Structural genetic muscle disorders comprehensive panel

Structural genetic muscle disorders comprehensive panel

[107 genes]

TOURNAROUND TIME: 6 WEEKS

ACTA1 ADSSL1 AGL ANO5 B3GALNT2 B4GAT1 BAG3 BIN1 BVES CAPN3
CAV3 CCDC78 CFL2 CNTN1 COL12A1 COL6A1 COL6A2 COL6A3 CRYAB CHKB
DAG1 DES DMD DNAJB6 DNM2 DOLK DPM1 DPM2 DPM3 DYSF
EMD FHL1 FKRP FKTN FLNC GAA GBE1 GMPPB GNE HACD1
HNRNPDL HRAS ISPD ITGA7 KBTBD13 KLHL40 KLHL41 KLHL9 LAMA2 LAMP2
LARGE1 (LARGE) LDB3 LIMS2 LMNA LMOD3 MATR3 MEGF10 MTM1 MYF6 MYH2
MYH7 MYOT MYPN NEB ORAI1 PABPN1 PHKA1 PLEC PMM2 PNPLA2
POGLUT1 POMGNT1 POMGNT2 POMK POMT1 POMT2 RXYLT1 RYR1 SELENON (SEPN1) SGCA
SGCB SGCD SGCG SIL1 SPEG STAC3 STIM1 SYNE1 SYNE2 TCAP
TIA1 TMEM43 TNNT1 TNPO3 TOR1AIP1 TPM2 TPM3 TRAPPC11 TRIM32 TRIM54
TRIM63 TRIP4 TRPV4 TTN VCP VMA21 XK
ACTA1 ADSSL1 AGL ANO5
B3GALNT2 B4GAT1 BAG3 BIN1
BVES CAPN3 CAV3 CCDC78
CFL2 CNTN1 COL12A1 COL6A1
COL6A2 COL6A3 CRYAB CHKB
DAG1 DES DMD DNAJB6
DNM2 DOLK DPM1 DPM2
DPM3 DYSF EMD FHL1
FKRP FKTN FLNC GAA
GBE1 GMPPB GNE HACD1
HNRNPDL HRAS ISPD ITGA7
KBTBD13 KLHL40 KLHL41 KLHL9
LAMA2 LAMP2 LARGE1 (LARGE) LDB3
LIMS2 LMNA LMOD3 MATR3
MEGF10 MTM1 MYF6 MYH2
MYH7 MYOT MYPN NEB
ORAI1 PABPN1 PHKA1 PLEC
PMM2 PNPLA2 POGLUT1 POMGNT1
POMGNT2 POMK POMT1 POMT2
RXYLT1 RYR1 SELENON (SEPN1) SGCA
SGCB SGCD SGCG SIL1
SPEG STAC3 STIM1 SYNE1
SYNE2 TCAP TIA1 TMEM43
TNNT1 TNPO3 TOR1AIP1 TPM2
TPM3 TRAPPC11 TRIM32 TRIM54
TRIM63 TRIP4 TRPV4 TTN
VCP VMA21 XK

The broad range of muscular disorders has greatly expanded in the last decades thanks to advances in the field of genetics. Although there are acquired causes of muscle disease (immunologic, toxic, endocrine-metabolic), genetic causes account for 80% of cases, with more than 200 known genes so far.

As a whole, they are considered rare diseases, with an overall prevalence of 1/3 500 live births. The increase in survival and the discovery of new therapeutic targets have contributed to the growing importance of this group of pathologies. It is worth noting that, although they are chronic and usually progressive degenerative diseases, over 50% have their onset in childhood.
We use the term “structural” for those forms of muscle disease that primarily affect the structure of muscle fibers and lead to alterations in their function.

To better assess this group of disorders, two main categories were considered based on the age of onset of symptoms:

  • Congenital structural genetic muscle disorders (present from birth)
  • Child- and adult-onset structural genetic muscle disorders

The group of congenital structural genetic muscle disorders includes all genes related to congenital myopathy and congenital muscular dystrophy.

Congenital myopathies comprise a group of disorders characterized by non-dystrophic morphological abnormalities on muscular biopsy. An approximate prevalence of 3.5-5/10 000 live births has been estimated (Sharma et al., 2009). Most of these diseases manifest at birth or shortly thereafter with hypotonia, delay in motor development, and static or non-progressive weakness. Although these symptoms may be present since birth, diagnosis is often not reached until well into childhood or even in adulthood, since many of these signs may go unnoticed.
On the other hand, congenital muscular dystrophies, despite showing symptoms from birth, usually have a more severe and progressive development and are characterized by the presence of muscular dystrophy on biopsy.

The group of child- and adult-onset structural genetic muscle disorders encompasses the rest of muscular dystrophies: a group of inherited diseases that affect skeletal muscle, characterized by a progressive degeneration of muscle fibers determining loss of strength. This heterogeneous group of diseases has been a subject of clinical and molecular studies for decades, leading to increasingly complex classifications based on genotype-phenotype correlation attempts.

So far, one of the most useful classifications for the clinical practice is still the prevailing weakness pattern, which allows identifying phenotypes to guide genetic studies. We have relied on this classification to guide clinical decision making aimed at selecting the most suitable panel for molecular diagnosis:

  • Dystrophinopathies (DMD)
  • Limb-girdle muscular dystrophies (both at the pelvic and shoulder level)
  • Emery-Dreifuss muscular dystrophy (characterized by a scapulohumeral-peroneal distribution and early contractures, associated with heart disease)
  • Distal myopathies (with a pattern of weakness predominantly involving distal muscles)
  • Oculopharyngeal muscular dystrophy*
  • Facioscapulohumeral muscular dystrophy**

With the exception of oculopharyngeal muscular dystrophy*, whose main pathogenic mechanism is a triplet repeat expansion in the PABPN1 gene (analyzed in our laboratory on specific request), and facioscapulohumeral muscular dystrophy**, whose main pathogenic mechanism is the contraction of a repetitive region in the DUX4 gene (detected by a technique not performed in our laboratory), there are specific panels for the study of the remaining pathologies. We have developed an additional panel for the study of myofibrillar myopathies, selected for their characteristic findings on muscle biopsy.

REFERENCES
  1. Darras BT, Menache-Stroninki CC, Hinton V, Kunkel LM. Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach, 2nd ed, Darras BT, Jones HR Jr, Ryan MM, De Vivo DC (Eds), Academic Press, San Diego 2015.
  2. Emery AE. The muscular dystrophies. Lancet 2002; 359:687.
  3. Puckelwartz M, McNally EM. Emery-Dreifuss muscular dystrophy. Handb Clin Neurol 2011; 101:155.
  4. Romero NB, Clarke NF. Congenital myopathies. Handb Clin Neurol 2013; 113:1321.
  5. Sewry CA, Jimenez-Mallebrera C, Muntoni F. Congenital myopathies. Curr Opin Neurol 2008; 21:569.
  6. Selcen D. Myofibrillar myopathies. Neuromuscul Disord 2011; 21:161.
  7. Sharma MC, Jain D, Sarkar C, Goebel HH. Congenital myopathies–a comprehensive update of recent advancements. Acta Neurol Scand. 2009 May;119(5):281-92.
  8. Wicklund MP. The muscular dystrophies. Continuum (Minneap Minn) 2013; 19:1535.

 

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INFORMED CONSENT
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VARIANT CLASSIFICATION
Variant classification and clinical usefulness criteria

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