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.

Familial Amyloid Cardiomyopathy; Familial Amyloid Polyneuropathy; Leptomeningeal Amyloidosis; Familial Oculoleptomeningeal Amyloidosis

Transthyretin (TTR) amyloidosis is characterized by a slowly progressive neuropathy and other problems associated with amyloid deposition in the heart, kidney, eye, and central nervous system. The disorder has a particularly high prevalence in Japan and Portugal, where onset is earlier (between ages 20 and 40) than in other regions. Reduced and age-related penetrance is observed, as well as variable expressivity. A small number of genotype-phenotype correlations have been documented.

TTR amyloidosis is an autosomal dominant condition caused exclusively by mutations in the TTR gene. The most frequent mutation, p.Val30Met, has been reported in individuals from many different ethnic backgrounds and is particularly common among Japanese, Portugese, and Swedish cases. Point mutations in TTR gene account for over 99% of disease alleles.

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of TTR amyloidosis.
2. Prenatal testing (technically feasible but not routinely performed – contact MGL to discuss):
   1. Pregnancies at risk of TTR amyloidosis where one of the parents has a pathogenic mutation in TTR.
3. Presymptomatic testing:
   1. Adults at risk of TTR amyloidosis due to a family history of molecularly confirmed TTR amyloidosis. Predictive testing will only be performed following genetic counselling by a recognized genetic service.

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

NM_000371.3 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.

Angelman syndrome (AS) is characterized by severe developmental delay or mental retardation, severe speech impairment, gait ataxia, microcephaly and seizures. Individuals with AS often have specific behavioural characteristics including frequent laughing, smiling, and general excitability.

AS is caused by the loss of the maternal expression of the UBE3A gene, which is normally silenced (not expressed) from the paternally-inherited allele. The loss of maternal expression can occur due to one of several different known genetic mechanisms: deletion of the maternal 15q11.2-q13 region (~68%); paternal uniparental disomy (~7%) of chromosome 15; mutation of the imprinting centre in the 15q11.2-q13 region (~3%); or a mutation in the maternal UBE3A allele (~11%).

1. Confirmation of diagnosis:
   1. This test should be used as the first line diagnostic test in a child with a suspected clinical diagnosis of AS as it provides information regarding methylation, regardless of underlying mechanism. See test algorithm for further details.
2. Prenatal testing (prenatal diagnosis requests are not normally accepted from physicians other than Medical Geneticists):
   1. In pregnancies at risk of AS due to a methylation abnormality. NB: The recurrence risk for couples who have a previous child with AS is generally quite low (< 1%) except in rare cases. Genetic counselling is recommended.   

Differential PCR amplification of bisulfite treated DNA at the CpG island of SNRPN to assess the methylation pattern of this region. Note: This assay detects the methylation patterns associated with both PWS and AS.

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.

Rare single nucleotide variants or polymorphisms could lead to false-negative or false-positive 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.

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.

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.

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.

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.

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.

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.