OVERVIEW

Hereditary metabolic disorders (also called inborn errors of metabolism) affect the body’s ability to convert food into energy and remove waste and unhealthy substances through complex chemical reactions. Enzymes break down carbohydrates, proteins, and fats in food to release energy or other substances that the body no longer needs, or make those it lacks. Alterations in these chemical processes due to a hormone or enzyme deficiency leads to a metabolic disorder. Inherited metabolic disorders can be categorized depending on the specific substance and whether it builds up in harmful amounts, it’s too low or it’s missing. There are hundreds of inherited metabolic disorders, caused by different genetic defects. Common and important genetic metabolic disorders include: Niemann-Pick disease (babies develop liver enlargement, difficulty feeding, and nerve damage), Krabbe disease (progressive nerve damage, developmental delay in young children; occasionally adults are affected), Maple syrup urine disease (nerve damage results, and the urine smells like syrup), Phenylketonuria (intellectual disability results if the condition is not recognized) and Glycogen storage diseases (low blood sugar levels, muscle pain, and weakness). Early identification of individuals at risk can help establish the right clinical management plan.

We offer comprehensive and syndrome-specific panels testing for metabolic disorders. The test can offer a molecular genetic diagnosis of a metabolic disorder that is observed or predicted in you/your child or a family member.

IMPORTANCE OF GETTING TESTED

If you or a family member has a risk of a metabolic disorder, identifying the cause can help to take actions to improve the outcome of the disorder. Additionally, family members can be informed and encouraged to also get tested. Our genetic counsellors can provide medical advice.

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You have a family history of metabolic disorders
and want to estimate the risk for your child

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You have a newborn with metabolic disorder symptoms
and confound screening results

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You/your child has a clinical diagnosis and
want to confirm/differentiate

POSSIBLE OUTCOMES OF THE TEST

A molecular genetic diagnostic report outlining the results of the sequencing analysis is provided. Changes in DNA sequences (variants) can be detrimental and lead to the development of a cardiac or aortic disorder, including asymptomatic disorders that develop later in life. We will report pathogenic and likely pathogenic variants as well as variants of unknown significance.
Pathogenic and likely pathogenic variants mean the genetic cause of the observed symptoms has been identified and may help determine the right treatment and management plan.
Variants of unknown significance means there was not enough evidence to classify the variant as either pathogenic or neutral. Annual variant reclassification and testing family members is recommended.
It is important to note that a negative result does not guarantee the absence of a disorder or that the disorder does not have a genetic cause. Genetic testing is an evolving field and may not detect all variants or there may not currently be enough evidence to classify all variants that lead to an inherited disease.

MEDICAL GENETIC COUNSELLING

We provide expert medical genetic counselling as part of a genetic testing journey. Genetic counselling is a process of communication that supports patients and their relatives before and after genetic testing. It is educational, impartial and nondirective. Prior to any genetic test, genetic counsellors will obtain a detailed family history, explain the method of testing that will be used, its risks and benefits, the limitations of the diagnosis and the implications of making a genetic diagnosis (Elliott and Friedman, 2018, Nat Rev Genet 19:735).

Upon receiving the genetic test results, genetic counselling can help the specialist physician and the patient to interpret them. They can be advised of the consequences of the results including the probability of developing the genetic disorder or passing it on to children, as well as ways to prevent, avoid or reduce these risks (Yang and Kim, 2018, Ann Lab Med 38:291). Our goal of counselling is to provide the patient with greater knowledge and thus, a better understanding of the results and the ability to make a more informed decision.

ACCEPTED MATERIAL

1 ml EDTA Blood

TURNAROUND TIME

15-25 working days

TECHNOLOGY

DNA is isolated and next generation sequencing is performed on all coding exons and conserved intronic regions. Single base pair changes, small deletions and duplications and copy number variants (CNV) are identified. Sequencing runs result in a Quality Score of >30 (accuracy >99.9%) in at least 75% of all bases with a coverage of >20-fold. CNV detection sensitivity is 76.99% and precision is 62.59% (with GC limitation between 0.4 and 0.6 per target sensitivity is 77.04% and precision is 84.10%). Variant classification is performed following ACMG guidelines (Richards et al. 2015, Genet Med 17:405; Kearney et al. 2011, Genet Med 13:680).

TEST METHODOLOGY
Sequencing

Next generation
sequencing (Illumina)

Enrichment

Twist Human Core
Exome plus Ref Seq
Spikeln

SNV and CNV data anlaysis

Illumina DRAGEN
Bio-IT Platform

Data Evaluation

VarSeq by
GoldenHelix

Reference Genome

hg38, NCBI GR38

Quality Criteria

>30 (precision >99,9%)
in min. 75% of bases

SNV detection sensitivity

99.92-99.93%; confirmation of reported SNV with Sanger
sequencing, data analysis with
SeqPilot

Classification of variants

Richards et al. 2015, Genet Med
17:405; Ellard et al. “ACGS Best
Practice Guidelines for Variant
Classification 2020″

in silico algorithms

MaxEntScan,
SpliceSiteFinder-like,
REVEL

Databases

HGMD Professional
release, ClinVar,
gnomAD

OUR TESTS

Abetalipoproteinemia

Genes: MTTP

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Alcohol intolerance

Genes: ADH1B, ALDH2

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ApoA-I deficiency

Genes: APOA1

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Biotinidase deficiency

Genes: BTD

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Chylomicronemia syndrome

Genes: APOA5, APOC2, GPIHBP1, LMF1, LPL

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CONGENITAL DISORDERS OF GLYCOSYLATION

Genes: ALG1, ALG11, ALG12, ALG13, ALG2, ALG3, ALG6, ALG8, ALG9, B4GALT1, CAD, CCDC115, COG1, COG4, COG5, COG6, COG7, COG8, DDOST, DOLK, DPAGT1, DPM1, DPM2, DPM3, MGAT2, MOGS, MPDU1, MPI, NGLY1, PGM1, PMM2, RFT1, SLC35A1, SLC35A2, SLC35C1, SLC39A8, SRD5A3, SSR4, STT3A, STT3B, TMEM165, TMEM199, TUSC3

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Crigler-Najjar syndrome

Genes: UGT1A1

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Dihyropyrimidine dehydrogenase deficiency

Genes: DPYD

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Fabry disease

Genes: GLA

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FATTY ACID OXIDATION DISORDERS

Genes: ACADM, ACADVL, ETFA, ETFB, ETFDH, HADHA, HADHB

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Fish-eye disease

Genes: LCAT

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FRUCTOSE INTOLERANCE

Genes: ALDOB

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Fructose-1,6-bisphosphatase deficiency

Genes: FBP1

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Galactosemia

Genes: GALT

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Gaucher disease

Genes: GBA

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Gilbert syndrome

Genes: UGT1A1

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GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (FAVISM)

Genes: G6PD

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Glutaric acidemia I (GA1)

Genes: GCDH

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Glycogen storage disease II (Pompe disease)

Genes: GAA

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Hepatic lipase deficiency

Genes: LIPC

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Hereditary hemochromatosis (extended)

Genes: BMP6, HAMP, HFE, HJV, SLC40A1, TFR2

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Hereditary hemochromatosis (standard)

Genes: HFE

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HYPERCHOLESTEROLEMIA, FAMILIAL (extended)

Genes: APOB, LDLR, LDLRAP1, PCSK9

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HYPERCHOLESTEROLEMIA, FAMILIAL (standard)

Genes: APOB

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Hyperhomocysteinemia

Genes: MTHFR

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Hyperlipoproteinemia, mixed

Genes: APOA1, APOE, LIPC

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Hyperlipoproteinemia, type Ib

Genes: APOC2

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Hyperlipoproteinemia, type III

Genes: APOE

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HYPEROXALURIA

Genes: AGXT, GRHPR, HOGA1

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HYPERTRIGLYCERIDEMIA, PRIMARY

Genes: APOA5, APOC2, GPIHBP1, LMF1, LPL

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Hypoalphalipoproteinemia

Genes: ABCA1, APOA1, LCAT

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Hypobetalipoproteinemia

Genes: ANGPTL3, APOB, MTTP, PCSK9

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HYPOBETALIPOPROTEINEMIA, FAMILIAL

Genes: APOB

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Isovaleric acidemia

Genes: IVD

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Krabbe disease

Genes: GALC

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Lactase deficiency, congenital

Genes: LCT

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LACTOSE INTOLERANCE

Genes: LCT

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Lipoprotein lipase deficiency

Genes: LPL

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MALIGNANT HYPERTHERMIA

Genes: CACNA1S, RYR1

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Maple syrup urine disease (MSUD)

Genes: BCKDHA, BCKDHB, DBT

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MATURITY ONSET DIABETES OF THE YOUNG

Genes: ABCC8, APPL1, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, KLF11, NEUROD1, PAX4, PDX1

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Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)

Genes: ACADM

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Methylmalonic aciduria

Genes: MMUT

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Mevalonic aciduria

Genes: MVK

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Mitochondrial carnitine-acylcarnitine cycle disorders

Genes: CPT1A, CPT2, SLC25A20

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MUCOPOLYSACCHARIDOSIS

Genes: ARSB, GALNS, GLB1, GUSB, HGSNAT, HYAL1, IDS, IDUA, NAGLU, SGSH

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Niemann-Pick disease

Genes: NPC1, NPC2, SMPD1

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Obesity

Genes: KSR2, LEP, LEPR, MC3R, MC4R, MRAP2, NTRK2, PCSK1, POMC, SH2B1, SIM1

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Phenylketonuria

Genes: PAH

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PORPHYRIA

Genes: ALAD, ALAS2, CPOX, FECH, HMBS, PPOX, UROD, UROS

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Propionicacidemia

Genes: PCCA, PCCB

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Smith-Lemli-Opitz syndrome

Genes: DHCR7

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Tangier disease

Genes: ABCA1

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Tay-Sachs disease (available from Q2/2021)

Genes: GM2A, HEXA

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Tyrosinemia, type I

Genes: FAH

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UREA CYCLE DISORDERS

Genes: ARG1, ASL, ASS1, CPS1, NAGS, OTC, SLC25A13, SLC25A15

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Wilson disease

Genes: ATP7B

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OUR NETWORK