3.R25G mutation in exon 1 of LMNA gene is associated with dilated cardiomyopathy and limb-girdle muscular dystrophy 1B.
Wo-liang YUAN ; Chun-yan HUANG ; Jing-feng WANG ; Shuang-lun XIE ; Ru-qiong NIE ; Ying-mei LIU ; Pin-ming LIU ; Shu-xian ZHOU ; Su-qin CHEN ; Wei-jun HUANG
Chinese Medical Journal 2009;122(23):2840-2845
BACKGROUNDMutations of the LMNA gene encoding lamin A and C are associated with dilated cardiomyopathy (DCM), conduction system defects and skeletal muscle dystrophy. Here we report a family with a mutation of the LMNA gene to identify the relationship between genotype and phenotype.
METHODSAll 30 members of the family underwent clinical and genetic evaluation. A mutation analysis of the LMNA gene was performed. All of the 12 exons of LMNA gene were extended with polymerase chain reaction (PCR) and the PCR products were screened for gene mutation by direct sequencing.
RESULTSTen members of the family had limb-girdle muscular dystrophy (LGMD) and 6 are still alive. Two patients suffered from DCM. Cardiac arrhythmias included atrioventricular block and atrial fibrillation; sudden death occurred in 2 patients. The pattern of inheritance was autosomal dominant. Mutation c.73C > G (R25G) in exon 1 encoding the globular domains was confirmed in all of the affected members, resulting in the conversion of arginine (Arg) to glycine (Gly).
CONCLUSIONSThe mutation R25G in exon 1 of LMNA gene we reported here in a Chinese family had a phenotype of malignant arrhythmia and mild LGMD, suggesting that patients with familial DCM, conduction system defects and skeletal muscle dystrophy should be screened by genetic testing for the LMNA gene.
Adult ; Cardiomyopathy, Dilated ; genetics ; Exons ; Humans ; Lamin Type A ; genetics ; Muscular Dystrophies, Limb-Girdle ; genetics ; Mutation
4.Analysis of clinical features and genetic variants in three Chinese pedigrees affected with Limb girdle muscular dystrophy type 2I.
Guangyu WANG ; Ling XU ; Dandan ZHAO ; Chuanzhu YAN ; Pengfei LIN
Chinese Journal of Medical Genetics 2022;39(11):1205-1210
OBJECTIVE:
To analyze the clinical features and genetic variants of three Chinese pedigrees affected with Limb girdle muscular dystrophy type 2I (LGMD2I).
METHODS:
Clinical data and peripheral blood samples of the three probands and their family members were collected. Whole exome sequencing was carried out for the probands. Candidate variants were verified by Sanger sequencing of their family members.
RESULTS:
Probands 1 and 2 both featured weakness in the lower limbs. Proband 1 had lost walking ability and had pulmonary ventilation dysfunction. Proband 3 had lower limb pain, palpitations and asthma after exercise. Genetic sequencing revealed that proband 1 harbored compound heterozygous c.545A>G (p.Y182C) and c.1391A>T (p.N464I) variants of the FKRP gene, proband 2 harbored compound heterozygous c.545A>G (p.Y182C) and c.941C>T (p.T314M) variants of the FKRP gene, and proband 3 harbored compound heterozygous c.545A>G (p.Y182C) and c.161G>A (p.R54Q) variants. Among these, the c.161G>A (p.R54Q) variant was unreported previously.
CONCLUSION
Compound heterozygous variants of the FKRP gene probably underlay the LGMD2I in the three patients. Whole exome sequencing is crucial for the diagnosis of LGMD2I. The identification of the novel variant also broadened the mutational spectrum of the FKRP gene.
Humans
;
Pedigree
;
Pentosyltransferases/genetics*
;
Muscle, Skeletal
;
Proteins/genetics*
;
Muscular Dystrophies, Limb-Girdle/genetics*
;
Mutation
;
China
5.Analysis of genetic variants in five pedigrees affected with Dysferlinopathy.
Yanjie XIA ; Panlai SHI ; Yaqin HOU ; Duo CHEN ; Peng DAI ; Xinyu ZHAO ; Xiangdong KONG
Chinese Journal of Medical Genetics 2021;38(3):205-209
OBJECTIVE:
To analyze the clinical phenotype and genetic variants in five Chinese pedigrees affected with Dysferlinopathy.
METHODS:
Next generation sequencing (NGS) was carried out for the probands from the five pedigrees. Suspected variants were validated by Sanger sequencing. Pathogenicity of the variants was assessed based on the standards and guidelines by the American College of Medical Genetics and Genomics (ACMG).
RESULTS:
Ten DYSF gene variants (including 5 frameshift variants, 3 splicing variants, 1 missense variant and 1 nonsense variant) were detected. Among these, c.1375dupA (p.Met459Asnfs*15), c.610C>T (p.Arg204X), c.1180+5G>A and c.1284+2T>C were known to be pathogenic, while c.4008_4010delCCTinsAC (p.Leu1337Argfs*8), c.1137_1169del (p.379_390del), c.754A>G(p.Thr252Ala), c.1175_1176insGCAGAGTG (p.Met394Serfs*7), c.3114_3115insCGGC (p.Arg1040Profs*74) and c.1053+3G>C were unreported previously. Of the six novel variants, c.1137_1169del, c.1175_1176insGCAGAGTG and c.3114_3115insCGGC were predicted as pathogenic (PVS1+PM2+PM3), c.4008_4010delCCTinsAC as likely pathogenic (PVS1+PM2), c.754A>G and c.1053+3G>C as variants of uncertain significance based on the ACMG standards and guidelines.
CONCLUSION
Variants of the DYSF gene probably underlay Dysferlinopathy in the patients among the five pedigrees. Above finding has enriched the spectrum of DYSF gene variants.
Humans
;
Muscular Dystrophies, Limb-Girdle/genetics*
;
Mutation
;
Pedigree
;
Phenotype
;
RNA Splicing
6.Analysis of clinical characteristics and genetic variants in two children with Limb-girdle muscular dystrophy autosomal recessive 9 FKRP-related.
Jie YU ; Min XU ; Le DING ; Yanjun HUANG ; Hu GUO ; Yan HE
Chinese Journal of Medical Genetics 2023;40(10):1217-1221
OBJECTIVE:
To explore the correlation between clinical manifestations of Limb-girdle muscular dystrophy autosomal recessive 9 FKRP-related (R9 FKRP-related) and variants of the FKRP gene.
METHODS:
Two children who had presented at the Children's Hospital of Nanjing Medical University respectively due to increased serum myocardial zymogram and hepatic dysfunction on September 30, 2018 and August 3, 2018 were selected as the study subjects. Clinical data of the children were collected. Both children were suspected for Duchenne or Becker muscular dystrophy for asymptomatic high creatine kinase (CK) levels. Peripheral blood samples of the children and their parents were collected for whole exome sequencing, and candidate variants were validated by Sanger sequencing.
RESULTS:
Genetic testing revealed that both children have carried compound heterozygous variants of the FKRP gene. The c.545A>G and c.941C>T variants in child 1 have been reported previously, among which the c.545A>G is a hot spot mutation in the Chinese population. Child 2 has carried c.602T>C and c.961G>A variants, both of which were unreported previously.
CONCLUSION
Both children have met the diagnostic criteria for LGMD R9 FKRP-related. Carriers of the c.545A>G variant may present milder symptoms. Compared with patients carrying null variants, carriers of compound heterozygous missense variants may present with a milder phenotype, manifesting as asymptomatic high CK level.
Humans
;
Child
;
Asian People/genetics*
;
Genetic Testing
;
Muscular Dystrophies, Limb-Girdle/genetics*
;
Muscular Dystrophy, Duchenne
;
Pentosyltransferases/genetics*
7.Limb-girdle muscular dystrophy type 2G: clinical, pathological and genetic analysis of a case.
Wei WANG ; Ying HAO ; Renbin WANG ; Miao JIN ; Jinsong JIAO
Chinese Journal of Medical Genetics 2014;31(4):476-478
OBJECTIVETo investigate TCAP gene mutation and clinical features of a Chinese patient with limb-girdle muscular dystrophy type 2G(LGMD 2G).
METHODSClinical data of the patient was analyzed. Exons of the TCAP gene were amplified and sequenced.
RESULTSThe patient has presented clinically as LGMD and pathologically as vacuolar myopathy. Genetic analysis has identified compound heterozygous mutations of exons 1 and 2 of the TCAP gene(c.100delC, c.166insG).
CONCLUSIONLGMD is a group of neuromuscular disorders with substantial phenotypic heterogeneity. Genetic diagnosis has become indispensable for accurate diagnosis for patients suspected to have the disease.
Adult ; Base Sequence ; Connectin ; genetics ; Exons ; Female ; Humans ; Molecular Sequence Data ; Muscular Dystrophies, Limb-Girdle ; genetics ; Young Adult
8.Analysis of TNPO3 gene variant and clinical phenotype in a neonate with limb-girdle muscular dystrophies form 1F.
Min GAO ; Liangchao HOU ; Kaihui ZHANG ; Yuqiang LYU ; Jian MA ; Dong WANG ; Zhongtao GAI ; Yi LIU
Chinese Journal of Medical Genetics 2022;39(9):979-982
OBJECTIVE:
To explore the genetic basis for a neonate featuring developmental delay.
METHODS:
Clinical examination and laboratory tests were carried out for the patient. Peripheral venous blood samples of the proband and his parents were extracted and subjected to target capture next generation sequencing. Candidate variant was verified by Sanger sequencing.
RESULTS:
The patient, a four-month-old male, has presented with developmental delay and weakness of limbs. Genetic testing revealed that he had harbored a novel c.1432C>T variant of the TNPO3 gene, which was inherited from his mother. The nonsense variant has resulted in premature termination of protein translation and was predicted to be pathogenic by bioinformatics analysis.
CONCLUSION
The heterozygous c.1432C>T variant of the TNPO3 gene probably underlay the limb-girdle muscular dystrophies form 1F in this patient. Above finding has enriched the variation spectrum of the TNPO3 gene.
Genetic Testing
;
Heterozygote
;
High-Throughput Nucleotide Sequencing
;
Humans
;
Infant
;
Male
;
Muscular Dystrophies, Limb-Girdle/genetics*
;
Mutation
;
Phenotype
;
beta Karyopherins/genetics*
9.Application of targeted capture technology and next generation sequencing in molecular diagnosis of inherited myopathy.
Xiaona FU ; Aijie LIU ; Haipo YANG ; Cuijie WEI ; Juan DING ; Shuang WANG ; Jingmin WANG ; Yun YUAN ; Yuwu JIANG ; Hui XIONG
Chinese Journal of Pediatrics 2015;53(10):741-746
OBJECTIVETo elucidate the usefulness of next generation sequencing for diagnosis of inherited myopathy, and to analyze the relevance between clinical phenotype and genotype in inherited myopathy.
METHODRelated genes were selected for SureSelect target enrichment system kit (Panel Version 1 and Panel Version 2). A total of 134 patients who were diagnosed as inherited myopathy clinically underwent next generation sequencing in Department of Pediatrics, Peking University First Hospital from January 2013 to June 2014. Clinical information and gene detection result of the patients were collected and analyzed.
RESULTSeventy-seven of 134 patients (89 males and 45 females, visiting ages from 6-month-old to 26-year-old, average visiting age was 6 years and 1 month) underwent next generation sequencing by Panel Version 1 in 2013, and 57 patients underwent next generation sequencing by Panel Version 2 in 2014. The gene detection revealed that 74 patients had pathogenic gene mutations, and the positive rate of genetic diagnosis was 55.22%. One patient was diagnosed as metabolic myopathy. Five patients were diagnosed as congenital myopathy; 68 were diagnosed as muscular dystrophy, including 22 with congenital muscular dystrophy 1A (MDC1A), 11 with Ullrich congenital muscular dystrophy (UCMD), 6 with Bethlem myopathy (BM), 12 with Duchenne muscular dystrophy (DMD) caused by point mutations in DMD gene, 5 with LMNA-related congenital muscular dystrophy (L-CMD), 1 with Emery-Dreifuss muscular dystrophy (EDMD), 7 with alpha-dystroglycanopathy (α-DG) patients, and 4 with limb-girdle muscular dystrophy (LGMD) patients.
CONCLUSIONNext generation sequencing plays an important role in diagnosis of inherited myopathy. Clinical and biological information analysis was essential for screening pathogenic gene of inherited myopathy.
Adolescent ; Child ; Child, Preschool ; Contracture ; DNA Mutational Analysis ; Female ; Genetic Diseases, Inborn ; diagnosis ; genetics ; Genetic Testing ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; Infant ; Male ; Molecular Diagnostic Techniques ; Muscular Diseases ; diagnosis ; genetics ; Muscular Dystrophies ; congenital ; Muscular Dystrophies, Limb-Girdle ; Muscular Dystrophy, Duchenne ; Muscular Dystrophy, Emery-Dreifuss ; Mutation ; Phenotype ; Sclerosis ; Walker-Warburg Syndrome ; Young Adult
10.Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations.
Hyung Jun PARK ; Hoon JANG ; Jung Hwan LEE ; Ha Young SHIN ; Sung Rae CHO ; Kee Duk PARK ; Duhee BANG ; Min Goo LEE ; Seung Min KIM ; Ji Hyun LEE ; Young Chul CHOI
Yonsei Medical Journal 2016;57(1):173-179
PURPOSE: This study was designed to investigate the characteristics of Korean patients with calpainopathy. MATERIALS AND METHODS: Thirteen patients from ten unrelated families were diagnosed with calpainopathy via direct or targeted sequencing of the CAPN3 gene. Clinical, mutational, and pathological spectra were then analyzed. RESULTS: Nine different mutations, including four novel mutations (NM_000070: c.1524+1G>T, c.1789_1790inA, c.2184+1G>T, and c.2384C>T) were identified. The median age at symptom onset was 22 (interquartile range: 15-28). Common clinical findings were joint contracture in nine patients, winged scapula in four, and lordosis in one. However, we also found highly variable clinical features including early onset joint contractures, asymptomatic hyperCKemia, and heterogeneous clinical severity in three members of the same family. Four of nine muscle specimens revealed lobulated fibers, but three showed normal skeletal muscle histology. CONCLUSION: We identified four novel CAPN3 mutations and demonstrated clinical and pathological heterogeneity in Korean patients with calpainopathy.
Adolescent
;
Adult
;
Amino Acid Sequence
;
Asian Continental Ancestry Group/*genetics
;
Calpain/*genetics
;
Female
;
Genetic Testing
;
Humans
;
Male
;
Molecular Sequence Data
;
Muscle Proteins/*genetics
;
Muscle, Skeletal/pathology
;
Muscular Dystrophies, Limb-Girdle/ethnology/*genetics/*pathology
;
*Mutation
;
Republic of Korea