Leigh Syndrome Associated with Isolated Complex I Deficiency via the NDUFA12 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8761 NDUFA12 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8761NDUFA1281479 81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

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

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Geneticist

Clinical Features and Genetics

Clinical Features

Leigh Syndrome (LS), also known as subacute necrotizing encephalomyelopathy, is a severe neurodegenerative disorder resulting from defects in the mitochondrial respiratory chain (Ruhoy and Saneto 2014; Zhu et al. 1998; Leigh 1951). The disease incidence for LS is estimated to be around 1:32,000 to 1:40,000 live births (Darin et al. 2001; Rahman et al. 1996).

The hallmark features that characterize this syndrome include elevated levels of lactate in blood and cerebral spinal fluid, in addition to the presence of bilateral symmetric necrotic lesions in the basal ganglia, brain stem, thalamus, and/or spinal cord (Wedatilake et al. 2013; Leigh 1951). Patients also present with isolated or combined mitochondrial complex deficiencies, psychomotor delay or regression, and neurologic manifestations such as hypotonia or ataxia. The term ‘Leigh-Like Syndrome (LLS)’ is used to describe a similar clinical presentation in which one or more of these diagnostic characteristics is atypical.

Symptomatic onset of this disorder usually occurs shortly after birth or within the first three years of life, although cases of adult-onset LS/LLS have been reported (Ronchi et al. 2011). LS/LLS infants often present with feeding difficulties, gastrointestinal distress, hypotonia, and growth delays, while older children (>1 years) may develop additional symptoms including developmental regression (loss of cognitive or motor skills), dysphagia, hypertrichosis, dystonic posturing, nystagmus, and opthalmoplegia (Wedatilake et al. 2013).

LS and LLS have been linked to pathogenic variants in over 60 different genes (Rahman 2015). However, while defects in certain genes are more likely to result in classic LS rather than atypical LLS, genotype-phenotype correlations are still poorly understood. To date, there has been only one report of a patient with NDUFA12-associated LS (Ostergaard et al. 2011). The affected individual presented with isolated complex I deficiency, lactic acidosis, developmental delay, loss of motor abilities, severe muscular atrophy, hypotonia, dystonia, and hypertrichosis.

Genetics

Leigh and Leigh-Like Syndromes (LS/LLS) are caused by defects in the mitochondrial oxidative phosphorylation (OXPHOS) complexes or associated proteins, such as the OXPHOS assembly factors or components of the pyruvate dehydrogenase (PDH) complex (Rahman 2015). As a result, the LS/LLS phenotypes exhibit significant genetic heterogeneity, and pathogenic variants in over 60 different genes have been reported to be causative for this disorder. Depending on the cellular localization of the affected gene(s), these syndromes may be inherited in an autosomal recessive, maternal, or X-linked recessive manner.

Nuclear genes associated with autosomal recessive inheritance of LS/LLS include: SURF1, BCS1L, C12ORF65, COX10, COX15, FOXRED1, GFM1, LRPPRC, NDUFA2, NDUFA4, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFAF2, NDUFAF5, NDUFAF6, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, PDSS2, PET100, SCO2, SDHA, SDHAF1, SLC19A3, SUCLA2, SUCLG1, TACO1, TTC19, UQCRQ, SERAC1, NDUFV2, MTFMT, HIBCH, TSFM, ECHS1, LIAS, PNPT1, POLG, LIPT1, DLD, TPK1, and ETHE1.

Mitochondrial genes associated with maternal inheritance of LS/LLS include: MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, and MT-CO3 .

X-linked genes associated with X-linked recessive inheritance of LS/LLS include: NDUFA1, AIFM1, PDHA1, PDHB, and PDHX. In this form of inheritance, male patients are more frequently affected, although heterozygous females may present with LS/LLS due to skewed X-inactivation (Patel et al. 2012).

The four-exon NDUFA12 gene encodes for an accessory subunit of the mitochondrial NADH:ubiquinone oxidoreductase (complex I), although the precise role of this protein is not yet clear (Rak and Rustin 2014). One pathogenic nonsense variant has been reported in NDUFA12 to date (Ostergaard et al. 2011).

Clinical Sensitivity - Sequencing with CNV PGxome

At this time, due to the limited number of reported cases, the clinical sensitivity of NDUFA12-related Leigh Syndrome is difficult to estimate. Analytical sensitivity should be high as the only reported pathogenic variant is detectable by sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the NDUFA12 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

NDUFA12 sequencing could be considered in patients with symptoms consistent with LS or a family history of childhood encephalopathy, particularly if those individuals also have negative sequencing results for more frequently reported LS genes, such as SURF1. We will also sequence the NDUFA12 gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
NDUFA12 614530
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Leigh Syndrome XL 256000

Related Tests

Name
NDUFA2-Related Leigh Syndrome (LS) via the NDUFA2 Gene
SURF1-Related Leigh Syndrome (LS) via the SURF1 Gene
Comprehensive Cardiology Panel
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 I Deficiency Panel (Nuclear Genes)
Mitochondrial Complex I Deficiency via the NDUFS4 Gene
Mitochondrial Complex III Deficiency Panel (Nuclear Genes)
Mitochondrial Complex IV Deficiency via the COX15 Gene

Citations

  • Darin N. et al. 2001. Annals of Neurology. 49: 377-83. PubMed ID: 11261513
  • Leigh D. 1951. Journal of Neurology, Neurosurgery, and Psychiatry. 14: 216-21. PubMed ID: 14874135
  • Ostergaard E. et al. 2011. Journal of Medical Genetics. 48: 737-40. PubMed ID: 21617257
  • Patel K.P. et al. 2012. Molecular Genetics and Metabolism. 105: 34-43. PubMed ID: 22079328
  • Rahman S. 2015. Nuclear Gene-Encoded Leigh Syndrome Overview. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 26425749
  • Rahman S. et al. 1996. Annals of Neurology. 39: 343-51. PubMed ID: 8602753
  • Rak M, Rustin P. 2014. FEBS Letters. 588: 1832-8. PubMed ID: 24717771
  • Ronchi D. et al. 2011. Biochemical and Biophysical Research Communications. 412: 245-8. PubMed ID: 21819970
  • Ruhoy I.S., Saneto R.P. 2014. The Application of Clinical Genetics. 7: 221-34. PubMed ID: 25419155
  • Wedatilake Y. et al. 2013. Orphanet Journal of Rare Diseases. 8: 96. PubMed ID: 23829769
  • Zhu Z. et al. 1998. Nature Genetics. 20: 337-43. PubMed ID: 9843204

Ordering/Specimens

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