BCS1L-Related Disorders (Mitochondrial Complex III Deficiency, GRACILE Syndrome, Björnstad Syndrome, and Leigh Syndrome) via the BCS1L Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesPrice Test CPT CodeGene CPT Codes Copy CPT Codes STAT
7593 BCS1L$640 8140581405,81479 Add to Order

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Mitochondrial complex III deficiency is a disorder of oxidative phosphorylation (OXPHOS) that arises due to pathogenic variants in either one of the mitochondrial complex III subunits or one of the assembly proteins (including LYRM7, TTC19, and BCS1L) required to form the mature complex (Fernandez-Vizarra and Zeviani. 2015. PubMed ID: 25914718). BCS1L deficiency can result in a spectrum of disease that ranges from relatively mild (Björnstad syndrome) to severe (GRACILE or Leigh syndrome).

Björnstad syndrome is characterized by sensorineural hearing loss (nerve deafness) and pili torti (twisted hairs). Affected individuals generally develop hair loss within the first two years of life, and they may present with hearing loss within the first three to four years. Age of onset and clinical severity can be variable, however. Patients with Björnstad syndrome have also been reported to present with hypogonadism and/or intellectual disability (Selvaag. 2000. PubMed ID: 10694305; Hinson et al. 2007. PubMed ID: 17314340).

GRACILE syndrome (Growth Retardation, Amino aciduria, Cholestasis, Iron overload, Lactic acidosis, and Early death) is a neonatal metabolic disorder characterized by severe intrauterine growth retardation and fulminant lactic acidosis during the first days of life, followed by Fanconi-type amino aciduria and abnormalities in iron metabolism, including liver hemosiderosis (Fellman et al. 1998. PubMed ID: 9482441; Fellman et al. 2000. PubMed ID: 10654962). Affected infants fail to thrive, and often die neonatally or in early infancy.

Leigh syndrome is a subacute necrotizing encephalopathy characterized by elevated levels of lactate in blood or cerebral spinal fluid; bilateral symmetric necrotic lesions in the basal ganglia, brain stem, thalamus, and/or spinal cord; psychomotor delay or regression; and neurologic manifestations such as hypotonia or ataxia (Rahman and Thorburn. 2015. PubMed ID: 26425749). Onset of this disorder usually occurs shortly after birth or within the first three years of life.

Genetics

Pathogenic variants in the BCS1L gene are inherited in an autosomal recessive manner. The BCS1L [BC1 (ubiquinol-cytochrome c reductase) synthesis-like] gene encodes for an assembly protein for complex III of the mitochondrial respiratory chain. Inactivation of BCS1L leads to disruption of complex III assembly, which in turn results in decreased activity of the mitochondrial respiratory chain and an increase in the production of reactive oxygen species (Hinson et al. 2007. PubMed ID: 17314340). Results from at least one study indicate that the levels of reactive oxygen species produced may be directly correlated with phenotypic severity (Hinson et al. 2007. PubMed ID: 17314340).

The majority of pathogenic variants described in this gene to date are missense; however, nonsense, splicing variants, and small frameshift deletions/insertions have also been reported (Human Gene Mutation Database). At least one BCS1L founder variant has been described in the Finnish population: c.232A>G (p.Ser78Gly) (Visapää et al. 2002. PubMed ID: 12215968).

Testing Strategy

This test provides full coverage of all coding exons of the BCS1L gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Clinical Sensitivity - Sequencing and CNV

At this time, due to the limited number of reported cases, the clinical sensitivity of BCS1L-related mitochondrial complex III deficiency is difficult to estimate. In one study carried out in Finland, twenty-one infants with a suspicion of mitochondrial disease had BCS1L gene sequencing; three infants harbored the known Finnish founder mutation (Fellman et al. 2008. PubMed ID: 18386115). All reported pathogenic variants in this gene are detectable by sequencing (Human Gene Mutation Database).

Indications for Test

Candidates for this test include neonates who present with severe intrauterine growth retardation and fulminant lactic acidosis during the first days of life, and who later display Fanconi-type amino aciduria and abnormalities in iron metabolism, including liver hemosiderosis. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in BCS1L.

Gene

Official Gene Symbol OMIM ID
BCS1L 603647
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Comprehensive Cardiology Panel
Leigh and Leigh-Like Syndrome Panel (Nuclear Genes Only)
Leigh Syndrome Associated with Isolated Complex I Deficiency via the NDUFA12 Gene
Leigh Syndrome Associated with Mitochondrial Complex I Deficiency via the NDUFA9 Gene
Leigh Syndrome Associated With Mitochondrial Complex I Deficiency via the NDUFAF2 Gene
Leigh Syndrome Associated with Mitochondrial Complex I Deficiency via the NDUFS7 Gene
Mitochondrial Complex III Deficiency Panel (Nuclear Genes)

Citations

  • Fellman et al. 1998. PubMed ID: 9482441
  • Fellman et al. 2000. PubMed ID: 10654962
  • Fellman et al. 2008. PubMed ID: 18386115
  • Fernandez-Vizarra and Zeviani. 2015. PubMed ID: 25914718
  • Hinson et al. 2007. PubMed ID: 17314340
  • Human Gene Mutation Database (Biobase).
  • Rahman and Thorburn. 2015. PubMed ID: 26425749
  • Selvaag. 2000. PubMed ID: 10694305
  • Visapää et al. 2002. PubMed ID: 12215968

Ordering/Specimens

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.

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.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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