Table 3 New variants and mutations identified in the samples

HapMap sample

PREPL[Genbank:NM_006036.3]: c.1769A>C (p.Asn590Ser) het

Possibly damaging*

Same variant present in orthologue Protease II [NP_360014]. PREPL was reported as one of the genes deleted in the homozygous 2p21 deletion syndrome

FXN[Genbank:NM_000144.3]: c.626A>G (p.Asp209Gly) het

Possibly damaging*

The FXN gene encodes the protein Frataxin, which is involved in mitochondrial iron metabolism. Clinical significance is unclear as this amino acid is not conserved in orthologues. Gly in mouse orthologue

DBT[Genbank:NM_001918.2]: c.725C>A (p.Ser242Stop) het

The DBT gene encodes the E2 component of branched-chain alpha-keto acid dehydrogenase complex involved in the catabolism of the branched-chain amino acids. Nonsense mutation at position 224 in single nucleotide polymorphism rs74103423

MRPL46[Genbank:NM_022163.3]: c.107C>T (p.Ala36Val) het

Benign*

Component of the large subunit of the mitochondrial ribosome. No mutations were reported in patients

SLC25A45[Genbank:NM_182556.2]: c.299T>C (p.Met100Thr) het

Benign*

Variant in pseudogene [NW_923184.1]. Thr in mouse orthologue

SLC25A3[Genbank:NM_213611.2]: c.1066A>C (p.Lys356Gln) het

Benign*

Mitochondrial phosphate carrier deficiency can be caused by mutation in the SLC25A3 gene, which encodes the mitochondrial phosphate carrier. Variant in pseudogene [NT_009775.16]. Gln in Armadillo orthologue

PAH[Genbank:NM_000277.1]: c.500A>G (p.Asn167Ser) het

Benign*

PAH encodes Phenylalanine hydroxylase. This variant was reported as a potential mutation for phenylketonuria [34]

Patient 1 sample: pyruvate dehydrogenase deficiency

PDHA1[Genbank:NM_000284]: c.787C>G (p.Arg263Gly)

Mutation ^†

The PDHA1 gene encodes the alpha subunit of Pyruvate decarboxylase, the first of three enzymes in the Pyruvate dehydrogenase complex

MTG1[Genbank:NM_138384.2]: c.151T>G (p.Cys51Gly) het

Probably damaging

MTG1 encodes a conserved protein required for assembly of the large ribosomal subunit. Glycine in this position in ribosomal biogenesis GTPase of Mycoplasma pneumoniae [NP_110345]. No mutations were reported in patients

SLC25A5[Genbank:NM_001152.3]: c.811T>C (p.Phe271Leu) het

Possibly damaging

ADP/ATP translocase. Variant in pseudogene [NW_923184.1]

MRPL9[Genbank:NM_031420.2]: c.637A>G (p.Ile213Val) het

Benign*

Component of the large subunit of the mitochondrial ribosome. No mutations have been reported in patients

HADHB[Genbank:NM_000183.2]:c.3G>T (p.Met1Ile) het

Benign*

The HADHB gene encodes the beta subunit of the mitochondrial trifunctional protein involved in mitochondrial beta-oxidation of fatty acids. This variant was not confirmed by Sanger sequencing. Visual inspection of the reads confirmed the Sanger sequencing results

PCK2[Genbank:NM_004563.2]: c.1470+2T>C het

PCK2 encodes Phosphoenolpyruvate carboxykinase 2. Mutations in this gene cause phosphoenolpyruvate carboxykinase deficiency

Patient 2 sample: long chain acyl-CoA dehydrogenase deficiency

HADHA[Genbank:NM_000182.4]: c.1528G>C (p.Glu510Gln) het

Mutation ^†

The HADHA gene encodes the alpha subunit of the mitochondrial trifunctional protein involved in mitochondrial beta-oxidation of fatty acids

HADHA[Genbank:NM_000182.4]: c.315-1G>A het

Mutation ^†

SLC25A15[Genbank:NM_014252.3]: c.269A>T (p.Gln90Leu) het

Benign

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is caused by mutations in the SLC25A15 gene, which encodes the mitochondrial ornithine transporter. Variant in pseudogene [NW_923184.1]

MRPS5[Genbank:NM_031902.3]: c.851G>A (p.Arg284Gln) het

Possibly damaging

Component of the small subunit of the mitochondrial ribosome. No mutations were reported in patients. This position is conserved but not invariant in MRPS5 orthologues

PREPL[Genbank:NM_006036.3]: c.1769A>C (p.Asn590Ser) het

Possibly damaging*

Notes as above

DBT[Genbank:NM_001918.2]: c.725C>A (p.Ser242Stop) het

This variant is present in the HapMap sample above

PAH[Genbank:NM_000277.1]: c.500A>G (p.Asn167Ser) het

Benign*

Notes as above

MRPL9[Genbank:NM_031420.2]: c.637A>G (p.Ile213Val) het

Benign*

Notes as above