcome was predicted. For 4/14 missense mutations a highly conserved amino acid was changed and for 4/10 other mutations a proline or cysteine was involved. We studied transcription of the mutant allele in five independent individuals carrying a different missense mutation. For all samples we found that wild type and mutant allele were equally expressed in PBMCs (Rf399 and Rf739) and myoblast (Rf683) and for Rf300 in both PBMCs and fibroblasts. This suggests that the steady state level of the missense mutant transcript is not affected and is suggestive for a dominant negative type mutation. The majority (n=19) of the identified splice site mutations were at the 5' splice site, while five were found at the 3' splice site (5S or 3S, respectively in column 13). Most of these mutations were in one of the highly conserved nucleotides at the 3' and 5' splice consensus sites. From 10 of these families we obtained RNA for transcription analysis. For most mutations we detected alternative splicing, mostly a complete skip and sometimes cryptic splicing or both events all involving the exon immediate adjacent to the mutation. Similar observations were done for the Dystrophin gene according to the Leiden Open (source) Variation Database (www.lovd.nl), where splice site mutations at the highly conserved nucleotides at the 3' and 5' splice consensus sites resulted in exon skipping in 81 out of 112 analyzed samples (not shown). Therefore, we predicted that all SMCHD1 splice site mutations involving one of the highly conserved nucleotides at the 3' and 5' splice consensus sites would result in a complete skip of the exon immediately adjacent to the mutation. In 7/10 families from whom we obtained material for Rf Country of Origin Inheritance carrier noncarrier average Fse average delta1 average delta2 genomic hg19 (GRCh37.p5) cDNA (NM_015295.2) protein (NP_056110.2) exon type D/P-ORF effect mutation at transcription nucleotide conservation amino acid conservation physico chemical difference Grantham difference Align GVGD (via Alamut) Grantham Variation (GV) and Deviation (GD) score SIFT (via Alamut) [Sorting Intolerant From Tolerant] 1 2 3 4 5 6 7 8
Archivos De Medicina Del Deporte Revista De La Federacion Espanola De Medicina Del Deporte Y De La Confederacion Iberoamericana De Medicina Del Deporte, 2011
, Summary of SMCHD1 mutations Table summarizing the mutation analysis in 60 FSHD2 families in all... more , Summary of SMCHD1 mutations Table summarizing the mutation analysis in 60 FSHD2 families in all protein-coding exons of SMCHD1 and their splice consensus sites. Mutations in SMCHD1 were identified in 51 families (85%), and for 9 families (15%) we could not find a mutation. Mutations that were identified in more families are highlighted in grey. The pathogenicity of the mutations was based on their segregation with D4Z4 hypomethylation, the absence in various SNP databases (dbSNP, the 1000 Genomes Project, the ESP Exome Variant Server, or in house databases) and nucleotide conservation (column 16). For missense mutations we evaluated the pathogenic effect of the point mutation by conservation analysis of the altered amino acid (column 17) and by checking the physicochemical difference between wild type and mutant amino acid (column 18). Further prediction whether an amino acid substitution affects protein function were done in columns 19-21 by Grantham difference, Align GVGD (Grantham Variation and Grantham Deviation) and SIFT (Sorting Intolerant from Tolerant). Column 1 shows the family number and column 2 the country of origin. In case the mutation was transmitted from the previous generation, column 3 shows from which parent it was inherited. The number of carriers and non-carriers identified are indicated in columns 4 and 5. The D4Z4 methylation, Delta 1 and Delta2 values for the index case or the average for families with multiple mutation carriers are shown in columns 7 and 8. Columns 9, 10, 11 and 12 show the position of the mutation with respect to genomic position, cDNA, protein and exon number, respectively. Mutation type categorization into Missense (M), Nonsense (N), Insertion/deletion (Indel) or Splicesite (5S or 3S) are shown in column 13. These mutation types can be further categorized into two main mutation types; D-ORF mutations (nonsense and splicing and indel frameshift mutations), which we predicted to result in reduced protein levels and P-ORF mutations (non-frame shifting; missense and in frame splicing mutations) that are interfering with the activity of the wild type allele (D-ORF and P-ORF in column 14). Mostly, these mutations can already be distinguished at the transcriptional level, as D-ORF mutations seem to be subjected to nonsense mediated mRNA decay (NMD) resulting in highly reduced levels of the mutant transcript, while P-ORF mutant transcripts can be found at levels similar to the wild type allele. Depending on the available material of SMCHD1 mutation carriers, we were able to study the effect of the mutation at the transcriptional level for 21 of these mutations and these results are summarized in column 15. For the other mutations in column 15, the transcriptional outcome was predicted. For 4/14 missense mutations a highly conserved amino acid was changed and for 4/10 other mutations a proline or cysteine was involved. We studied transcription of the mutant allele in five independent individuals carrying a different missense mutation. For all samples we found that wild type and mutant allele were equally expressed in PBMCs (Rf399 and Rf739) and myoblast (Rf683) and for Rf300 in both PBMCs and fibroblasts. This suggests that the steady state level of the missense mutant transcript is not affected and is suggestive for a dominant negative type mutation. The majority (n=19) of the identified splice site mutations were at the 5' splice site, while five were found at the 3' splice site (5S or 3S, respectively in column 13). Most of these mutations were in one of the highly conserved nucleotides at the 3' and 5' splice consensus sites. From 10 of these families we obtained RNA for transcription analysis. For most mutations we detected alternative splicing, mostly a complete skip and sometimes cryptic splicing or both events all involving the exon immediate adjacent to the mutation. Similar observations were done for the Dystrophin gene according to the Leiden Open (source) Variation Database (www.lovd.nl), where splice site mutations at the highly conserved nucleotides at the 3' and 5' splice consensus sites resulted in exon skipping in 81 out of 112 analyzed samples (not shown). Therefore, we predicted that all SMCHD1 splice site mutations involving one of the highly conserved nucleotides at the 3' and 5' splice consensus sites would result in a complete skip of the exon immediately adjacent to the mutation. In 7/10 families from whom we obtained material for Rf Country of Origin Inheritance carrier noncarrier average Fse average delta1 average delta2 genomic hg19 (GRCh37.p5) cDNA (NM_015295.2) protein (NP_056110.2) exon type D/P-ORF effect mutation at transcription nucleotide conservation amino acid conservation physico chemical difference Grantham difference Align GVGD (via Alamut) Grantham Variation (GV) and Deviation (GD) score SIFT (via Alamut) [Sorting Intolerant From Tolerant] 1 2 3 4 5 6 7 8
We report here four families with congenital contractural arachnodactyly (CCA) in which a wide ra... more We report here four families with congenital contractural arachnodactyly (CCA) in which a wide range of phenotypic expression is observed. In one family with a large number of affected individuals the condition is mildly expressed. These individuals usually have crumpled ears, camptodactyly with ulnar deviation of the fingers, adducted thumbs, limited elbow and/or knee extension, and hypoplasia of the calf muscles. Arachnodactyly is not a constant feature. No spinal deformities are present and only the proband has clubfoot deformities. With time, affecteds have experienced spontaneous improvement of their contractures and their condition in adulthood has not interfered with a normal lifestyle. Within this family there is little phenotypic variation between affected individuals. Those affected within each of the other families have had varying degrees of severity of the condition. A review of 29 other kindreds described in the literature with congenital contractural arachnodactyly shows that in this condition the most common features are abnormally formed ears, camptodactyly, arachnodactyly, adducted thumbs, limited movement of the elbows and knees, and underdevelopment of the calf muscles. Spontaneous improvement of the contractures with age is reported in 94% of cases. Kyphosis, scoliosis or kyphoscoliosis occurred in 50% and these defects were present in those who where more severely affected with CCA. No ocular problems have been reported in this syndrome, but congenital heart defects have occurred in 14.7%. Marfan syndrome is the most important condition to differentiate from congenital contractural arachnodactyly since these two conditions are similar phenotypically. However, in the former there are frequently serious ocular and cardiovascular problems which lead to significant morbidity and/or early death.
Habilidad Motriz Revista De Ciencias De La Actividad Fisica Y Del Deporte, 2004
Información del artículo Análisis de la actuación del entrenador de deporte escolar: un estudio e... more Información del artículo Análisis de la actuación del entrenador de deporte escolar: un estudio en voleibol.
, Summary of SMCHD1 mutations Table summarizing the mutation analysis in 60 FSHD2 families in all... more , Summary of SMCHD1 mutations Table summarizing the mutation analysis in 60 FSHD2 families in all protein-coding exons of SMCHD1 and their splice consensus sites. Mutations in SMCHD1 were identified in 51 families (85%), and for 9 families (15%) we could not find a mutation. Mutations that were identified in more families are highlighted in grey. The pathogenicity of the mutations was based on their segregation with D4Z4 hypomethylation, the absence in various SNP databases (dbSNP, the 1000 Genomes Project, the ESP Exome Variant Server, or in house databases) and nucleotide conservation (column 16). For missense mutations we evaluated the pathogenic effect of the point mutation by conservation analysis of the altered amino acid (column 17) and by checking the physicochemical difference between wild type and mutant amino acid (column 18). Further prediction whether an amino acid substitution affects protein function were done in columns 19-21 by Grantham difference, Align GVGD (Grantham Variation and Grantham Deviation) and SIFT (Sorting Intolerant from Tolerant). Column 1 shows the family number and column 2 the country of origin. In case the mutation was transmitted from the previous generation, column 3 shows from which parent it was inherited. The number of carriers and non-carriers identified are indicated in columns 4 and 5. The D4Z4 methylation, Delta 1 and Delta2 values for the index case or the average for families with multiple mutation carriers are shown in columns 7 and 8. Columns 9, 10, 11 and 12 show the position of the mutation with respect to genomic position, cDNA, protein and exon number, respectively. Mutation type categorization into Missense (M), Nonsense (N), Insertion/deletion (Indel) or Splicesite (5S or 3S) are shown in column 13. These mutation types can be further categorized into two main mutation types; D-ORF mutations (nonsense and splicing and indel frameshift mutations), which we predicted to result in reduced protein levels and P-ORF mutations (non-frame shifting; missense and in frame splicing mutations) that are interfering with the activity of the wild type allele (D-ORF and P-ORF in column 14). Mostly, these mutations can already be distinguished at the transcriptional level, as D-ORF mutations seem to be subjected to nonsense mediated mRNA decay (NMD) resulting in highly reduced levels of the mutant transcript, while P-ORF mutant transcripts can be found at levels similar to the wild type allele. Depending on the available material of SMCHD1 mutation carriers, we were able to study the effect of the mutation at the transcriptional level for 21 of these mutations and these results are summarized in column 15. For the other mutations in column 15, the transcriptional outcome was predicted. For 4/14 missense mutations a highly conserved amino acid was changed and for 4/10 other mutations a proline or cysteine was involved. We studied transcription of the mutant allele in five independent individuals carrying a different missense mutation. For all samples we found that wild type and mutant allele were equally expressed in PBMCs (Rf399 and Rf739) and myoblast (Rf683) and for Rf300 in both PBMCs and fibroblasts. This suggests that the steady state level of the missense mutant transcript is not affected and is suggestive for a dominant negative type mutation. The majority (n=19) of the identified splice site mutations were at the 5' splice site, while five were found at the 3' splice site (5S or 3S, respectively in column 13). Most of these mutations were in one of the highly conserved nucleotides at the 3' and 5' splice consensus sites. From 10 of these families we obtained RNA for transcription analysis. For most mutations we detected alternative splicing, mostly a complete skip and sometimes cryptic splicing or both events all involving the exon immediate adjacent to the mutation. Similar observations were done for the Dystrophin gene according to the Leiden Open (source) Variation Database (www.lovd.nl), where splice site mutations at the highly conserved nucleotides at the 3' and 5' splice consensus sites resulted in exon skipping in 81 out of 112 analyzed samples (not shown). Therefore, we predicted that all SMCHD1 splice site mutations involving one of the highly conserved nucleotides at the 3' and 5' splice consensus sites would result in a complete skip of the exon immediately adjacent to the mutation. In 7/10 families from whom we obtained material for Rf Country of Origin Inheritance carrier noncarrier average Fse average delta1 average delta2 genomic hg19 (GRCh37.p5) cDNA (NM_015295.2) protein (NP_056110.2) exon type D/P-ORF effect mutation at transcription nucleotide conservation amino acid conservation physico chemical difference Grantham difference Align GVGD (via Alamut) Grantham Variation (GV) and Deviation (GD) score SIFT (via Alamut) [Sorting Intolerant From Tolerant] 1 2 3 4 5 6 7 8
Archivos De Medicina Del Deporte Revista De La Federacion Espanola De Medicina Del Deporte Y De La Confederacion Iberoamericana De Medicina Del Deporte, 2011
, Summary of SMCHD1 mutations Table summarizing the mutation analysis in 60 FSHD2 families in all... more , Summary of SMCHD1 mutations Table summarizing the mutation analysis in 60 FSHD2 families in all protein-coding exons of SMCHD1 and their splice consensus sites. Mutations in SMCHD1 were identified in 51 families (85%), and for 9 families (15%) we could not find a mutation. Mutations that were identified in more families are highlighted in grey. The pathogenicity of the mutations was based on their segregation with D4Z4 hypomethylation, the absence in various SNP databases (dbSNP, the 1000 Genomes Project, the ESP Exome Variant Server, or in house databases) and nucleotide conservation (column 16). For missense mutations we evaluated the pathogenic effect of the point mutation by conservation analysis of the altered amino acid (column 17) and by checking the physicochemical difference between wild type and mutant amino acid (column 18). Further prediction whether an amino acid substitution affects protein function were done in columns 19-21 by Grantham difference, Align GVGD (Grantham Variation and Grantham Deviation) and SIFT (Sorting Intolerant from Tolerant). Column 1 shows the family number and column 2 the country of origin. In case the mutation was transmitted from the previous generation, column 3 shows from which parent it was inherited. The number of carriers and non-carriers identified are indicated in columns 4 and 5. The D4Z4 methylation, Delta 1 and Delta2 values for the index case or the average for families with multiple mutation carriers are shown in columns 7 and 8. Columns 9, 10, 11 and 12 show the position of the mutation with respect to genomic position, cDNA, protein and exon number, respectively. Mutation type categorization into Missense (M), Nonsense (N), Insertion/deletion (Indel) or Splicesite (5S or 3S) are shown in column 13. These mutation types can be further categorized into two main mutation types; D-ORF mutations (nonsense and splicing and indel frameshift mutations), which we predicted to result in reduced protein levels and P-ORF mutations (non-frame shifting; missense and in frame splicing mutations) that are interfering with the activity of the wild type allele (D-ORF and P-ORF in column 14). Mostly, these mutations can already be distinguished at the transcriptional level, as D-ORF mutations seem to be subjected to nonsense mediated mRNA decay (NMD) resulting in highly reduced levels of the mutant transcript, while P-ORF mutant transcripts can be found at levels similar to the wild type allele. Depending on the available material of SMCHD1 mutation carriers, we were able to study the effect of the mutation at the transcriptional level for 21 of these mutations and these results are summarized in column 15. For the other mutations in column 15, the transcriptional outcome was predicted. For 4/14 missense mutations a highly conserved amino acid was changed and for 4/10 other mutations a proline or cysteine was involved. We studied transcription of the mutant allele in five independent individuals carrying a different missense mutation. For all samples we found that wild type and mutant allele were equally expressed in PBMCs (Rf399 and Rf739) and myoblast (Rf683) and for Rf300 in both PBMCs and fibroblasts. This suggests that the steady state level of the missense mutant transcript is not affected and is suggestive for a dominant negative type mutation. The majority (n=19) of the identified splice site mutations were at the 5' splice site, while five were found at the 3' splice site (5S or 3S, respectively in column 13). Most of these mutations were in one of the highly conserved nucleotides at the 3' and 5' splice consensus sites. From 10 of these families we obtained RNA for transcription analysis. For most mutations we detected alternative splicing, mostly a complete skip and sometimes cryptic splicing or both events all involving the exon immediate adjacent to the mutation. Similar observations were done for the Dystrophin gene according to the Leiden Open (source) Variation Database (www.lovd.nl), where splice site mutations at the highly conserved nucleotides at the 3' and 5' splice consensus sites resulted in exon skipping in 81 out of 112 analyzed samples (not shown). Therefore, we predicted that all SMCHD1 splice site mutations involving one of the highly conserved nucleotides at the 3' and 5' splice consensus sites would result in a complete skip of the exon immediately adjacent to the mutation. In 7/10 families from whom we obtained material for Rf Country of Origin Inheritance carrier noncarrier average Fse average delta1 average delta2 genomic hg19 (GRCh37.p5) cDNA (NM_015295.2) protein (NP_056110.2) exon type D/P-ORF effect mutation at transcription nucleotide conservation amino acid conservation physico chemical difference Grantham difference Align GVGD (via Alamut) Grantham Variation (GV) and Deviation (GD) score SIFT (via Alamut) [Sorting Intolerant From Tolerant] 1 2 3 4 5 6 7 8
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