Genotype/phenotype analysis in Chinese laminin‐α2 deficient congenital muscular dystrophy patients

Xiong, Hui; Tan, Dandan; Wang, S.; Song, Seng; Yang, Haiyuan; Gao, Kai; Liu, Aijie; Jiao, Hui; Mao, Bing; Ding, Jie; Chang, Xingzhi; Wang, J.; Wu, Ye; Yuan, Yun; Jiang, Yuwu; Zhang, Feng; Wu, Huizi; Wu, Xiru

doi:10.1111/cge.12366

Cited by 54 publications

(70 citation statements)

References 17 publications

(29 reference statements)

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“…In terms of the mutation spectrum of the LAMA2 gene, four independent studies described cohorts with more than twenty patients (Geranmayeh et al., ; Oliveira et al., ; Pegoraro et al., ; Xiong et al., ). The most frequent reported genotypes include variants that create premature termination codons (PTC) in both disease alleles, and are associated with complete deficiency of laminin‐α2 in muscle biopsy as well as an MDC1A phenotype.…”

Section: Introductionmentioning

confidence: 99%

LAMA2gene mutation update: Toward a more comprehensive picture of the laminin-α2 variome and its related phenotypes

Oliveira

Gruber²,

Cardoso

et al. 2018

Human Mutation

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Congenital muscular dystrophy type 1A (MDC1A) is one of the main subtypes of early-onset muscle disease, caused by disease-associated variants in the laminin-α2 (LAMA2) gene. MDC1A usually presents as a severe neonatal hypotonia and failure to thrive. Muscle weakness compromises normal motor development, leading to the inability to sit unsupported or to walk independently. The phenotype associated with LAMA2 defects has been expanded to include milder and atypical cases, being now collectively known as LAMA2-related muscular dystrophies (LAMA2-MD). Through an international multicenter collaborative effort, 61 new LAMA2 disease-associated variants were identified in 86 patients, representing the largest number of patients and new disease-causing variants in a single report. The collaborative variant collection was supported by the LOVD-powered LAMA2 gene variant database (https://www.LOVD.nl/LAMA2), updated as part of this work. As of December 2017, the database contains 486 unique LAMA2 variants (309 disease-associated), obtained from direct submissions and literature reports. Database content was systematically reviewed and further insights concerning LAMA2-MD are presented. We focus on the impact of missense changes, especially the c.2461A > C (p.Thr821Pro) variant and its association with late-onset LAMA2-MD. Finally, we report diagnostically challenging cases, highlighting the relevance of modern genetic analysis in the characterization of clinically heterogeneous muscle diseases.

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Section: Introductionmentioning

confidence: 99%

LAMA2gene mutation update: Toward a more comprehensive picture of the laminin-α2 variome and its related phenotypes

Oliveira

Gruber²,

Cardoso

et al. 2018

Human Mutation

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“…Candidate gene testings including Sanger sequencing to amplify the open reading frame and intron/exon boundaries, long‐range polymerase chain reaction (PCR) to detect the highly recurrent intronic mutation in COL6A1 , a three PCR‐primer method to detect the retrotransposition element insertion in FKTN and multiplex ligation‐dependent probe amplification or array‐based comparative genomic hybridization to detect copy number variations were performed on the basis of clinical phenotype. The methods have been reported for LAMA2 , the three collagen VI genes, POMT1 , FKRP , POMT2 , FKTN , POMGNT1 , and LMNA …”

Section: Methodsmentioning

confidence: 99%

Congenital muscular dystrophies in China

et al. 2019

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Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous conditions. We launched a nationwide study to determine the frequency of CMD in the Chinese population and assess the status of diagnosis and disease management for CMD in China. Cases were chosen from databases in 34 tertiary academic hospitals from 29 first‐level administrative divisions (provinces, municipalities, autonomous regions, and special administrative regions), and medical records were reviewed to confirm the diagnoses. The study included 409 patients, of those patients who consented to genetic testing (n = 340), mutations were identified in 286 of them. The most common forms identified were LAMA2‐related CMD (36.4%), followed by COL6‐related CMD (23.2%) and α‐dystroglycanopathy (21.0%). The forms of CMD related to mutations in LMNA and SEPN1 were less frequent (12.5% and 2.4%, respectively). We also recorded a significant difference in the diagnostic capabilities and disease management of CMD, with this being relatively backward in research centers from less developed regions. We provide, for the first time, comprehensive epidemiologic information of CMD in a large cohort of Chinese people. To our knowledge, this is the largest sample size of its kind so far highlighting the prevalence of CMD in China.

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“…Discussion MDC1A, originally described in 1994 (6), was shown to result from mutations in the laminin-α2 gene (LAMA2), which encodes the extracellular matrix protein merosin. Most mutations detected to date have been nonsense and splicing site point mutations and frame shift mutations (7). The absence of merosin results in early weakness, delayed development milestones, high blood levels of CK and normal cognition with white matter abnormalities on brain MRI (8,9).…”

Section: Molecular Genetic Testingmentioning

confidence: 99%

Muscle MRI findings in a one-year-old girl with merosin-deficient congenital muscular dystrophy type 1A due to LAMA2 mutation: A case report

Liang¹,

Li²,

Chen³

et al. 2017

Biomedical Reports

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Abstract. The objective of the present study was to characterize the muscle magnetic resonance imaging (MRI) features of a 1-year-old girl with merosin-deficient congenital muscular dystrophy type 1A (MDC1A). Beginning as an infant, this patient exhibited severe hypotonia and proximal weakness, as well as delays in developmental milestones. Her serum creatine kinase levels at 3 months, 8 months and 1 year were 2,959, 1,621 and 1,659 U/l, respectively. Brain MRI indicated symmetric, mild T1WI low, mild T2WI and FLAIR high radial patterns in the white matter of the Cornu posterius of the ventricular lateral. Gene sequencing demonstrated a heterozygous frame-shift mutation in the LAMA2 gene, consisting of an AG deletion at nucleotides 2049-2050 (LAMA2 c.2049_2050delAG). Lower limb muscle MRI presented obvious fatty infiltration of the muscles and muscle atrophy during the early stage of the disease. The gluteus maximus, erector spinae, vastus intermedius, vastus lateralis, adductor magnus, soleus and gastrocnemius muscles were involved, whereas the piriformis, obturator internus, pectineus, adductor longus, adductor brevis and sartorius muscles presented mild or no involvement. Fatty infiltration of the erector spinae was observed during the early stage of the disease. As an additional tool in the differential diagnosis of muscle disorders, muscle MRI can delay the need for muscle biopsy.

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Genotype/phenotype analysis in Chinese laminin‐α2 deficient congenital muscular dystrophy patients

Cited by 54 publications

References 17 publications

LAMA2gene mutation update: Toward a more comprehensive picture of the laminin-α2 variome and its related phenotypes

LAMA2gene mutation update: Toward a more comprehensive picture of the laminin-α2 variome and its related phenotypes

Congenital muscular dystrophies in China

Muscle MRI findings in a one-year-old girl with merosin-deficient congenital muscular dystrophy type 1A due to LAMA2 mutation: A case report

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