Case# Subject 2, F, 5mo died, Kurdish

CasePresentingHPOs HP:0001319, HP:0008872, HP:0002033, HP:0003128, HP:0002490, HP:0001531, HP:0040288, HP:0001712, HP:0001410, HP:0002098, HP:0002910, HP:0002126, HP:0000365, HP:0002151 (Neonatal hypotonia, Feeding difficulties in infancy, Poor suck, Hyperlactatemia, Increased CSF lactate level, Failure to thrive in infancy, Nasogastric tube feeding, Left ventricular hypertrophy, Decreased liver function, Respiratory distress, Elevated transaminases, Polymicrogyria, Deafness, Elevated serum lactate)

HPOFreeText: After caesarean delivery, neonatal hypotonia, poor feeding, and sucking. (3 months) failure to thrive, nasogastric feeding, left ventricular hypertrophy and impaired liver function. Brain MRI: bifrontal polymicrogyria and acoustic oto-emissions suggested deafness (4 months). Died of respiratory distress at 5 months.

CaseNotHPOs n/a

CasePreviousTesting Serum lactate (7.4 mmol/L; normal range 0.90–1.70 mmol/L), lactate to pyruvate ratio (170; normal range 30–50), CSF lactate (3.1 mmol/L; control < 2.2 mmol/L), liver function (AST: 84 UI/L, normal range 15–60; ALT: 52 UI/L, normal range 7–40; gGT: 262 UI/L, normal range 6–25 UI/L). Screened panel of known mitochondrial disease genes. Analysis of mtDNA and mtDNA copy number from patient muscle DNA were normal, thus excluding mtDNA rearrangements and point mutations.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with Sanger in patient and parents to confirm in trans

Variant NM_017819.3(TRMT10C):c.542G>T (p.Arg181Leu) -homozygous

ClinVar 224316

gnomAD 0.0003508(Latino), 0.0001121(Total) -no homozygotes on record

VariantEvidence n/a

CaseAddInfo non-consanguineous, healthy older brother, c.542G>T variant in ExAC (10/120,324 alleles) and ESP6500 (1/11,824 alleles)

CaseAddPMIDs n/a

Case# Subject 1, M, 5mo died, British

CasePresentingHPOs HP:0001319, HP:0003324, HP:0008872, HP:0001531, HP:0002020, HP:0000407, HP:0002910, HP:0002151, HP:0002490, HP:0003198, HP:0003200, HP:0003688, HP:0002098, HP:0003348 (Neonatal hypotonia, Generalized muscle weakness, Feeding difficulties in infancy, Failure to thrive in infancy, Gastroesophageal reflux, Sensorineural hearing impairment, Elevated transaminases, Increased serum lactate, Increased CSF lactate level, Myopathy, Ragged red muscle fibers, Cytochrome C oxidase-negative muscle fibers, Respiratory distress, Elevated blood alanine)

HPOFreeText: Hypotonic and weak soon after birth, had difficulty feeding, slow weight gain and gastro-esophageal reflux, confirmed sensorineural deafness after neonatal screen. Lateral skull X-ray showed fused sutures, supporting possible craniosynostosis. Died of 5.5 months of respiratory distress after rhinovirus bronchiolitis.

CaseNotHPOs HP:0045045 (Elevated acylcarnitine)

CasePreviousTesting Alanine transaminase (439 U/L; normal range 4–45 U/L), blood lactate (5 to 10 mmol/L; normal range 0.7–2.1 mmol/L). Screened panel of known mitochondrial disease genes. Analysis of mtDNA and mtDNA copy number were normal in patient muscle cells, thus excluding mtDNA rearrangements and point mutations.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with Sanger in patient and parents to confirm in trans

Variant (1) NM_017819.3(TRMT10C):c.542G>T (p.Arg181Leu), (2) NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala)

ClinVar (1) 224316, (2) 224317

gnomAD (1) 0.0003508(Latino), 0.0001121(Total) - no homozygotes listed (2) n/a

VariantEvidence n/a

CaseAddInfo non-consanguineous, healthy older sister, c.542G>T variant in ExAC (10/120,324 alleles) and ESP6500 (1/11,824 alleles), c.814A>G was not in ExAC, ESP6500 or COSMIC

CaseAddPMIDs n/a

NM_017819.3(TRMT10C):c.542G>T (p.Arg181Leu)

ClinVar 224316

CAID CA2520544

gnomAD 0.0003508(Latino), 0.0001121(Total)

RescuePatientCell CL:0000057

GeneAlteration NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala) and/or NM_017819.3(TRMT10C):c.542G>T (p.Arg181Leu)

RescuePhenotype defective oxidative phosphorylation and tRNA 5' processing affecting high energy demand tissues: HP:0001508 (Failure to thrive)

RescueMethod Fibroblasts transfected with lentiviral vector containing single copy of WT TRMT10C.

RescueEvidence Transfected patient cells had increased MRPP1 expression, restored mitochondrial translation, normalized levels of respiratory chain complexes and mt-tRNA precursors which rescues the reduced cellular oxidative phosphorylation and slowed growth. 21857155 demonstrates both the restriction of translation and reduction of the rate of oxidative phosphorylation during MRPP1 knockdown in HeLa cells (Fig 5). Those result corroborate the gap between reduced MRPP1 expression and reduction in translation of oxidative phosphorylation machinery.

RescueVariants n/a

Metodiev, 2016 (AJHG)

-2 cases with variants:

NM_017819.3(TRMT10C):c.542G>T (p.Arg181Leu)

NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala)

-variant evidence

-rescue patient cells experiment

PatientCell CL:0000057 (fibroblast)

GeneFunction GO:0070131 (positive regulation of mitochondrial translation)

GeneAlteration n/a

FunctionalEvidence (Figure 2D) Labelling patient fibroblast proteins with EasyTag EXPRESS35S Protein Labeling Mix showed decreased assembly of complex I (NDUFB8) and IV (COXI) which corroborates the reduced mean enzyme activity and mitochondrial translation in Table 1.

FAVariants NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala)

ClinVar: 224317

and

NM_017819.3(TRMT10C):c.542G>T (p.Arg181Leu)

ClinVar: 224316

NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala)

ClinVar 224317

CAID CA10575895

gnamAD n/a