Publications about genetic testing for neurological disorders
  1. SMN-negative spinal muscular atrophy panel

SMN-negative spinal muscular atrophy panel

August 03, 2018

Disease summary:

Spinal muscular atrophies (SMAs) are hereditary degenerative disorders of lower motor neurons associated with progressive muscle weakness and atrophy. The onset of muscle weakness ranges from the prenatal period to adolescence or young adulthood, with infantile-onset SMA being the most common genetic cause of infant mortality3.

Although the majority of SMA cases (>95%) are caused by homozygous deletions of exon 7 and/or exon 8 in the SMN1 gene1, 2, other genes have also been associated with SMA. These diseases must be considered in the differential diagnosis when SMN1 testing is negative. Other genes to be tested include ATP7A, BICD2, BSCL2, CHCHD10, DCTN1, DNAJB2, DYNC1H1, EXOSC3, EXOSC8, FBXO38, GARS, HSPB1, HSPB3, HSPB8, IGHMBP2, TRPV4, UBA1 and VAPB  1, 4, 5 (Table 1). 


Autosomal recessive, autosomal dominant, X-linked inheritance

4-10/1,000,000 (incidence of SMN-negative SMA)1, 6, 7, 8

Major clinical symptoms of SMA 1, 2, 3:

  • Progressive muscle weakness and atrophy
  • The onset ranges from before birth to adolescence/young adulthood
  • Poor weight gain, growth failure

Other clinical findings1, 2, 3:

  • Severe neonatal or later-onset hypotonia
  • Respiratory failure, abdominal breathing
  • Joint contractures, scoliosis
  • Facial weakness, tongue fasciculations

Specific clinical symptoms of the various differential diagnoses  are listed in Table 1.

  • Presence of the specific clinical features
  • Identification of pathogenic variant(s) in one of the associated genes (ATP7A, BICD2, BSCL2, CHCHD10, DCTN1, DNAJB2, DYNC1H1, EXOSC3, EXOSC8, FBXO38, GARS, HSPB1, HSPB3, HSPB8, IGHMBP2, TRPV4, UBA1, VAPB)

There is no cure for SMN-negative spinal muscular atrophy to date, but symptomatic treatments can relieve symptoms 1, 2, 3:

  • Nutritional support (gastronomy tube)
  • Respiratory support
  • Surgical repair for scoliosis and joint problems
  • Prader-Willi syndrome
  • Congenital myotonic dystrophies
  • Myotonic dystrophy type 1
  • Congenital myasthenic syndromes
  • Duchenne/Becker muscular dystrophy
  • Amyotrophic lateral sclerosis
  • Spinal and bulbar muscular atrophy

To confirm/establish the diagnosis, CENTOGENE offers the following tests:

  • SMN-negative spinal muscular atrophy NGS Panel Plus which includes sequencing of the genes ATP7A, BICD2, BSCL2, CHCHD10, DCTN1, DNAJB2, DYNC1H1, EXOSC3, EXOSC8, FBXO38, GARS, HSPB1, HSPB3, HSPB8, IGHMBP2, TRPV4, UBA1, VAPB
  • SMN-negative spinal muscular atrophy NGS Panel Plus + CNV which includes sequencing and additionally detection of large deletions and duplications from the NGS data
  • Individuals with a positive family history of SMN-negative spinal muscular atrophy
  • Individuals with symptoms suggestive of SMA with previously negative SMN1 and SMN2 testing (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of SMN-negative spinal muscular atrophy can allow for genetic counseling and may direct medical management.


Table 1. Overview of genes included in SMN-negative spinal muscular atrophy

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ATP7A 300011 Spinal muscular atrophy, distal, X-linked 3; Occipital horn syndrome; Menkes disease XL R 15
BICD2 609797 Spinal muscular atrophy, lower extremity-predominant, 2, AD AD 11
BSCL2 606158 Lipodystrophy, congenital generalized, type 2; Silver spastic paraplegia syndrome; Neuropathy, distal hereditary motor, type VA; Encephalopathy, progressive, with or without lipodystrophy AD, AR 16
CHCHD10 615903 Spinal muscular atrophy, Jokela type; Frontotemporal dementia and/or amyotrophic lateral sclerosis 2; ?Myopathy, isolated mitochondrial, autosomal dominant AD 0
DCTN1 601143 Amyotrophic lateral sclerosis, susceptibility to; Perry syndrome; Neuropathy, distal hereditary motor, type VIIB AD, AR 11
DNAJB2 604139 Spinal muscular atrophy, distal, autosomal recessive, 5 AR 1
DYNC1H1 600112 Spinal muscular atrophy, lower extremity-predominant 1, AD; Charcot-Marie-Tooth disease, axonal, type 20; Mental retardation, autosomal dominant 13 AD 53
EXOSC3 606489 Pontocerebellar hypoplasia, type 1B AR 2
EXOSC8 606019 Pontocerebellar hypoplasia, type 1C AR 0
FBXO38 608533 Neuronopathy, distal hereditary motor, type IID AD 1
GARS 600287 Neuropathy, distal hereditary motor, type VA; Charcot-Marie-Tooth disease, type 2D AD 23
HSPB1 602195 Charcot-Marie-Tooth disease, axonal, type 2F; Neuropathy, distal hereditary motor, type IIB AD 9
HSPB3 604624 ?Neuronopathy, distal hereditary motor, type IIC AD 0
HSPB8 608014 Neuropathy, distal hereditary motor, type IIA; Charcot-Marie-Tooth disease, axonal, type 2L AD 3
IGHMBP2 600502 Neuronopathy, distal hereditary motor, type VI; Charcot-Marie-Tooth disease, axonal, type 2S AR 11
TRPV4 605427 Brachyolmia type 3; Metatropic dysplasia; Parastremmatic dwarfism; Scapuloperoneal spinal muscular atrophy; SED, Maroteaux type; Spondylometaphyseal dysplasia, Kozlowski type; Spinal muscular atrophy, distal, congenital nonprogressive; Hereditary motor and sensory neuropathy, type IIc; Digital arthropathy-brachydactyly, familial; [Sodium serum level QTL 1]; ?Avascular necrosis of femoral head, primary, 2 AD 11
UBA1 314370 Spinal muscular atrophy, X-linked 2, infantile XL R 0
VAPB 605704 Spinal muscular atrophy, late-onset, Finkel type; Amyotrophic lateral sclerosis 8 AD 3