Facioscapulohumeral Muscular Dystrophy 2 via the SMCHD1 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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NextGen Sequencing

Test Code Test Copy GenesPriceCPT Code Copy CPT Codes
3055 SMCHD1$640.00 81479 Add to Order

New York State Approved Test

Pricing Comments

Our most cost-effective testing approach is NextGen sequencing with Sanger sequencing supplemented as needed to ensure sufficient coverage and to confirm NextGen calls that are pathogenic, likely pathogenic or of uncertain significance. If, however, full gene Sanger sequencing only is desired (for purposes of insurance billing or STAT turnaround time for example), please see link below for Test Code, pricing, and turnaround time information.

For Sanger Sequencing click here.
Targeted Testing

For ordering sequencing of targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

Heterozygous SMCHD1 mutations were found in affected members of 15 of 19 families with FSHD in which FSHD1 was ruled out by molecular methods (Lemmers et al. Nature Genet 44:1370-1374, 2012). In each case with a SCHMD1 mutation, at least one copy of the permissive 4qA allele was also found.

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Del/Dup via aCGH

Test Code Test Copy GenesPriceCPT Code Copy CPT Codes
600 SMCHD1$990.00 81479 Add to Order
Pricing Comments

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Targeted Testing

For ordering sequencing of targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Features

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscle disorder with a prevalence between 1 and 5 in 100,000. Most patients with FSHD present by age 20 years, although marked variability in age of onset and severity is known to occur with some patients remaining asymptomatic. The disease course is progressive with approximately 20% of patients eventually requiring a wheelchair. Affected muscles include facial, scapular, upper arm, lower leg, and hip girdle. Patients exhibit forward sloping shoulders, however, the cardinal clinical feature is scapular winging (Tawil et al. Ann Neurol 43:279–282, 1998). Additional muscle groups involved include lower abdominal muscles, biceps, and triceps. Weak abdominal muscles result in protuberance of the abdomen and lumbar lordosis. Retinal vasculopathy occurs in 40%-60% of patients and high-tone sensorineural hearing loss occurs in approximately 60% of patients (Lemmers et al. GeneReviews, 2012). Serum CK levels are normal to mildly elevated. Muscle biopsies reveal necrotic fibers and fiber size variation. FSHD1 (OMIM 158900) and FSHD2 (OMIM 158901) have different underling genetic causes (see Genetics section), however, their clinical features are quite similar. One differentiating feature may be age of onset. In a series of 33 FSHD2 patients average age at onset was reported to be 26 years, which is nearly 10 years later than in FSHD1 (de Greef et al. Neurology 75:1548-1554, 2010).


FSHD1 (OMIM 158900), the more common form of facioscapulohumeral muscular dystrophy, is inherited as an autosomal dominant disorder secondary to contraction of the 3.3 kb D4Z4 microsatellite repeat at the subtelomeric region of chromosome 4q (Wijmenga et al. Nature Genet 2:26-30, 1992). Contraction of the D4Z4 array to DUX4 gene (OMIM 606009) in skeletal muscle. However, in addition to D4Z4 contraction, expression of the FSHD1 phenotype also requires that the contracted D4Z4 allele be on the same 4q allele as a polymorphism that creates a polyA signal for the most distal DUX4 gene (van Geel et al. Genomics 79: 210-217, 2002). 4qA is the term used to describe the 4q allele that bears this polymorphism. Abnormally close proximity of this polyA signal to the DUX4 gene permits stable expression of the normally silent DUX4 gene (Lemmers et al. Science 329: 1650-1653, 2010). FSHD2 (OMIM 158901) is inherited as a digenic disorder, requiring inheritance of two unlinked genetic factors: 1) a permissive 4qA allele and 2) a loss of function mutation of the SMCHD1 gene (OMIM 614982) which is found on chromosome 18p11 (Lemmers et al. Nature Genet 44:1370-1374, 2012). Notably, contraction of the D4Z4 array on chromosome 4q is not necessary for expression of FSHD2. Co-occurrence of the 4qA allele and a SMCHD1 gene mutation in FSHD2 has the same effect on DUX4 expression as does the 4qA/contracted D4Z4 haplotype in FSHD1, ie, both mechanisms permit stable expression of the normally silent DUX4 gene. The SMCHD1 gene encodes a protein involved with X chromosome inactivation (Blewitt et al. Nature Genet 40: 663-669, 2008) and genome-wide D4Z4 hypomethylation (Lemmers et al. Nature Genet 44:1370-1374, 2012). Currently, only loss of function mutations of the SMCHD1 gene have been reported.

Testing Strategy

Testing for D4Z4 array contractions, 4qA/4qB status, and methylation status are not currently offered by PreventionGenetics. For this Next Generation (NextGen) test, the full coding regions plus ~10 bp of non-coding DNA flanking each exon are sequenced for the gene listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

Indications for Test

Patients with an FSHD clinical phenotype who have had FSHD1 ruled-out via a negative test for a contracted D4Z4 repeat ( < 11 units) on the permissive 4qA allele.


Official Gene Symbol OMIM ID
SMCHD1 614982
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Facioscapulohumeral Muscular Dystrophy 2 158901

Related Tests

Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection
Comprehensive Neuromuscular Sequencing Panel
Limb-Girdle Muscular Dystrophy (LGMD) Sequencing Panel


Genetic Counselors
  • Blewitt, M. E. et al. (2008). PubMed ID: 18425126
  • de Greef, J. C. et al. (2010). PubMed ID: 20975055
  • Lemmers R.J. et al. (2012). PubMed ID: 20301616
  • Lemmers, R. J. et al. (2012). PubMed ID: 23143600
  • Lemmers, R. J. L. F et al. (2010). PubMed ID: 20724583
  • Tawil, R., D. A. Figlewicz, et al. (1998). PubMed ID: 9506542
  • van Geel, M. et al. (2002). PubMed ID: 11829491
  • Wijmenga, C. et al. (1992). PubMed ID: 1363881
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NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~10 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are often covered by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~10 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most cases, we are unable to determine the phase of sequence variants.  In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited.  Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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