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Invitae Metabolic Non-Immune Fetal Hydrops Panel

Test description

The Invitae Metabolic Causes of Non-Immune Fetal Hydrops Panel analyzes up to 53 genes that are associated with metabolic conditions that may include a prenatal onset presentation of fetal hydrops (hydrops fetalis), edema, or ascites. Nonimmune hydrops fetalis (NIHF) comprises the subgroup of cases not caused by red cell alloimmunization. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions as many metabolic disorders are treatable. This test is specifically designed for metabolic Mendelian disorders known to be associated with fetal hydrops and is not appropriate for hydrops due to red cell alloimmunization, infection, chromosomal abnormalities, hematologic disorders, or malformations.

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Primary panel (51 genes)

AHCY ALG1 ALG12 ALG8 ALG9 ARSB ASAH1 CTSA DHCR7 G6PD GAA GALC GALNS GBE1 GLB1 GLUL GNPTAB GUSB HADH HADHA HADHB IDUA LIPA MVK NEU1 NPC1 NPC2 PEX1 PEX10 PEX12 PEX13 PEX14 PEX16 PEX19 PEX2 PEX26 PEX3 PEX5 PEX6 PEX7 PHGDH PIGA PMM2 PSAT1 SLC17A5 SLC22A5 SLC26A2 SMPD1 SUMF1 TAZ TRIP11

Add-on Limited Evidence Gene (1 gene)

This gene is associated with congenital dyserythropoietic anemia, type II, which has been associated with NIFH (PMID). This gene is optional because it also has a preliminary association with autosomal dominant Cowden syndrome.

SEC23B

  • Aminoacidopathy
    • S-adenosylhomocysteine hydrolase deficiency
  • Congenital disorders of glycosylation
    • ALG1-CDG (CDG-Ik)
    • ALG12-CDG (CDG-Ig)
    • ALG8-CDG (CDG-Ih)
    • ALG9-CDG (CDG-IL)
    • CCDC115-CDG (CDG20)
    • multiple congenital anomalies-hypotonia-seizures syndrome 2 (PIGA-CDG)
    • PMM2-CDG (CDG-Ia)
    • SLC26A2-CDG (achondrogenesis, type 1B, atelosteogenesis type 2, diastrophic dysplasia, and multiple epiphyseal dysplasia 4)
    • TRIPP11-CDG (achondrogenesis, type 1A)
  • Congenital glutamine deficiency
  • Glucose-6-phosphatase deficiency
  • Glutamine synthetase deficiency
  • Fatty acid oxidation defects
    • long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD)
    • medium/short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (M/SCHAD)
    • mitochondrial trifunctional protein (MTP) deficiency
    • primary carnitine deficiency
  • Glycogen storage diseases
    • GSDII (Pompe disease)
    • GSD IV and adult polyglucosan body disease
  • Lysosomal storage disorders
    • acid ceramidase deficiency (Farber lipogranulomatosis)
    • acid sphingomyelinase (ASM) deficiency (Niemann Pick type A and B)
    • galactosialidosis
    • GM1 gangliosidosis
    • Krabbe disease
    • lysosomal acid lipase (LAL) deficiency
    • mucolipidosis type II alpha/beta (ML II) (I-cell disease)
    • mucolipidosis type III alpha/beta (ML III) (pseudo-Hurler polydystrophy)
    • MPS1 (Hurler/Scheie syndrome)
    • MPS IVA (Morquio A syndrome)
    • MPS IVB (Morquio B syndrome)
    • MPS VI (Maroteaux-Lamy syndrome)
    • MPS VII (Sly syndrome)
    • multiple sulfatase deficiency
    • Niemann-Pick disease type C
    • sialic acid storage disorders (infantile free sialic acid storage disease and Salla disease)
    • sialidosis types I and II
  • Neurotransmitter disorders
    • phosphoglycerate dehydrogenase deficiency (Neu-Laxova syndrome)
    • phosphoserine aminotransferase deficiency (Neu-Laxova syndrome type 2)
  • Organic acidemia
    • 3-methylglutaconic aciduria type II (Barth syndrome)
  • Peroxisomal biogenesis disorders
    • Zellweger spectrum disorders
    • rhizomelic chondrodysplasia punctata
    • Refsum disease
  • Sterol biosynthesis disorders
    • mevalonate kinase deficiency
    • mevalonic aciduria
    • hyper-IgD syndrome
    • porokeratosis
    • Smith-Lemli-Opitz syndrome (SLOS)

Hydrops fetalis is a prenatal-onset condition characterized by excessive fluid accumulation in the extravascular compartment of the fetus and manifests as two or more findings of skin edema, pleural effusion, ascites, or polyhydramnios. It is divided into 2 general categories: immune hydrops fetalis is caused by red cell alloimmunization and is attributed to 10% of cases, whereas non-immune hydrops fetalis (NIHF) is heterogenous and comprises approximately 90% of cases. The many possible causes of NIHF include chromosome abnormalities, hematologic disorders, cardiovascular conditions, malformations (such as cardiac, urinary tract, thoracic, lymphatic, or gastrointestinal), infection, syndromic conditions, skeletal dysplasias, metabolic disorders, twin-to-twin transfusion, fetal tumors, and placental or umbilical cord lesions. Although the prognosis is dependent on the etiology, NIHF is associated with a high rate of fetal demise and also an increased risk for postnatal mortality or complications.

The clinical sensitivity for this test is unknown. Causes of NIFH are clinically and genetically heterogeneous, and the percentage of patients with NIFH and pathogenic variants in one of the genes offered in this panel has not been determined.

The majority of metabolic conditions associated with fetal hydrops are inherited in an autosomal recessive manner. Glucose-6-phosphate dehydrogenase deficiency, multiple congenital anomalies-hypotonia-seizures syndrome 2 and methylglutaconic aciduria type 2 (Barth syndrome) are inherited in an X-linked manner. MVK-related conditions are inherited in an autosomal recessive (melvalonic aciduria and hyper-IgD syndrome) or autosomal dominant manner (porokeratosis). PEX6-related peroxisome biogenesis disorder 4B can be inherited in an autosomal recessive or an autosomal dominant manner.

The overall prevalence of NIHF ranges from 1/1500 to 1/4000 births.

This test is appropriate for patients with fetal hydrops where chromosomal abnormalities, hematologic conditions and infectious causes have been ruled out.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
AHCY NM_000687.3
ALG1 NM_019109.4
ALG12 NM_024105.3
ALG8 NM_024079.4
ALG9 NM_024740.2
ARSB NM_000046.3
ASAH1 NM_177924.3
CTSA NM_000308.3
DHCR7 NM_001360.2
G6PD NM_001042351.2
GAA* NM_000152.3
GALC* NM_000153.3
GALNS NM_000512.4
GBE1 NM_000158.3
GLB1 NM_000404.2
GLUL NM_002065.6
GNPTAB NM_024312.4
GUSB NM_000181.3
HADH NM_005327.4
HADHA NM_000182.4
HADHB NM_000183.2
IDUA NM_000203.4
LIPA NM_000235.3
MVK NM_000431.3
NEU1 NM_000434.3
NPC1 NM_000271.4
NPC2 NM_006432.3
PEX1 NM_000466.2
PEX10 NM_153818.1
PEX12 NM_000286.2
PEX13 NM_002618.3
PEX14 NM_004565.2
PEX16 NM_004813.2
PEX19 NM_002857.3
PEX2 NM_000318.2
PEX26 NM_017929.5
PEX3 NM_003630.2
PEX5 NM_001131025.1
PEX6 NM_000287.3
PEX7 NM_000288.3
PHGDH NM_006623.3
PIGA NM_002641.3
PMM2 NM_000303.2
PSAT1 NM_058179.3
SEC23B NM_006363.4
SLC17A5 NM_012434.4
SLC22A5 NM_003060.3
SLC26A2* NM_000112.3
SMPD1 NM_000543.4
SUMF1 NM_182760.3
TAZ NM_000116.4
TRIP11 NM_004239.4

GAA: Analysis includes the promoter variant NM_000152.3:c.-32-13T>G as well as the common exon 18 deletion.
GALC: Analysis includes the large (30 kb) deletion for Krabbe Disease.
SLC26A2: Analysis includes the intronic variant NM_000112.3:c.-26+2T>C.