Case# Pt1, female, 16yo diagnosis, French

CasePresentingHPOs HP:0001433, HP:0001263, HP:0001252, HP:0001395, HP:0000744, HP:0000718, HP:0000713, HP:0001397, HP:0003651, HP:0012465, HP:0001999, HP:0003155, HP:0003124, HP:0010837, HP:0011967, HP:0012852 (Hepatosplenomgaly, Psychomotor delay, Hypotonia, Hepatic fibrosis, Low tolerance to frustration, Aggressiveness, Agitation, Hepatic steatosis, Foamy histiocytes, Increased liver iron, Dysmorphic facies, Elevated alkaline phosphatase, High cholesterol, Decreased ceruloplasmin, Copper deficiency, Hepatic bridging fibrosis)

HPOsFreeText Hepatospenomegaly and cholestasis(spontaneously resolved) (neonate); Elevated liver enzymes, psychomotor delay, hypotonia(6mo); liver cytolysis, portal-to-portal bridging fibrosis without regenerative nodules, fatty hepatocytes, foamy histiocytes, and iron overload(4yo); behavioral issues, dysmorphic features, elevated relative exchangeable and urinary copper and other metabolic abnormalities(13yo);enlarged portal tracts and liver tissue abnormalities (Fig1)

CaseNotHPOs HP:0200032 (Kayser-Fleischer ring)

CasePreviousTesting Negative for NPC and Wilson disease(ATP7B variants) as well as TMEM199 variants. Metabolic results: ASAT 56 U/L, ALAT 45 U/L [N < 40 U/L]; ALP 196 U/L [N < 119 U/L], cholesterol 5.50 mmol/L [N < 5.20 mmol/L], ceruloplasmin 0.55 μmol/L [N = 2–4.5 μmol/L], total copper 5.44 μmol/L [N = 12.5–22.5 μmol/L], y-gutamyltransferase, bilirubin, CK, glucose, lactic acid, plasma amino acids, urinary organic acids, and lysosomal acid lipase were normal, Bis(Monoacylglycero)Phosphate was also elevated.

CaseMethod1 Direct sequencing

CaseMethod2 n/a

CaseGenotypingMethod Sequenced CCDC115 and TMEM199 in patients and parents

Variant (1) NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser) (2) NM_032357.3:c.19C>T(p.Arg7Ter)

ClinVar (1) 218967 (2) n/a

CAID (2) CA1871401

gnomAD (1) 0.00002384(European (Non-Finnish)), 0.00001086(Total) (2) 0.00002691(European (Non-Finnish)), 0.00001220(Total)

VariantEvidence see note on Fig 2

CaseAddInfo nonconsanguineous

CasePMIDs 26833332

Case# Pt2, male, 20yo report, French

CasePresentingHPOs HP:0200123, HP:0003155, HP:0003236, HP:0003124, HP:0003141, HP:0010837, HP:0006580, HP:0012852, HP:0025321 (Chronic Hepatitis, Elevated alkaline phosphatase, Elevated CK, High cholesterol, Elevated LDL cholesterol, Decreased ceruloplasmin, Portal fibrosis, Hepatic bridging fibrosis, Liver copper accumulation)

CaseNotHPOs HP:0002240, HP:0001744, HP:0001999, HP:0200032 (Hepatomegaly, Splenomegaly, Dysmorphic facies, Kayser-Fleischer ring)

CasePreviousTesting Negative for NPC and Wilson disease(ATP7B variants) as well as TMEM199 variants. Metabolic workup: ALAT 154 U/L, ASAT 137 U/L [N < 40 U/L] for >6 months, GGT was normal, ALP 218 U/L [N < 119 U/L], CK 519 U/L [N < 190 U/L], cholesterol 8.16 mmol/L [N < 5.7 mmol/L], ceruloplasmin 0.54 μmol/L [N = 2–4.5 μmol/L], normal urinary copper, REC 19% [N = 3.0–8.1%], liver copper 2.47 μmol/g, [N = 0.3–0.9 μmol/g]

CaseMethod1 Direct sequencing

CaseMethod2 n/a

CaseGenotypingMethod Sequenced CCDC115 and TMEM199 in patients and parents

Variant (1) NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser) (2) NM_032357.3:c.38T>C(p.Leu13Pro)

ClinVar (1) 218967 (2) n/a

CAID (2) CA348488009

gnomAD (1) 0.00002384(European (Non-Finnish)), 0.00001086(Total) (2) n/a

VariantEvidence see note on Fig 2

CaseAddInfo nonconsanguineous

CasePMIDs 26833332

Case# Pt3, male, 16yo diagnosis, French

CasePresentingHPOs HP:0009062, HP:0001433, HP:0001396, HP:0003124, HP:0012852, HP:0001414, HP:0011924, HP:0001409, HP:0001394, HP:0011343, HP:0002342, HP:0003236, HP:0001315, HP:0010837, HP:0010836 (Infantile axial hypotonia, Hepatosplenomegaly, Cholestasis, High cholesterol, Hepatic bridging fibrosis, Microvesicular hepatic steatosis, Mitochondrial complex III deficiency, Portal hypertension, Cirrhosis, Moderate global developmental delay, Moderate ID, Elevated CK, Absent deep tendon reflexes Decreased ceruloplasmin, Abnormal copper homeostasis)

HPOsFreeText Hepatosplenomegaly and choleostasis reported at birth. Enlarged portal tracts, focal portal inflammation, loss of interlobular ducts in 1/3 of portal tracts and proliferation of bile ductules, lobular steatosis

CaseNotHPOs HP:0003200 (Ragged red fibers)

NotHPOsFreeText foamy hepatoocytes, bile plug

CasePreviousTesting Negative for NPC, Gaucher and Wilson disease(ATP7B variants) as well as TMEM199 variants. Excluded acid lipase deficiency. Negative for disease causing variants in any known genes involved in mitochondrial metabolism. Ruled out type IV glycogen storage disease. Metabolic results: cholesterol 9.92 mmol/L [N < 5.2 mmol/L], ceruloplasmin 0.09 g/L [N = 0.2–0.5 g/L], REC 18% [N = 3.0–8.1%], normal serum(4.16 μmol/L) and exchangeable copper(0.75 μmol/L). Glycogen and cytochrome oxidases were normal.

CaseMethod1 Exome sequencing

CaseMethod2 n/a

CaseGenotypingMethod Exome sequenced patient DNA, direct sequenced CCDC115 and TMEM199 in parents

Variant (1) NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser) (2) NM_032357.3:c.19C>T(p.Arg7Ter)

ClinVar (1) 218967 (2) n/a

CAID (2) CA1871401

gnomAD (1) 0.00002384(European (Non-Finnish)), 0.00001086(Total) (2) 0.00002691(European (Non-Finnish)), 0.00001220(Total)

VariantEvidence see note on Fig 2

CaseAddInfo nonconsanguineous

CasePMIDs 26833332

Case# Pt1, female, 16yo diagnosis, French

CasePresentingHPOs HP:0001433, HP:0001263, HP:0001252, HP:0001395, HP:0000744, HP:0000718, HP:0000713, HP:0001397, HP:0003651, HP:0012465, HP:0001999, HP:0003155, HP:0003124, HP:0010837, HP:0011967, HP:0012852 (Hepatosplenomgaly, Psychomotor delay, Hypotonia, Hepatic fibrosis, Low tolerance to frustration, Aggressiveness, Agitation, Hepatic steatosis, Foamy histiocytes, Increased liver iron, Dysmorphic facies, Elevated alkaline phosphatase, High cholesterol, Decreased ceruloplasmin, Copper deficiency, Hepatic bridging fibrosis)

HPOsFreeText Hepatospenomegaly and cholestasis(spontaneously resolved) (neonate); Elevated liver enzymes, psychomotor delay, hypotonia(6mo); liver cytolysis, portal-to-portal bridging fibrosis without regenerative nodules, fatty hepatocytes, foamy histiocytes, and iron overload(4yo); behavioral issues, dysmorphic features, elevated relative exchangeable and urinary copper and other metabolic abnormalities(13yo);enlarged portal tracts and liver tissue abnormalities (Fig1)

CaseNotHPOs HP:0200032 (Kayser-Fleischer ring)

CasePreviousTesting Negative for NPC and Wilson disease(ATP7B variants) as well as TMEM199 variants. Metabolic results: ASAT 56 U/L, ALAT 45 U/L [N < 40 U/L]; ALP 196 U/L [N < 119 U/L], cholesterol 5.50 mmol/L [N < 5.20 mmol/L], ceruloplasmin 0.55 μmol/L [N = 2–4.5 μmol/L], total copper 5.44 μmol/L [N = 12.5–22.5 μmol/L], y-gutamyltransferase, bilirubin, CK, glucose, lactic acid, plasma amino acids, urinary organic acids, and lysosomal acid lipase were normal, Bis(Monoacylglycero)Phosphate was also elevated.

CaseMethod1 Direct sequencing

CaseMethod2 n/a

CaseGenotypingMethod Sequenced CCDC115 and TMEM199 in patients and parents

Variant (1) NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser) (2) NM_032357.3:c.19C>T(p.Arg7Ter)

ClinVar (1) 218967 (2) n/a

CAID (2) CA1871401

gnomAD (1) 0.00002384(European (Non-Finnish)), 0.00001086(Total) (2) 0.00002691(European (Non-Finnish)), 0.00001220(Total)

VariantEvidence see note on Fig 2

CaseAddInfo nonconsanguineous

CasePMIDs 26833332

Case# Pt2, male, 20yo report, French

CasePresentingHPOs HP:0200123, HP:0003155, HP:0003236, HP:0003124, HP:0003141, HP:0010837, HP:0006580, HP:0012852, HP:0025321 (Chronic Hepatitis, Elevated alkaline phosphatase, Elevated CK, High cholesterol, Elevated LDL cholesterol, Decreased ceruloplasmin, Portal fibrosis, Hepatic bridging fibrosis, Liver copper accumulation)

CaseNotHPOs HP:0002240, HP:0001744, HP:0001999, HP:0200032 (Hepatomegaly, Splenomegaly, Dysmorphic facies, Kayser-Fleischer ring)

CasePreviousTesting Negative for NPC and Wilson disease(ATP7B variants) as well as TMEM199 variants. Metabolic workup: ALAT 154 U/L, ASAT 137 U/L [N < 40 U/L] for >6 months, GGT was normal, ALP 218 U/L [N < 119 U/L], CK 519 U/L [N < 190 U/L], cholesterol 8.16 mmol/L [N < 5.7 mmol/L], ceruloplasmin 0.54 μmol/L [N = 2–4.5 μmol/L], normal urinary copper, REC 19% [N = 3.0–8.1%], liver copper 2.47 μmol/g, [N = 0.3–0.9 μmol/g]

CaseMethod1 Direct sequencing

CaseMethod2 n/a

CaseGenotypingMethod Sequenced CCDC115 and TMEM199 in patients and parents

Variant (1) NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser) (2) NM_032357.3:c.38T>C(p.Leu13Pro)

ClinVar (1) 218967 (2) n/a

CAID (2) CA348488009

gnomAD (1) 0.00002384(European (Non-Finnish)), 0.00001086(Total) (2) n/a

VariantEvidence see note on Fig 2

CaseAddInfo nonconsanguineous

CasePMIDs 26833332

Case# Pt3, male, 16yo diagnosis, French

CasePresentingHPOs HP:0009062, HP:0001433, HP:0001396, HP:0003124, HP:0012852, HP:0001414, HP:0011924, HP:0001409, HP:0001394, HP:0011343, HP:0002342, HP:0003236, HP:0001315, HP:0010837, HP:0010836 (Infantile axial hypotonia, Hepatosplenomegaly, Cholestasis, High cholesterol, Hepatic bridging fibrosis, Microvesicular hepatic steatosis, Mitochondrial complex III deficiency, Portal hypertension, Cirrhosis, Moderate global developmental delay, Moderate ID, Elevated CK, Absent deep tendon reflexes Decreased ceruloplasmin, Abnormal copper homeostasis)

HPOsFreeText Hepatosplenomegaly and choleostasis reported at birth. Enlarged portal tracts, focal portal inflammation, loss of interlobular ducts in 1/3 of portal tracts and proliferation of bile ductules, lobular steatosis

CaseNotHPOs HP:0003200 (Ragged red fibers)

NotHPOsFreeText foamy hepatoocytes, bile plug

CasePreviousTesting Negative for NPC, Gaucher and Wilson disease(ATP7B variants) as well as TMEM199 variants. Excluded acid lipase deficiency. Negative for disease causing variants in any known genes involved in mitochondrial metabolism. Ruled out type IV glycogen storage disease. Metabolic results: cholesterol 9.92 mmol/L [N < 5.2 mmol/L], ceruloplasmin 0.09 g/L [N = 0.2–0.5 g/L], REC 18% [N = 3.0–8.1%], normal serum(4.16 μmol/L) and exchangeable copper(0.75 μmol/L). Glycogen and cytochrome oxidases were normal.

CaseMethod1 Exome sequencing

CaseMethod2 n/a

CaseGenotypingMethod Exome sequenced patient DNA, direct sequenced CCDC115 and TMEM199 in parents

Variant (1) NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser) (2) NM_032357.3:c.19C>T(p.Arg7Ter)

ClinVar (1) 218967 (2) n/a

CAID (2) CA1871401

gnomAD (1) 0.00002384(European (Non-Finnish)), 0.00001086(Total) (2) 0.00002691(European (Non-Finnish)), 0.00001220(Total)

VariantEvidence see note on Fig 2

CaseAddInfo nonconsanguineous

CasePMIDs 26833332