Familial Mediterranean Fever; Recurrent Polyserositis; Familial Paroxysmal Polyserositis; Familial Periodic Fever; TNF receptor-associated periodic syndrome; TRAPS; Familial Hibernian Fever; Autosomal dominant periodic fever syndrome; Hyper-IgD syndrome; Mevalonate Kinase Deficiency; Periodic Fever, Dutch Type; Hypergammaglobulinemia D and periodic fever syndrome

The periodic fever syndromes are disorders of the innate immune system characterized by recurrent episodes of inflammation and fever. The periodic fever syndromes may be inherited or acquired; the hereditary syndromes include familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS) and hyperimmunoglobulin D syndrome (HIDS), among others.

Familial Mediterranean Fever (FMF) in its classic form (Type 1) is characterized by recurrent episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. Amyloidosis, which can lead to renal failure, is the most severe complication. Amyloidosis is the first clinical manifestation in Type 2 FMF. The disorder predominantly affects individuals of Mediterranean descent, particularly North African Jews.

TNF receptor-associated periodic syndrome (TRAPS) is most frequently characterized by recurrent fevers (seen in 95% of cases); arthralgia/myalgia and abdominal pain are also common symptoms. Approximately 15% of individuals with TRAPS eventually go on to develop amyloidosis. The conditions typically presents in early childhood, although this, like the clinical symptoms, is highly variable, both within and between families.

Hyperimmunoglobulin D Syndrome (HIDS) is characterized by recurrent episodes of fever, gastrointestinal symptoms and lymphadenopathy. Individuals often have a high serum immunoglobulin D (IgD) and immunoglobulin A (IgA), and these remain elevated even in the absence of symptoms. The disorder mainly affects individuals with ancestry that can be traced to Northwestern Europe, although it has been reported in other ethnic groups.

FMF is an autosomal recessive disorder caused by mutations in the MEFV gene. MEFV is expressed exclusively in granulocytes and encodes pyrin, a protein critical in regulating the immune response.

TRAPS is an autosomal dominant condition caused by mutations in the TNFRSF1A gene, a member of the TNF-receptor superfamily. Most mutations are found in exons 2 to 4, and around 50% are substitutions of highly conserved cysteines in the extracellular domain. The exact mechanism by which mutations in TNFRSF1A cause TRAPS remains unclear, but most theories suggest that mutations lead to excess TNFR1 signalling. The majority of mutations are highly penetrant, but two recurrent variants (p.Pro46Leu and p.Arg92Gln) that can be seen in patients with milder symptoms of TRAPS can also be seen in healthy individuals.

HIDS is an autosomal recessive disease caused by mutations in the MVK gene. MVK encodes mevalonate kinase, an enzyme in the cholesterol, farnasyl and isoprenoid biosynthesis pathway. Most mutations in MVK that cause HIDS are missense variants that cause a reduction of MVK activity; however, more severe mutations that cause a near complete reduction in MVK activity cause the much more severe condition, mevalonic aciduria.

NOTE: TRAPS and HIDS may only be ordered or must be recommended* by a rheumatologist. 

        *consult letter must be provided

1. Confirmation of diagnosis:

       a.  In individuals with clinical features suggestive of FMF, TRAPS and/or HIDS.

2. Carrier testing

       a.  FMF and HIDS: Adults at risk to be carriers of either FMF or HIDS due to a family history confirmed with molecular testing.

3. Prenatal testing (technically feasible but not routinely performed – contact MGL to discuss):

       a.  Pregnancies known to be at risk of FMF, TRAPS or HIDS due to a family history. The mutation(s) segregating in the family must be known.

4. Presymptomatic testing:

       a.  Individuals at risk to have FMF, TRAPS or HIDS due to a family history of the condition. The mutation(s) segregating in the family must be known. Genetic counseling is recommended prior to presymptomatic testing.

Bi-directional Sanger sequencing across coding regions and flanking intronic sequences of the MEFV, TNFRSF1A and MVK genes.

In cases where FMF, TRAPS, and/or HIDS are requested for the same patient and priority of testing is not indicated, testing will proceed sequentially, starting with FMF. If FMF testing is negative, testing for TRAPS will be performed, followed by testing for HIDS.

MEFV: NM_000243.2

TNFRSF1A: NM_001065.2

MVK: NM_000431.2

The ‘A’ within the initiation codon, ATG, is designated as nucleotide number 1.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., large genomic deletions/duplications, promoter mutations, regulatory element mutations).

For carrier/predictive testing due to a family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Steriod Sulphatase Deficiency

Ichthyosis is a genetically heterogeneous disorder of the skin. Onset of the X-linked form of ichthyosis is generally at birth or within the first year of life. Scaling of the skin may occur over the scalp, ears, neck, trunk, extremities and some flexures. Most individuals demonstrate only dermatologic features. In a minority of cases, however, the ichthyosis occurs as part of a contiguous gene deletion disorder that can include developmental delay/mental retardation, Kallmann syndrome, ocular albinism, and/or chondrodysplasia punctata. It is not uncommon for male fetuses with X-linked ichthyosis to be detected prenatally as an incidental finding during maternal serum screening due to significantly decreased serum unconjugated estriol (uE3).

Approximately 85% of males with isolated X-linked ichthyosis have the condition due to a 1 – 2 Mb deletion that encompasses the STS gene; most of the remaining isolated cases harbor STS point mutations. Contiguous gene deletions of varying sizes involving surrounding genes have been described in approximately 8% of X-linked ichthyosis and invariably present with additional phenotypic features beyond that of ichthyosis.

1. Confirmation of diagnosis:
   1. Males suspected to have X-linked ichthyosis
2. Carrier testing: 
   1. This testing can only be ordered by Medical Geneticists after the patient has had genetic counselling. Pregnant women carrying a male fetus and presenting with significantly reduced unconjugated estriol (uE3) on maternal serum screening ONLY IF the decision regarding whether or not to pursue amniocentesis will be impacted by the results of the testing.

      NB: Carrier testing for any other indication should be performed by the Vancouver Hospital Cytogenetics Lab using fluorescent in situ hybridization (FISH).
       

3. Prenatal testing (prenatal diagnosis requests are not normally accepted from physicians other than Medical Geneticists):
   1. Pregnancies at risk of X-linked ichthyosis due to a significantly reduced unconjugated estriol (uE3) and where the fetus has been found to be male by ultrasound.
   2. Pregnancies of known STS deletion carriers. Prior to testing for STS, fetal sexing is performed; if the fetus is female, further testing is not indicated.

In males, multiplex PCR analysis is used to assess for the presence of deletion of the STS gene; if a deletion is identified, additional PCR testing is performed to estimate the extent of the deletion.

Carrier testing in females is typically performed by the Vancouver Hospital Cytogenetics laboratory using fluorescent in situ hybridization (FISH). In females where molecular analysis is indicated, multiplex ligation-dependent probe amplification (MLPA) analysis is carried out with the P160-A2 probe mix (MRC-Holland) to detect each of the 10 exons of STS, as well as the NLGN4X, HDHD1A, KAL1, and OA1 genes.

Pregnancy-related/Prenatal

If pregnancy management will be altered, 3 weeks; otherwise, routine TAT.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays).  

Prenatal Specimens
Prenatal testing REQUIRES LABORATORY CONSULTATION PRIOR TO THE PROCEDURE and can only be ordered by a Medical Geneticist. Contact the laboratory at 604-875-2852 and choose the appropriate option for the Molecular Geneticist on service.
Chorionic Villi: 20 mg.
Direct Amniotic fluid: 25 mL collected in two separate tubes of equal volume.
Cultured Amniocytes: Two (2) 100% confluent T-25 flasks.
DNA extracted from prenatal specimens: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth. Ship samples by overnight courier with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays) as follows:

• Villi – on wet ice or in media at room temperature
• Amniocytes, Amniotic fluid, DNA – at room temperature

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., point mutations in the coding region, promoter mutations, and regulatory element mutations). In rare cases, a point mutation could be detected.

For carrier/predictive testing due to family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

5 alpha reductase deficiency; 5ARD.

5-α reductase deficiency is characterized by feminization of the external genitalia in individuals with an 46,XY karyotype and can range from normal female genitalia to undermasculinized genitalia. Individuals with classic 5-α reductase deficiency present at birth with ambiguous genitalia characterized by perineoscrotal hypospadias with pseudovagina, microphallus, and cryptorchidism. 

5-α reductase deficiency is an autosomal recessive disorder caused by mutations in the SRD5A gene. Nucleotide substitutions and small deletions account for the vast majority of mutations described to date. 

1)       Confirmation of diagnosis:

• Patients with clinical findings consistent with 5-α reductase deficiency.
• Test requested by an Endocrinologist or Medical Geneticist.

2)      Carrier testing:

• Carrier testing is not-generally indicated unless a couple is at increased risk of having an affected child, and this information is warranted for risk prediction and/or consideration of reproductive options.  Examples include:
  • Couples where one member of the couple has a family history of 5-α reductase deficiency and the other partner is of an ethnicity with an increased incidence of 5- α reductase deficiency;
  • Couples who have a previously affected child with confirmed 5-α reductase deficiency, when warranted for reproductive decision making.

Bidirectional Sanger sequencing of the coding sequence and flanking intronic sequences of the SRD5A gene.

NM_000348.3 The ‘A’ within the initiation codon, ATG, is designated as nucleotide number 1.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., large genomic deletions/duplications, promoter mutations, regulatory element mutations).

For carrier/predictive testing due to a family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Werdnig-Hoffmann Disease; Infantile Muscular Atrophy; Kugelberg-Welander Syndrome; Juvenile Muscular Atrophy; Proximal SMA

Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by progressive muscle weakness caused by the degeneration of anterior horn cells of the spinal cord and the brain stem nuclei. Onset ranges from before birth to young adulthood. Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications. Subtypes include: SMA 0 (proposed name; also referred to as prenatal), with prenatal onset and severe joint contractures, facial diplegia, and respiratory failure; SMA 1, with onset before six months of age; SMA 2, with onset between six and 12 months; SMA3, with onset in childhood after 12 months; and SMA 4, with adult onset.

Two adjacent genes, SMN1 and SMN2, are associated with SMA. The two genes differ by only five base pairs and none of these base pair differences change the amino acids encoded by the genes. Nonetheless, the two genes do not encode identical proteins. SMN1 produces full-length transcripts while SMN2 primarily produces transcripts that lack exon 7 because one of the base pair changes in exon 7 disrupts SMN2 gene splicing.

SMN1 is the SMA disease gene. Approximately 95 – 98% of individuals with a clinical diagnosis of SMA are homozygous for an apparent deletion of exon 7 in SMN1. The remaining 2 – 5% are compound heterozygotes for an apparent deletion of exon 7 of SMN1 and an intragenic point mutation in SMN1.

The copy number of the SMN2 gene varies, ranging from zero to five. Although SMN2 does not produce the full length transcript with high efficiency, some full length transcript is produced. In some individuals with SMA who also have an increased copy number of the SMN2 gene, the small amount of full-length transcript generated SMN2 may help to produce a milder phenotype.

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of SMA.
2. Carrier testing:
   1. Adults at risk to be carriers of SMA due to a family history.
      NB: For the most accurate assessment of carrier status, please provide the results of SMN1 molecular analysis of the parents of the affected individual.
3. Prenatal testing (prenatal diagnosis requests are not normally accepted from physicians other than Medical Geneticists):
   1. Pregnancies at risk of SMA, where the parents have been confirmed by molecular analysis to each carry an SMN1 deletion.
      NB: If only one of the parents has been confirmed to be a carrier, contact the Molecular Geneticist on-service to discuss options.
4. Presymptomatic testing:
   1. Adults at risk of developing a milder form of SMA due to a family history confirmed to be due to SMN1 deletions.

The copy number of exons 7 and 8 of both the SMN1 and SMN2 genes is assessed by multiplex ligation-dependent probe amplification (MLPA) using the P060 probe mix (MRC-Holland).

Pregnancy-related/Prenatal

If pregnancy management will be altered, 3 weeks; otherwise, routine TAT.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: NOT ACCEPTED

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Prenatal Specimens
Prenatal testing REQUIRES LABORATORY CONSULTATION PRIOR TO THE PROCEDURE and can only be ordered by a Medical Geneticist. Contact the laboratory at 604-875-2852 and choose the appropriate option for the Molecular Geneticist on service.
Chorionic Villi: 20 mg.
Direct Amniotic fluid: 25 mL collected in two separate tubes of equal volume.
Cultured Amniocytes: Two (2) 100% confluent T-25 flasks.

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth. Ship samples by overnight courier with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays) as follows:

• Villi – on wet ice or in media at room temperature
• Amniocytes, Amniotic fluid, DNA – at room temperature

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., point mutations in the coding region, promoter mutations, and regulatory element mutations). In rare cases, a point mutation could be detected.

For carrier/predictive testing due to family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Glucose Transporter Protein Syndrome

Glucose transporter type 1 deficiency syndrome (Glut1-DS) typically presents in early infancy with seizures refractory to anticonvulsants, a variety of additional neurological manifestations (e.g., spasticity, ataxia), deceleration of head growth, and delays in mental and motor development.

Glut1-DS is an autosomal dominant condition caused by mutations in the SLC2A1 gene, the only gene known to be associated with this disorder. Probands with Glut1-DS often have the condition as a result of a de novo mutation.

1. Confirmation of diagnosis: 
   All 3 of the criteria below (a, b and c) must be met to request diagnostic testing. 
   A completed Glut1-DS Supplemental Information Form must be received before testing will proceed.
   1. GLUT1-DS Phenotype:
      1. Classical
         1. Epilepsy (particularly if refractory to ≥ 2 anti-epileptic drugs)
            AND
            Developmental delay / intellectual disability 
      2. Atypical
         1. Absence seizures with early onset (< 4 years of age)
            OR 
         2. Paroxysmal exercise-induced dyskinesia
            OR 
         3. Ataxia and/or hyperkinetic movement disorder
            AND
            Developmental delay / intellectual disability
            AND
            One or more of: epilepsy, migraine, microcephaly, positive family history
   2. CSF glucose ≤ 2.5 mmol/L AND CSF:fasting serum glucose ratio < 0.6
   3. Test requested by a Neurologist or a Biochemical Diseases specialist.

      Cases that do not meet all criteria may be reviewed with Dr. Michelle Demos (mdemos[at]cw.bc.ca) or Dr. Sylvia Stockler (sstockler[at]cw.bc.ca) for further consideration.  
       

2. Carrier testing: 
   1. Although this is an autosomal dominant condition, carrier testing may be relevant to identify non-penetrant / variably-expressive mutation carriers. The familial mutation must be known.
       
3. Prenatal testing (prenatal diagnosis requests are not normally accepted from physicians other than Medical Geneticists):
   1. Pregnancies at risk of GLUT1-DS and the familial mutation is known.

Bidirectional Sanger sequencing of the entire coding region and flanking intronic sequences of the SLC2A1 gene. Deletion/duplication analysis of SLC2A1 (by multiplex ligation-probe amplification – MLPA) is performed if sequencing is negative.

NM_006516.2 The ‘A’ within the initiation codon, ATG, is designated as nucleotide number 1.

Pregnancy-related/Prenatal

If pregnancy management will be altered, 3 weeks; otherwise, routine TAT.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

NOTE: DNA is only accepted for requests for sequencing analysis.  If MLPA is required, EDTA blood must be collected.

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Prenatal Specimens
Prenatal testing REQUIRES LABORATORY CONSULTATION PRIOR TO THE PROCEDURE and can only be ordered by a Medical Geneticist. Contact the laboratory at 604-875-2852 and choose the appropriate option for the Molecular Geneticist on service.
Chorionic Villi: 20 mg.
Direct Amniotic fluid: 25 mL collected in two separate tubes of equal volume.
Cultured Amniocytes: Two (2) 100% confluent T-25 flasks.
DNA extracted from prenatal specimens: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth. Ship samples by overnight courier with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays) as follows:

• Villi – on wet ice or in media at room temperature
• Amniocytes, Amniotic fluid, DNA – at room temperature

A completed Glut1-DS Supplemental Information Form MUST accompany the requisition. 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., promoter mutations, regulatory element mutations).

For carrier/predictive testing due to family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Sudden Unexplained Nocturnal Death Syndrome; SUNDS

Brugada Syndrome is a cardiac conduction abnormality characterized by malignant ventricular arrhythmias, usually in an adult who reports a history of syncopal episodes. Sudden death is not uncommon. Classic cases have a typical ECG pattern, characterized by coved-type ST-segment elevation in the right precordial leads (so-called “type 1 Brugada ECG”), along with a personal history arrhythmia and/or a family history of premature sudden cardiac death or the characteristic ECG pattern.

Autosomal dominant inheritance with reduced penetrance. The primary gene associated with Brugada syndrome is SCN5A; mutations are identified in 15 to 30% of cases of individuals with type 1 Brugada ECG. Fewer than 5% of cases are accounted for by mutations in one of at least 11 other additional genes. 

NOTE: for BC patients, criteria must be met in order for testing to proceed.

1. Confirmation of diagnosis:

a. Persistent or provocable type I Brugada ECG pattern (ST elevation of a cove-shaped pattern in leads VI and V2); AND

• identified by EP Cardiologist (a cardiologist with further certification/training in cardiac electrophysiology);
• no structural heart disease
• no drugs known to cause Brugada-like ECG pattern

b. Test requested by Cardiologist or Medical Geneticist;

2. Family Testing:

• SCN5A mutation identified in index case
• First-degree relative (parent, sibling, child) of index case or other mutation-positive family member;
• Test requested by Medical Geneticist or Cardiologist

3. Prenatal testing (technically feasible but not routinely performed – contact MGL to discuss):

• Pregnancies to couples in which one person has confirmed Brugada syndrome and a known SCN5A mutation.
• Test requested by Medical Genetics

Bidirectional Sanger sequencing of the entire coding region and flanking intronic sequences of the SCN5A gene.

NM_198056.2 The ‘A’ within the initiation codon, ATG, is designated as nucleotide number 1.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., large genomic deletions/duplications, promoter mutations, regulatory element mutations).

For carrier/predictive testing due to a family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Hypokalemic periodic paralysis manifests in a paralytic form (reversible, flaccid paralysis characteristically triggered by a carbohydrate-rich meal or post-exercise rest) and a myopathic form (exercise intolerance due to progressive muscle weakness). The myopathy is independent of paralytic symptoms and may be the sole manifestation of the condition.

CACNA1S and SCN4A are the only two genes known to be associated with hypokalemic periodic paralysis (HypoPP).  Inheritance is autosomal dominant and most affected individuals will have an affected parent.  This assay will detect recurrent variants in CACNA1S exons 11 and 30 (including c.1583G>A (p.Arg528His), c.1582C>G (p.Arg528Gly), c.3716G>A (p.Arg1239His), c.3715C>G (p.Arg1239Gly) and c.1466G>A (p.Arg489His)) accounting for approximately 43-67% of cases, and recurrent variants in SCN4A exon 12 (including c.2005C>G (p.Arg669Gly), c.2006G>A (p.Arg669His), c.2014C>A (p.Arg672Ser), c.2015G>A (p.Arg672His), c.2014C>G (p.Arg672Gly), c.2014C>T (p.Arg672Cys)) accounting for an additional 4-15% of cases.  Around one third of individuals with HypoPP will have no variants identified.

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of hypokalemic periodic paralysis.
2. Prenatal testing (technically feasible but not routinely performed – contact MGL to discuss):
   1. Pregnancies known to be at risk of hypokalemic periodic paralysis when the CACNA1S or SCN4A mutation is known.
3. Presymptomatic testing:
   1. Asymptomatic children and adults at risk of this condition because of a family history. The CACNA1S or SCN4A mutation must be known.

Bidirectional Sanger sequencing of CACNA1S exons 11 and 30 and of SCN4A exon 12, and their flanking intronic sequences. These exons encompass the recurrent mutations described for this disorder.

CACNA1S: NM_000069. The ‘A’ within the initiation codon, ATG, is designated as nucleotide number 1.

SCN4A: NM_000334.4. The ‘A’ within the initiation codon, ATG, is designated as nucleotide number 1.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., mutations outside the regions tested as described above, large genomic deletions, promoter mutations, regulatory element mutations).

For carrier/predictive testing due to family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In rare cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Gamstorp Disease; Adynamia Episodica Hereditaria With Myotonia; Adynamia Episodica Hereditaria Without Myotonia; Normokalemic Periodic Paralysis; Sodium Channel Muscle Disease

Hyperkalemic periodic paralysis is characterized by attacks of flaccid limb weakness, which may be accompanied by weakness of the eyes, throat and trunk. During attacks, serum potassium concentration is >5 mmol/L or has increased by at least 1.5 mmol/L over baseline. Muscle strength and serum postassium concentration are normal between attacks. Onset is generally before 20 years of age.

SCN4A is the only gene identified to date that is known to be associated with hyperkalemic periodic paralysis. Four recurrent mutations account for almost all of the SCN4A disease alleles; together these account for approximately 55% of cases.

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of hyperkalemic periodic paralysis.
2. Prenatal testing (technically feasible but not routinely performed – contact MGL to discuss):
   1. Pregnancies known to be at risk of hyperkalemic periodic paralysis and the SCN4A mutation is known.
3. Presymptomatic testing:
   1. Asymptomatic children and adults at risk of this condition because of a family history. The SCN4A mutation must be known.

Bidirectional Sanger sequencing of SCN4A exons 13 and 24 and their flanking intronic sequences, which encompass the four common mutations associated with hyperkalemic periodic paralysis: c.2065C>A (p.Leu689Ile), c.2078T>C (p.Ile693Thr), c.2111C>T (p.Thr704Met) and c.4774A>G (p.Met1592Val).

NM_000334.4 The ‘A’ within the initiation codon, ATG, is designated as nucleotide number 1.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., mutations outside the regions tested as described above, large genomic deletions, promoter mutations, regulatory element mutations).

For carrier/predictive testing due to family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In rare cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Familial Recurrent Polyneuropathy; Tomaculous Neuropathy

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) is characterized by repeated focal pressure neuropathies such as carpal tunnel syndrome and peroneal palsy with foot drop, typically with a family history consistent with autosomal dominant inheritance. Prolonged distal nerve conduction latencies is found on electrophysiologic studies of all individuals, symptomatic or not.

In the majority of cases (80%), HNPP is caused a 1.5 Mb contiguous gene deletion at 17p11.2, which includes the PMP22 gene. In the remaining 20%, the condition is caused by a point mutation in the PMP22 gene. Inheritance is autosomal dominant, although 20% of cases arise due to de novo mutations.

1. Confirmation of diagnosis:
   1. In individuals wtih clinical features suggestive of HNPP.
2. Prenatal diagnosis (technically feasible but not routinely performed – contact MGL to discuss):
   1. Pregnancies to couples in which one person has HNPP
3. Presymptomatic testing:
   1. Adults at risk of inheriting HNPP from a parent and who are not yet symptomatic may be referred for predictive testing for HNPP.
   2. Requests to test asymptomatic children who are at risk of developing HNPP are only accepted following genetic counselling by a recognized genetic service.

Multiplex ligation-dependent probe amplification (MLPA) analysis is carried out with the P033-B2 probe mix (MRC-Holland) to determine the gene dosage (i.e. number of copies) of the PMP22 gene. Note: This assay will detect both CMT1A and HNPP.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: NOT ACCEPTED

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., point mutations in the coding region, promoter mutations, and regulatory element mutations). In rare cases, a point mutation could be detected.

For carrier/predictive testing due to family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Hereditary Motor and Sensory Neuropathy 1A

Charcot-Marie-Tooth disease is a chronic motor and/or sensory neuropathy typically characterized by distal muscle weakness, sensory loss, and pes cavus deformity. Charcot-Marie-Tooth Type 1A (CMT1A) accounts for ~75% of Charcot-Marie-Tooth type 1 (CMT1), and CMT1 accounts for nearly half of all Charcot-Marie-Tooth disease.

CMT1A is caused by an 1.5 Mb duplication in 17p11.2, which results in the inheritance of three copies of the PMP22 gene. Inheritance is autosomal dominant; 20 – 33% of cases are due to de novo duplications. Rare cases of homozygous duplications (resulting in a total of four copies of PMP22) have been described and, in general, manifest a more severe phenotype than the typical three-copy cases.

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of CMT1.
2. Prenatal testing (technically feasible but not routinely performed – contact MGL to discuss):
   1. Pregnancies to couples in which one person has confirmed CMT1A .
3. Presymptomatic testing
   1. Adults at risk of inheriting CMT1A from a parent may be referred for presymptomatic testing for CMT1A.
   2. Requests to test asymptomatic children who are at risk of developing CMT1A are only accepted following genetic counselling by a recognized genetic service.

Multiplex ligation-dependent probe amplification (MLPA) analysis is carried out with the P033-B2 probe mix (MRC-Holland) to determine the gene dosage (i.e. number of copies) of the PMP22 gene. Note: This assay will detect both CMT1A and HNPP.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: NOT ACCEPTED

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., point mutations in the coding region, promoter mutations, and regulatory element mutations). In rare cases, a point mutation could be detected.

For carrier/predictive testing due to family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.