NDUFAF6-Related Leigh Syndrome (LS) via the NDUFAF6 Gene

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; Zhu et al. 1998; Leigh 1951). The disease incidence for LS is estimated to be 1:32,000 to 1:40,000 live births (Darin et al. 2001; Rahman et al. 1996).

The hallmark features of this syndrome are 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). Although certain genes are associated with classic LS more frequently than atypical LLS, genotype-phenotype correlations remain poorly understood. To date, only one family has been identified with NDUFAF6-associated LS (Pagliarini et al. 2008). Affected individuals within this family presented in infancy with classic LS, focal seizures, and ataxia.

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 (for a review, see 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 NDUFAF6 (C8orf38) gene, composed of nine exons, encodes an assembly factor for the mitochondrial NADH-ubiquinone oxidoreductase (also known as Complex I) (McKenzie et al. 2011). To date, only one pathogenic variant, a homozygous missense change (Gln99Arg), has been documented as a primary cause of NDUFAF6-associated LS (Pagliarini et al. 2008).

NDUFAF6-associated Leigh Syndrome has been described in only one family to date (Pagilarini et al. 2008). Although we cannot accurately estimate clinical sensitivity at this time, NDUFAF6 appears to be a rare cause of Leigh Syndrome.

This test provides full coverage of all coding exons of the NDUFAF6 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.