AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyse...AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.展开更多
Background Infantile proximal spinal muscular atrophy （SMA） is a common autosomal recessive neuromuscular disorder. Approximately 90-95% cases of SMA result from homozygous deletion of survival motor neuron gene 1（...Background Infantile proximal spinal muscular atrophy （SMA） is a common autosomal recessive neuromuscular disorder. Approximately 90-95% cases of SMA result from homozygous deletion of survival motor neuron gene 1（SMN1） and 5% cases are caused by compound heterozygous mutation （a SMN1 deletion on one allele and a subtle mutation on the other allele）.Methods In this research, two unrelated patients were clinically diagnosed according to the criteria of proximal SMA. Genetic diagnosis was performed to detect the homozygous deletion of exon 7 of SMN1 by PCR-restriction fragment length polymorphism （RFLP） and genomic sequencing. Multiplex ligation-dependent probe amplification （MLPA） analysis was carried out to measure copy numbers of SMN1, SMN2 and neuronal apoptosis inhibitor protein （NAIP） in the patients. Further sequencing of SMN1allele-specific PCR （AS-PCR） and SMN1 clones were also performed to analyze the point mutation of SMN1 gene. Additionally,the pedigree analysis of these two families was carried out to identify the transmission of the mutation.Results The inconsistent results using PCR-RFLP and genomic sequencing showed homozygous deletion of exon 7 of SMN1 and heterozygous deletion accompanied with a suspicious mutation in SMN1 gene, respectively. MLPA analysis of these two cases exhibited one SMN1 copy deletion. One identical c.863G〉T （p. Arg288Met） mutation was found in two cases by sequencing the SMN1 clones, which confirmed that both cases were SMA compound heterozygotes. One case showed partial conversion to form hybrid SMN （SMN2 17/SMN1 E8） identified by clones sequencing and another case carrying 3 SMN2 implied complete conversion from SMN1 to SMN2.Conclusion p. Arg288Met is more a disease-causing mutation than a polymorphism variation, and children with this mutation may have more severe phenotypes.展开更多
BACKGROUND Lissencephaly(LIS)is a malformation of cortical development with broad gyri,shallow sulci and thickened cortex characterized by developmental delays and seizures.Currently,20 genes have been implicated in L...BACKGROUND Lissencephaly(LIS)is a malformation of cortical development with broad gyri,shallow sulci and thickened cortex characterized by developmental delays and seizures.Currently,20 genes have been implicated in LIS.However,GRP56-related LIS has never been reported.GRP56 is considered one of the causative genes for bilateral frontoparietal polymicrogyria.Here,we report a twin infant with LIS and review the relevant literature.The twins both carried the novel compound heterozygous GPR56 mutations.CASE SUMMARY A 5-mo-old female infant was hospitalized due to repeated convulsions for 1 d.The patient had a flat head deformity that manifested as developmental delays and a sudden onset of generalized tonic-clonic seizures at 5 mo without any causes.The electroencephalography was normal.Brain magnetic resonance imaging revealed a simple brain structure with widened and thickened gyri and shallow sulci.The white matter of the brain was significantly reduced.Patchy long T1 and T2 signals could be seen around the ventricles,which were expanded,and the extracerebral space was widened.Genetic testing confirmed that the patient carried the GPR56 gene compound heterozygous mutations c.228delC(p.F76fs)and c.1820_1821delAT(p.H607fs).The unaffected father carried a heterozygous c.1820_1821delAT mutation,and the unaffected mother carried a heterozygous c.228delC mutation.The twin sister carried the same mutations as the proband.The patient was diagnosed with LIS.CONCLUSION This is the first case report of LIS that is likely caused by mutations of the GPR56 gene.展开更多
Mutations in MPV17 lead to severe mitochondrial DNA depletion syndrome(MTDPS).All known p.R50W variants in MPV17 are lethal.The homozygous variant p.R50Q in MPV17 among patients with Navajo neurohepatopathy is known t...Mutations in MPV17 lead to severe mitochondrial DNA depletion syndrome(MTDPS).All known p.R50W variants in MPV17 are lethal.The homozygous variant p.R50Q in MPV17 among patients with Navajo neurohepatopathy is known to allow longer survival,although heterozygous variants p.R50Q have not been reported.This is the first clinical report in compound heterozygosity MPV17 mutation(p.R50W/p.R50Q).Three siblings were admitted due to multiple hepatic nodules;none presented neurological abnormalities.However,they suffered from severe hypoglycemia and cyclic vomiting.The diagnosis of MPV17-related MTDPS was confirmed by detection of a compound heterozygous MPV17 mutation(p.R50W/p.R50Q),and striking reduction of hepatic mitochondrial DNA.One patient developed pediatric-onset of hepatocellular carcinoma.Notably,all patients survived for extended periods,including two patients who received liver transplantation,which contrasted the high mortality rate associated with p.R50W mutations,as previously reported.The p.R50Q mutation might be associated with longer survival and improved liver transplantation outcomes.展开更多
BACKGROUND Adenylosuccinate lyase(ADSL)deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene.It can cause severe neurological impairment and diverse clinical manifest...BACKGROUND Adenylosuccinate lyase(ADSL)deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene.It can cause severe neurological impairment and diverse clinical manifestations,including epilepsy.CASE SUMMARY Here,we describe a 3-year-old Chinese boy who had both psychomotor retardation and refractory epilepsy.Magnetic resonance imaging showed myelin hypoplasia.Electroencephalography findings supported a diagnosis of epilepsy.Whole-exon sequencing revealed the presence of a novel complex heterozygous mutation in the ADSL gene:The splicing mutation c.154-3C>G and the missense mutation c.71C>T(p.Pro24Leu).Considering the patient’s clinical presentation and genetic test results,the complex heterozygous mutation was predicted to prevent both ADSL alleles from producing normal ADSL,which may have led to ADSL deficiency.Finally,the child was diagnosed with ADSL deficiency.CONCLUSION We identified a novel complex heterozygous mutation in the ADSL gene associated with ADSL deficiency,thus expanding the known spectrum of pathogenic mutations that cause ADSL deficiency.Additionally,we describe epilepsy that occurs in patients with ADSL deficiency.展开更多
BACKGROUND Crumbs homolog 2(CRB2)is a recently discovered gene that is closely related to the maintenance of normal polarity in podocytes;mutations can directly lead to steroid-resistant nephrotic syndrome(SRNS).Howev...BACKGROUND Crumbs homolog 2(CRB2)is a recently discovered gene that is closely related to the maintenance of normal polarity in podocytes;mutations can directly lead to steroid-resistant nephrotic syndrome(SRNS).However,the characteristics of nephrotic syndrome(NS)caused by CRB2 mutations have not been described.CASE SUMMARY We report a novel compound heterozygous mutation of the CRB2 gene in two siblings with SRNS.The two siblings had edema,proteinuria,hypoproteinemia and hyperlipidemia.Both their father and mother had normal phenotypes(no history of NS).Whole exon sequencing(WES)of the family showed a novel compound heterozygous mutation,c.2290(exon 8)C>T and c.3613(exon 12)G>A.Glucocorticoid therapy(methylprednisolone pulse therapy or oral prednisone)and immunosuppressive agents(tacrolimus)had no effect.During a 3-year follow-up after genetic diagnosis by WES,proteinuria persisted,but the patient was healthy.CONCLUSION CRB2 mutations related to SRNS often occur in exons 7,10,and 12.Clinical manifestations of SRNS caused by CRB2 mutations are often less severe than in other forms of SRNS.展开更多
BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar at...BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.To date,many gene dysfunctions have been reported to be associated with SCAR4.CASE SUMMARY Here,we report a novel compound heterozygous mutation,c.3288delA(p.Asp1097-ThrfsTer6),in the VPS13D gene in a young female Chinese patient.The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital,including ataxia,neuropathy,and positive pyramidal signs.She was then diagnosed with SCAR4 and went home with symptomatic schemes.CONCLUSION SCAR4 is a hereditary disease characterized by ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.We report a novel compound heterozygous mutation,c.3288delA(p.Asp1097ThrfsTer6),in the VPS13D gene,which enriches the gene mutation spectrum and provides additional information about SCAR4.展开更多
文摘AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 81050034） and from the Foundation of Capital Institute of Pediatrics （No.10-B09）.
文摘Background Infantile proximal spinal muscular atrophy （SMA） is a common autosomal recessive neuromuscular disorder. Approximately 90-95% cases of SMA result from homozygous deletion of survival motor neuron gene 1（SMN1） and 5% cases are caused by compound heterozygous mutation （a SMN1 deletion on one allele and a subtle mutation on the other allele）.Methods In this research, two unrelated patients were clinically diagnosed according to the criteria of proximal SMA. Genetic diagnosis was performed to detect the homozygous deletion of exon 7 of SMN1 by PCR-restriction fragment length polymorphism （RFLP） and genomic sequencing. Multiplex ligation-dependent probe amplification （MLPA） analysis was carried out to measure copy numbers of SMN1, SMN2 and neuronal apoptosis inhibitor protein （NAIP） in the patients. Further sequencing of SMN1allele-specific PCR （AS-PCR） and SMN1 clones were also performed to analyze the point mutation of SMN1 gene. Additionally,the pedigree analysis of these two families was carried out to identify the transmission of the mutation.Results The inconsistent results using PCR-RFLP and genomic sequencing showed homozygous deletion of exon 7 of SMN1 and heterozygous deletion accompanied with a suspicious mutation in SMN1 gene, respectively. MLPA analysis of these two cases exhibited one SMN1 copy deletion. One identical c.863G〉T （p. Arg288Met） mutation was found in two cases by sequencing the SMN1 clones, which confirmed that both cases were SMA compound heterozygotes. One case showed partial conversion to form hybrid SMN （SMN2 17/SMN1 E8） identified by clones sequencing and another case carrying 3 SMN2 implied complete conversion from SMN1 to SMN2.Conclusion p. Arg288Met is more a disease-causing mutation than a polymorphism variation, and children with this mutation may have more severe phenotypes.
基金Supported by the Six Talent Peaks Project in Jiangsu Province,No.2016-YY-055.
文摘BACKGROUND Lissencephaly(LIS)is a malformation of cortical development with broad gyri,shallow sulci and thickened cortex characterized by developmental delays and seizures.Currently,20 genes have been implicated in LIS.However,GRP56-related LIS has never been reported.GRP56 is considered one of the causative genes for bilateral frontoparietal polymicrogyria.Here,we report a twin infant with LIS and review the relevant literature.The twins both carried the novel compound heterozygous GPR56 mutations.CASE SUMMARY A 5-mo-old female infant was hospitalized due to repeated convulsions for 1 d.The patient had a flat head deformity that manifested as developmental delays and a sudden onset of generalized tonic-clonic seizures at 5 mo without any causes.The electroencephalography was normal.Brain magnetic resonance imaging revealed a simple brain structure with widened and thickened gyri and shallow sulci.The white matter of the brain was significantly reduced.Patchy long T1 and T2 signals could be seen around the ventricles,which were expanded,and the extracerebral space was widened.Genetic testing confirmed that the patient carried the GPR56 gene compound heterozygous mutations c.228delC(p.F76fs)and c.1820_1821delAT(p.H607fs).The unaffected father carried a heterozygous c.1820_1821delAT mutation,and the unaffected mother carried a heterozygous c.228delC mutation.The twin sister carried the same mutations as the proband.The patient was diagnosed with LIS.CONCLUSION This is the first case report of LIS that is likely caused by mutations of the GPR56 gene.
基金This study was supported by the following grants.Kei Murayama was supported by the Practical Research Project(19ek0109273,18ek0109177)
文摘Mutations in MPV17 lead to severe mitochondrial DNA depletion syndrome(MTDPS).All known p.R50W variants in MPV17 are lethal.The homozygous variant p.R50Q in MPV17 among patients with Navajo neurohepatopathy is known to allow longer survival,although heterozygous variants p.R50Q have not been reported.This is the first clinical report in compound heterozygosity MPV17 mutation(p.R50W/p.R50Q).Three siblings were admitted due to multiple hepatic nodules;none presented neurological abnormalities.However,they suffered from severe hypoglycemia and cyclic vomiting.The diagnosis of MPV17-related MTDPS was confirmed by detection of a compound heterozygous MPV17 mutation(p.R50W/p.R50Q),and striking reduction of hepatic mitochondrial DNA.One patient developed pediatric-onset of hepatocellular carcinoma.Notably,all patients survived for extended periods,including two patients who received liver transplantation,which contrasted the high mortality rate associated with p.R50W mutations,as previously reported.The p.R50Q mutation might be associated with longer survival and improved liver transplantation outcomes.
基金Supported by the Natural Science Foundation of Shandong Province,No.ZR2019MH060。
文摘BACKGROUND Adenylosuccinate lyase(ADSL)deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene.It can cause severe neurological impairment and diverse clinical manifestations,including epilepsy.CASE SUMMARY Here,we describe a 3-year-old Chinese boy who had both psychomotor retardation and refractory epilepsy.Magnetic resonance imaging showed myelin hypoplasia.Electroencephalography findings supported a diagnosis of epilepsy.Whole-exon sequencing revealed the presence of a novel complex heterozygous mutation in the ADSL gene:The splicing mutation c.154-3C>G and the missense mutation c.71C>T(p.Pro24Leu).Considering the patient’s clinical presentation and genetic test results,the complex heterozygous mutation was predicted to prevent both ADSL alleles from producing normal ADSL,which may have led to ADSL deficiency.Finally,the child was diagnosed with ADSL deficiency.CONCLUSION We identified a novel complex heterozygous mutation in the ADSL gene associated with ADSL deficiency,thus expanding the known spectrum of pathogenic mutations that cause ADSL deficiency.Additionally,we describe epilepsy that occurs in patients with ADSL deficiency.
文摘BACKGROUND Crumbs homolog 2(CRB2)is a recently discovered gene that is closely related to the maintenance of normal polarity in podocytes;mutations can directly lead to steroid-resistant nephrotic syndrome(SRNS).However,the characteristics of nephrotic syndrome(NS)caused by CRB2 mutations have not been described.CASE SUMMARY We report a novel compound heterozygous mutation of the CRB2 gene in two siblings with SRNS.The two siblings had edema,proteinuria,hypoproteinemia and hyperlipidemia.Both their father and mother had normal phenotypes(no history of NS).Whole exon sequencing(WES)of the family showed a novel compound heterozygous mutation,c.2290(exon 8)C>T and c.3613(exon 12)G>A.Glucocorticoid therapy(methylprednisolone pulse therapy or oral prednisone)and immunosuppressive agents(tacrolimus)had no effect.During a 3-year follow-up after genetic diagnosis by WES,proteinuria persisted,but the patient was healthy.CONCLUSION CRB2 mutations related to SRNS often occur in exons 7,10,and 12.Clinical manifestations of SRNS caused by CRB2 mutations are often less severe than in other forms of SRNS.
文摘BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.To date,many gene dysfunctions have been reported to be associated with SCAR4.CASE SUMMARY Here,we report a novel compound heterozygous mutation,c.3288delA(p.Asp1097-ThrfsTer6),in the VPS13D gene in a young female Chinese patient.The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital,including ataxia,neuropathy,and positive pyramidal signs.She was then diagnosed with SCAR4 and went home with symptomatic schemes.CONCLUSION SCAR4 is a hereditary disease characterized by ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.We report a novel compound heterozygous mutation,c.3288delA(p.Asp1097ThrfsTer6),in the VPS13D gene,which enriches the gene mutation spectrum and provides additional information about SCAR4.
