FHL1-Myopathies via the FHL1 Gene

Disorders of skeletal muscle resulting from mutations in the FHL1 gene vary by age of onset, rate of progression, severity of clinical presentation, and findings from muscle histopathology. Severe, early onset reducing body myopathy (OMIM 300717) is characterized by early onset and progressive hypotonia, proximal muscle weakness, contractures, and respiratory insufficiency. Patients are normal at birth until they develop proximal weakness as toddlers (Kiyomoto et al. J Neurol Sci 128:58-65, 1995; Schessl et al. Brain 132:452-464, 2009). In the reported patients, disease progression was rapid and respiratory failure occurred 2-3 years after disease onset. Initial clinical signs included frequent falls, abnormal gait, progressive proximal muscle weakness, contractures, and scoliosis. Childhood onset reducing body myopathy (OMIM 300718) exhibits onset between 5 and 16 years of age. Disease progression is also rapid with patients becoming wheelchair bound one and three years from the time of onset (Goebel et al. Neuropediatrics 32:196-205, 2001; Schessl et al. J Clin Invest 118:904-912, 2008). Clinical features include proximal weakness, joint contractures, spinal rigidity, scoliosis, scapular winging, Gowers sign, and decreased deep tendon reflexes (Ohsawa et al. Brain Dev 29:112-116, 2007, Liewluck et al. Muscle Nerve 35:322-326, 2007). Mothers of affected boys have milder symptoms later in life compared to their children.

X linked myopathy with postural muscle atrophy (OMIM 300696) is an adult onset disorder with weakness and atrophy of muscles required for postural stability. Patients often exhibit muscle hypertrophy early in life and in non proximal muscle groups. Among a group of seven unrelated families, disease onset was between 8 and 45 years of age and women carriers were either asymptomatic or mildly affected (Schoser et al. Neurology 73:543-551, 2009). Patients in this study had early-onset neck rigidity, contractures of the Achilles tendon, progressive limb girdle muscle weakness, postural muscle atrophy, rigid spine, scapular winging, gait abnormalities, and respiratory insufficiency.

Emery-Dreifuss muscular dystrophy-6 (OMIM 300696) is a closely related clinical phenotype to that of X linked myopathy with postural muscle atrophy. Age at onset has been found to be in the first to second decades of life in two studies (Gueneau et al. Am J Hum Genet 85:338-353, 2009; Knoblauch et al. Ann Neurol 67:136-140, 2010). Patients develop cardiac muscle involvement, including arrhythmias and hypertrophic cardiomyopathy, after onset of skeletal muscle symptoms. Clinical features include joint contractures, neck stiffness, and limb girdle muscle weakness and atrophy.

All patients reported have remained ambulatory. Female carriers are rarely affected (Gueneau et al. Am J Hum Genet 85: 338-353, 2009). Scapuloperoneal myopathy (OMIM 300695) has been described in a single family (Wilhelmsen et al. Ann Neurol 39:507-520, 1996). Clinical features include foot drop, proximal arm weakness which precedes hand weakness, and scapular winging. Affected men showed signs earlier in life than women and were more severely affected (Quinzii et al. Am J Hum Genet 82:208-213, 2008).

Patients with myofibrilar myopathy with reducing bodies seen in muscle biopsies have also been found with FHL1 gene mutations (Selcen et al. Neurology 77:1951, 2011).

Reducing bodies are irregularly shaped cytoplasmic inclusions that appear dark with menadione-NBT stain, confirming the presence of sulfhydryl groups. FHL1 protein, both mutant and normal forms, is the most abundant protein found in reducing bodies (Schessl et al. J Clin Invest 118:904–912, 2008; Schessl et al. Brain 132:452-464, 2009). Muscle biopsies of patients with FHL1 myopathies reveal variation in fiber size, internally placed nuclei, mild inflammation, rimmed vacuoles, and reducing bodies that stain with NBT.

FHL1-related myopathies are inherited as X-linked recessive disorders or, in the case of scapuloperoneal myopathy, as an X-linked dominant disorder. In familial cases, mothers of affected males are themselves clinically less affected with symptoms appearing later in life. Severe, early onset reducing body myopathy results from de novo missense mutation of conserved amino acids of the second LIM domain (Schessl et al. J Clin Invest 118:904-912, 2008; Shalaby et al. Neurology 72:375-376, 2009). Mutations involving the zinc coordinating residue p.His123 result in a severe clinical course, while mutations in another zinc coordinating residue (p.Cys153) are associated with a milder phenotype. Childhood onset reducing body myopathy results from inherited mutations of the second LIM domain. The scapuloperoneal myopathy mutation is found in the second LIM domain and affects a conserved residue (p.Trp122Ser). Patients with Emery-Dreifuss muscular dystrophy-6 more often have FHL1 mutations in the fourth LIM domain. The majority of reported mutations in FHL1 are missense or nonsense (Human Gene Mutation Database).

Analytical sensitivity should be high because nearly all FHL1 mutations reported to date are detectable by direct sequencing of genomic DNA.

This test provides full coverage of all coding exons of the FHL1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).