Publications about genetic testing for neurological disorders
  1. NGS Panel – Genetic Testing for Nemaline Myopathy

Nemaline Myopathy

April 13, 2018

Disease summary

Nemaline myopathy (NEM, NM) is one of the most common congenital myopathies characterized by hypotonia, weakness and absent deep tendon reflexes. NEM is classified into six forms based on onset and severity of motor and respiratory involvement  To date, 10 genes involved in muscle thin filament structure and function, have been linked to NEM: ACTA1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, NEB, TNNT1, TPM2, TPM3 (Table 1)1.

Autosomal dominant, autosomal recessive

1/50,000 live births1, 9; 1/500 in the Amish community1, 10, 11.

Major clinical symptoms for NEM include the following1:

  • Muscle weakness of face, neck and trunk and upper arms and legs (proximal muscle weakness)
  • Hypotonia
  • Decreased or absent deep tendon reflexes
  • Feeding and swallowing difficulties
  • Breathing difficulties and recurrent respiratory infections due to respiratory muscles weakness
  • Joint contractures
  • Diagnosis of NEM is based on clinical findings and the observation of characteristic rod-shaped structures (nemaline bodies) on muscle biopsy.
  • Diagnosis is confirmed by identification of a pathogenic variant in one of the following genes:  ACTA1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, NEB, TNNT1, TPM2, TPM3.

There is no cure for NEM to date, but a number of procedurescould significantly improve the quality of life 1, 15:

  • Treatment of lower respiratory tract infections
  • Ventilator use for nocturnal hypoxia
  • Special feeding techniques
  • Physical therapy to help prevent joint contractures
  • Speech therapy
  • Congenital myasthenic syndromes
  • Mitochondrial myopathies
  • Prader-Willi syndrome
  • Metabolic myopathies (Pompe disease)
  • Spinal muscular atrophy
  • Seconardy nemaline myopathies, including mitochondrtial myopathy, dermatomyositis, myotonic dystrophy type 1, and Hodgkin’s disease, and in normal human extraocular muscle

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for nemaline myopathy using NGS Panel Genomic:

Step 1: Whole genome sequencing from a single filter card (drop of blood), covering the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the nemaline myopathy . Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variant is identified in Step1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.   

  • Individuals with a positive family history of nemaline myopathy.
  • Individuals with most common symptoms of nemaline myopathy (regardless of family history).

Confirmation of a clinical diagnosis through genetic testing of nemaline myopathy can allow for genetic counseling and may direct medical management.

Overview of genes in Nemaline myopathy panel

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ACTA1 102610 Myopathy, nemaline, 3; Myopathy, congenital, with fiber-type disproportion AD, AR 24
CFL2 601443 nemaline myopathy type 7 AR 14
KBTBD13 613727 Nemaline Myopathy 6 AD 1
KLHL40 615340 Nemaline myopathy 8, autosomal recessive 3
KLHL41 607701 Nemaline myopathy 9 AR 0
LMOD3 616112 Nemaline myopathy 10 AR 0
NEB 161650 nemaline myopathy type 2 AR 127
TNNT1 191041 Nemaline myopathy 5, Amish type AR 10
TPM2 190990 Nemaline myopathy type 4, autosomal dominant AD 15
TPM3 191030 Myopathy, congenital, with fiber-type disproportion; Nemaline myopathy 1, autosomal dominant or recessive AD, AR 8