Limb-Girdle Muscular Dystrophy (LGMD) Type 1B: LMNA Gene Sequencing

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Condition Description

Limb-girdle muscular dystrophy (LGMD) is a descriptive term applied to a clinically and genetically heterogeneous group of childhood- or adult-onset muscular dystrophies. LGMD is characterized by weakness and wasting restricted to the limb musculature, proximal greater than distal. Most individuals with LGMD show relative sparing of the heart and bulbar muscles, although exceptions occur, depending on the genetic subtype. Onset, progression, and distribution of the weakness and wasting vary considerably among individuals and genetic subtypes. Serum creatine kinase (CK) levels in individuals with LGMD are usually elevated, and muscle biopsy reveals dystrophic changes. Immunohistochemistry (IHC) testing of a muscle biopsy sample can be used to determine the presence or absence of specific proteins, and confirmatory genetic testing is available in some cases. LGMDs are distinct from the much more common X-linked dystrophinopathies, which include Duchenne and Becker muscular dystrophy (DMD/BMD).

LGMD 1B, also referred to as laminopathy, can have an age of onset from birth through adulthood, with about half of affected individuals having childhood onset. Both proximal lower limb muscle weakness and cardiac involvement are present by the third decade. The onset of skeletal muscle weakness occurs prior to the onset of cardiac involvement, which may manifest in the teenage years or later. Left ventricular hypertrophy and atrioventricular conduction defect are common and can progress to second-degree heart block requiring a pacemaker; rarely, dilated cardiomyopathy is present. Serum CK levels are normal to mildly elevated, and IHC is normal. LGMD 1B is inherited in an autosomal dominant manner.

Mutations in the LMNA gene (1q21.2) cause LGMD 1B. Mutations in LMNA also result in at least ten other allelic conditions, including autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy, Dunnigan-type familial partial lipodystrophy (FPLD), mandibuloacral dysplasia, Hutchinson-Gilford progeria syndrome, and Charcot-Marie-Tooth type 2B1.

For patients with suspected LGMD 1B, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

Visit www.ThinkGenetic.com for patient-friendly information on limb-girdle muscular dystrophy.

References:

  • Bonnemann, C. Limb-girdle muscular dystrophy in childhood. Pediatric Annals. 2005; 34(7):569-577.
  • GeneTests: Limb-Girdle Muscular Dystrophy Overview: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=lgmd-overview.

Genes (1)

Indications

This test is indicated for:

  • Confirmation of a clinical diagnosis of LGMD 1B

Methodology

PCR amplification of 12 exons contained in the LMNA gene is performed on the patient's genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient's gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.

Detection

Clinical Sensitivity: Unknown. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Submit only 1 of the following specimen types

Preferred specimen type: Whole Blood

Type: Whole Blood

Specimen Requirements:

In EDTA (purple top) or ACD (yellow top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

Type: Saliva

Specimen Requirements:

OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.

Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of Emory Genetics Laboratory, please submit a copy of the sequencing report with the test requisition.

  • Deletion/duplication analysis of the LMNA gene by CGH array is available for those individuals in whom sequence analysis is negative.
  • An LGMD sequencing panel that includes 11 LGMD genes is also available.
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available to individuals who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.
  • Full gene sequencing is available for the ZMPSTE24 gene.

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