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Molecular Genetics Laboratory

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FHL1-RELATED MYOPATHIES (FHL1 Sequence Analysis)

  • Synonyms: Myofibrillar Myopathy, SCAPULOPERONEAL MYOPATHY, X-LINKED DOMINANT; SPM, MYOPATHY, X-LINKED, WITH POSTURAL MUSCLE ATROPHY; XMPMA, MYOPATHY, REDUCING BODY, X-LINKED, CHILDHOOD-
  • LIS Mnemonic: MBFHL1SEQ

    Collect

    Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA is acceptable

    Volume Required

    5 ml whole blood or 3 ug extracted DNA

    Minimum Required

    3 ml whole blood

    Transport

    Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday within 24 hours of collection.

    Stability

    Whole blood can be refrigerated until shipment.

    Unacceptable conditions

    Heparinized specimens, severely hemolyzed specimens, frozen, clotted or possibly commingled specimens, blood in non-sterile or leaky containers, mislabeled or inappropriately labeled specimens.

    Specimen Handling

    Do not heat, freeze or centrifuge blood before shipment. Refrigerate sample until shipment.

Days Performed

Mon - Fri 9:00am to 4:00pm

Reported

4-6 weeks

CPT

81404

Disease Information

Clinical Features:

Mutations in the FHL1 gene (Four-and-a-half LIM Domains 1) have been identified in X-linked Scapuloperoneal Myopathy, X-linked Myopathy with Postural Muscle Atrophy, Emery-Dreifuss Muscular Dystrophy 6 and in X-Linked Reducing Body Myopathy (Windpassinger et al.2008; Gueneau et al.2009; Schessl et al., 2009). Scapuloperoneal syndrome encompasses heterogeneous neuromuscular disorders characterized by weakness in the shoulder girdle and peroneal muscles. The X-linked dominant form is caused due to mutations in the FHL1 gene. X-linked myopathy with postural muscle atrophy (XMPMA) is an X-linked recessive progressive muscular dystrophy with onset in adulthood. Affected individuals develop a proximal myopathy characterized by specific atrophy of postural muscles, limited neck flexion, bent spine, contractures of the Achilles tendon, respiratory problems, and cardiomyopathy (Windpassinger et al.2008). The clinical features of Emery-Dreifuss muscular dystrophy classically include the triad of muscle weakness, joint contractures, and cardiac involvement, thus showing clinical overlap with XMPMA. The X-linked form of Emery-Dreifuss muscular dystrophy is due to mutations in the FHL1 gene (Gueneau et al. 2009). Heterozygous female carriers are either asymptomatic or have cardiac disease and/or mild myopathy. X-linked Reducing Body Myopathy is a severe progressive fatal muscle disorder. Clinical presentation of these patients has ranged from early onset fatal, through childhood onset to adult onset. Features include hypotonia, contractures, and respiratory muscle weakness. Skeletal muscle biopsy shows fiber size variation without inflammation and intracytoplasmic dark inclusion bodies that reduced nitroblue tetrazolium (NBT), indicating the presence of sulfhydryl-containing compounds. Electron microscopy showed that these 'reducing bodies' are composed of dense osmiophilic material consisting of closely packed fibrillar particles (Schessl et al., 2009). This is an X-linked dominant condition with males and females both being affected. REFERENCES Gueneau et al. Am. J. Hum. Genet. 85: 338-353, 2009. Schessl et al. Brain. 132: 454-464, 2009 Windpassinger et al. Am. J. Hum. Genet. 82: 88-99, 2008.

Molecular Genetics:

The FHL1 protein is a 32 kDa protein that contains four and a half LIM domains which are cysteine- rich tandem-zinc finger protein interaction motifs. The FHL1 gene is located on Xq26.3 and is highly expressed in skeletal and cardiac muscles. Although missense are the most common type of mutation, splice-site mutations, indels and large deletions have also been previously reported.

Test Methods:

We offer DNA sequence analysis of the entire coding region of the FHL1 gene. PCR amplification and sequence analysis is performed on all coding exons including splice junctions. The patient’s gene sequence is then compared to a reference sequence. Sequence variants are classified as mutations, variants of unknown significance or benign variants unrelated to disease. Variants of unknown significance may warrant further studies in the patient and other family members. Mutations in promoters, deep intronic regions and other regulatory regions will not be identified with this assay.

Results:

Test results with interpretation will be mailed and/or faxed to the referring physician following completion of the test. Additional reports will be provided as requested.

Utility:

The clinical utility of the assay is to support a clinical diagnosis of the disease, facilitate genetic counseling, assess the risk to other first degree relatives and to facilitate testing of at - risk family members.

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