Leigh and Leigh-Like Syndrome Panel (Nuclear Genes Only)

Leigh Syndrome (LS), also known as subacute necrotizing encephalomyelopathy, is a severe neurodegenerative disorder resulting primarily from defects in the mitochondrial respiratory chain (Ruhoy and Saneto. 2014. PubMed ID: 25419155; Zhu et al. 1998. PubMed ID: 9843204; Leigh. 1951. PubMed ID: 14874135). The disease incidence for LS is estimated to be around 1:32,000 to 1:40,000 live births (Darin et al. 2001. PubMed ID: 11261513; Rahman et al. 1996. PubMed ID: 8602753).

The hallmark features that characterize this syndrome are elevated levels of lactate in blood and cerebral spinal fluid, and the presence of bilateral symmetric necrotic lesions in the basal ganglia, brain stem, thalamus, and/or spinal cord (Wedatilake et al. 2013. PubMed ID: 23829769; Leigh. 1951. PubMed ID: 14874135). 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.

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. PubMed ID: 21819970). 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. PubMed ID: 23829769). LS and LLS have been linked to pathogenic variants in over 60 different genes (Rahman and Thorburn. 2015. PubMed ID: 26425749). 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.

Leigh and Leigh-Like Syndromes (LS/LLS) are caused by defects in the mitochondrial oxidative phosphorylation (OXPHOS) complexes or associated proteins, such as OXPHOS assembly factors or the pyruvate dehydrogenase (PDH) complex (Rahman and Thorburn. 2015. PubMed ID: 26425749). 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. Please note that genes located in the mitochondrial genome are currently not included in this panel.

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. PubMed ID: 22079328).

In the general population, pathogenic variation in the SURF1 gene is one of the most frequent causes of Leigh Syndrome (LS) associated with cytochrome c oxidase (COX) deficiency (Tiranti et al. 1998. PubMed ID: 9837813; Zhu et al. 1998. PubMed ID: 9843204). One large cohort study was complicated by the presence of a founder mutation in the affected population, resulting in a high prevalence of SURF1-related LS that is likely not representative of the general population (Böhm et al. 2006. PubMed ID: 16326995).

Overall sensitivity of this panel is difficult to predict, as no large cohort studies have been published to date. For more information regarding predicted clinical sensitivity for a number of the genes involved in this panel, please refer to Rahman and Thorburn (2015. PubMed ID: 26425749).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

This panel typically provides 99.5% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).