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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 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 + 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 X-linked distal spinal muscular atrophy type 3; Occipital horn syndrome; Menkes disease XLR 19
BICD2 609797 autosomal dominant lower extremity-predominant spinal muscular atrophy type 2 AD 13
BSCL2 606158 Lipodystrophy, congenital generalized, type 2; spastic paraplegia 17; Neuropathy, distal hereditary motor, type V; Encephalopathy, progressive, with or without lipodystrophy AD, AR 16
CHCHD10 615903 Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 AD 3
DCTN1 601143 amyotrophic lateral sclerosis 1; Perry syndrome; Neuronopathy, Distal Hereditary Motor, Type Viib AD, AR 12
DNAJB2 604139 autosomal recessive distal spinal muscular atrophy type 5 AR 1
DYNC1H1 600112 lower extremity-predominant spinal muscular atrophy type 1; type 2O Charcot-Marie-Tooth disease; mental retardation-13 AD 56
EXOSC3 606489 pontocerebellar hypoplasia type 1B AR 2
EXOSC8 606019 AR 0
FBXO38 608533 distal hereditary motor neuronopathy type IID AD 2
GARS 600287 Neuropathy, distal hereditary motor, type V; type 2D Charcot-Marie-Tooth disease AD 23
HSPB1 602195 type 2F Charcot-Marie-Tooth disease; Neuropathy, distal hereditary motor, type IIB AD 10
HSPB3 604624 Neuronopathy, distal hereditary motor, type iic AD 0
HSPB8 608014 Neuropathy, distal hereditary motor, type IIA; type 2L Charcot-Marie-Tooth disease AD 2
IGHMBP2 600502 spinal muscular atrophy with respiratory distress type 1; type 2S Charcot-Marie-Tooth disease AR 12
TRPV4 605427 Brachyolmia type 3; Metatropic dysplasia; Spondylometaphyseal dysplasia, Kozlowski type; Hereditary motor and sensory neuropathy, type IIc AD 11
UBA1 314370 XLR 0
VAPB 605704 Finkel type late-onset spinal muscular atrophy; amyotrophic lateral sclerosis 8 AD 3