Case# F5-II1, female, 7mo death, Portuguese

CasePresentingHPOs HP:0006579, HP:0001433, HP:0001508, HP:0001582, HP:0001290, HP:0001943, HP:0001987, HP:0002611, HP:0001399, HP:0001903, HP:0012115, HP:0001298, HP:0012358, HP:0012347, HP:0003155, HP:0003141, HP:0001394 (Neonatal jaundice, Hepatosplenomegaly, Failure to thrive, Redundant skin, Hypotonia, Hypoglycemia, Hyperammonemia, Cholestatic liver disease, Liver failure, anemia, Hepatitis, Encephalopathy, O-glycosylation, N-glycosylation, Elevated alkaline phosphatase, High cholesterol, Increased LDL cholesterol, Cirrhosis)

HPOsFreeText persisting jaundice, hepatosplenomegaly, FTT, redundant skin, poor muscle volume, generalized hypotonia(5mo) abnormal coagulation factors, perinuclear iron deposition, severe cholestatic hepatitis, multi-organ failure, elevated aminotransferases, on bone marrow biopsy: dyserythropoiesis, lipidic histiocytes and erythrophagocytosis

CaseNotHPOs n/a

CasePreviousTesting type 2 CDG, metabolic work up: AST 207–972 U/l[normal range, 0–50 U/l], ALT 48–153 U/l[normal range, 0–50 U/l], ALP 850–1,031 U/l[normal range, < 360 U/l], cholesterol 431 mg/dl[normal range, 120–200 mg/dl], LDL cholesterol 314 mg/dl[normal range, 50–130 mg/dl], low FVII and high FVIII, INR 0.79–3.0, HB 7 g/dl

CaseMethod1 WES

CaseMethod2 n/a

CaseGenotypingMethod WES on proband, Sanger on parents. Variants with frequency of >0.2%, synonymous variants, deep intronic variants, and variants in UTRs were excluded.

Variant (1) NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser), (2)NM_032357.3(CCDC115):c.(?-258) (∗1245_?) del(p.0?), compound heterozygous

ClinVar (1) 218967(2) n/a

gnomAD (1) 0.00002384(European (Non-Finnish)), 0.00001086(Total)-3 heterozygotes

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs 29759592

Family#PresentingHPOs HP:0001999, HP:0003155, HP:0003124, HP:0003141, HP:0012347, HP:0012358, HP:0001399 (Dysmorphic facies, Elevated alkaline phosphatase, High cholesterol, Increased LDL cholesterol, Abnormal protein N-linked glycosylation, Abnormal protein O-linked glycosylation, Liver failure)

HPOsFreeText elevated AT

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Turkish

Race n/a

Family#PreviousTesting Metabolic work up: Elevated AT, ALP, total cholesterol and LDL cholesterol, abnormal N- and O- glycosylation

Family#Method1 Sanger

Family#Method2 n/a

Family#GenotypingMethod Sanger on proband targeting CCDC115

Affected 2

Unaffected 0

Segregations n/a

PublishedLOD n/a

eLOD n/a

AddSegregationInfo consanguinity

ProbandLabel F4-II1, male,9yo death

Case1PreviousTesting Metabolic results: AST 192–669 U/l[normal range, 0–50 U/l], ALT 83–308 U/l [normal range, 0–50 U/l], ALP 702 U/l[normal range, < 360 U/l]

Case2 F4-II2, female, 8yo diagnosis

Case2PreviousTesting Metabolic results: AST 98–422 U/l [normal range, 0–50 U/l], ALT 98–178 U/l [normal range, 0–50 U/l], ALP 710–985 U/l [normal range, < 360 U/l]. AT and CDG profile normalized after liver transplant.

Variant NM_032357.3(CCDC115):c.31G>T (p.Asp11Tyr), homozygous

ClinVar 218963

gnomAD n/a

VariantEvidence n/a

FamilyAddInfo n/a

FamilyPMIDs n/a

Case# F3-II2, female, 1yo onset, French

CasePresentingHPOs HP:0006579, HP:0003155, HP:0001290, HP:0001397, HP:0001395, HP:0001263, HP:0001250, HP:0000718, HP:0000713, HP:0000709, HP:0012347, HP:0003124, HP:0003141, HP:0010837 (Neonatal Jaundice, Elevated alkaline phosphatase, Hypotonia, Steatosis, Hepatic fibrosis, Psychomotor delay, Seizures, Aggressive behavior, Agitation, Psychosis, Abnormal protein N-linked glycosylation, High cholesterol, Increased LDL cholesterol, Low ceruloplasmin)

HPOsFreeText Persistent moderate hypotonia, elevated AT, necrotic lesions on liver biopsy, steatosis and fibrosis(1yo), developed various behavioral issues by age 25

CaseNotHPOs n/a

CasePreviousTesting Metabolic work up: AST 1,780 U/l[normal range, 0–50 U/l], ALT 390 U/l[normal range, 0–50 U/l], and ALP 950 U/l [normal range, < 360 U/l], with increased bone fraction, ceruloplasmin 10 mg/dl[normal range, 15–60 mg/dl], type 2 CDG, abnormal N-glycosylation

CaseMethod1 Sanger

CaseMethod2 n/a

CaseGenotypingMethod Sanger on proband targeting CCDC115.

Variant NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser), homozygous

ClinVar 218967

gnomAD 0.00002384(European (Non-Finnish)), 0.00001086(Total)-3 heterozygotes

VariantEvidence n/a

CaseAddInfo unaffected brother

CasePMIDs 29759592

Case# F2-II1, male, Italian, 2yo diagnosis

CasePresentingHPOs HP:0006579, HP:0001433, HP:0010837, HP:0003124, HP:0003155, HP:0001263, HP:0001999, HP:0025321, HP:0012358, HP:0012347, HP:0003141 (Neonatal jaundice, Hepatosplenomegaly, Decreased ceruloplasmin, High cholesterol, Elevated alkaline phosphatase, Psychomotor delay, Dysmorphic facies, Liver copper accumulation, Abnormal protein O-linked glycosylation, Abnormal protein N-linked glycosylation, Increased LDL cholesterol)

HPOsFreeText Elevated AT, ALT, cholesterol, jaundice, hepatosplenomegaly, low blood ceruloplasmin(neonate), Mild psychomotor disability, mild dysmorphic facies (2yo)

CaseNotHPOs n/a

CasePreviousTesting Failed to detect ATP7B on suspected Wilson disease. Metabolic work up: AST 422 U/l[normal range, 0–50 U/l], ALT 588 U/l[normal range, 0–50 U/l], ALP 976 U/l[normal range, < 360 U/l], type 2 CDG (2yo). Hepatic copper 125 μg/g dry weightnormal range, <40 μg/g, Altered ApoC3 pattern, type 2 CDG pattern

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with Sanger homozygosity in proband and heterozygosity in parents. Variants with frequency of >0.2%, synonymous variants, deep intronic variants, and variants in UTRs were excluded.

Variant NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser), homozygous

ClinVar 218967

gnomAD 0.00002384(European (Non-Finnish)), 0.00001086(Total)-3 heterozygotes

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs 26833332, 29759592

Family#PresentingHPOs HP:0001263, HP:0001433, HP:0003155, HP:0012358, HP:0012347, HP:0010837, HP:0001999 (Pyschomotor delay, Hepatosplenomegaly, Abnormal protein O-linked glycosylation, Abnormal protein N-linked glycosylation, Decreased ceruloplasmin, Dysmorphic facies)

HPOsFreeText Elevated aminotranseferases, type 2 CDG

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Turkish

Race n/a

Family#PreviousTesting Metabolic screen indicated elevated AT, bone derived ALP, and low ceruloplasmin.

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod WES confirmed with Sanger homozygosity in siblings and heterozygosity in parents. Variants with frequency of >0.2%, synonymous variants, deep intronic variants, and variants in UTRs were excluded.

Affected 3

Unaffected 1

Segregations 3

PublishedLOD n/a

eLOD 1.32

AddSegregationInfo consanguinity

ProbandLabel F1-II1, female, 9yo report

Case1PresentingHPOs HP:0001252, HP:0003236 (Hypotonia, Elevated CK)

HPOsFreeText decreased coagulation factors

Case1PreviousTesting Metabolic work up: AST 130–158 U/l [normal range, 0–50 U/l], ALT 85–101 U/l [normal range, 0–50 U/l], and ALP 1,016 –1,193 U/l [normal range, < 360 U/l], serum ceruloplasmin (4 mg/dl [normal range, 15–60 mg/dl]. No change in CD59 and CD55 expression in EBV-transformed lymphoblasts.

Case2 F1-II2, male, 5yo report

Case2PresentingHPOs HP:0003124, HP:0000276, HP:0000508, HP:0000592, HP:0000494, HP:0100295, HP:0001433 (Hypercholesterolemia, Long face, Ptosis, Blue sclera, Downslanting palpebral fissures, Muscle fiber atrophy, Hepatosplenomegaly)

HPOsFreeText Hepatosplenomegaly normalized with age, abnormal coagulation factors

Case2PreviousTesting Metabolic work up: AST 96–436 U/l [normal range, 0–50 U/l], ALT 140–995 U/l [normal range, 0–50 U/l], and ALP 1,070–1,577 U/l [normal range, < 360 U/l], serum ceruloplasmin (4 mg/dl [normal range, 15–60 mg/dl], cholesterol 289 mg/dl [normal range, 120–200 mg/dl]

Variant NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser), homozygous

ClinVar 218967

gnomAD 0.00002384(European (Non-Finnish)), 0.00001086(Total)-3 heterozygotes

VariantEvidence n/a

FamilyAddInfo A third ungenotyped sibling, F1-II4 did not have hypotonia, but otherwise presented similarly.

FamilyPMIDs 29759592

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