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.

1. Multiples of the same sex for whom determination of zygosity is required to:
   1. aid in understanding of whether different clinical presentations could be explained by dizygosity or;
   2. assess risk in asymptomatic multiple(s), in the context of a genetic condition of variable expressivity having been confirmed in one of the multiples.

Testing is only performed for the indications listed above. If the motivation is to pursue testing for other reasons, private genetic testing companies will perform this analysis for a fee.

The AmpFlSTR® Identifiler™ kit is used to compare multiples (twins, triplets, etc) at highly polymorphic short tandem repeats across the autosomes. Monozygotic (identical) multiples share identical alleles at all markers. Dizygotic/Trizygotic/etc (fraternal) multiples will typically have non-identical alleles at more than one locus.

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.  This test is only available to individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) and who meet test utilization guidelines or policy. For those without this coverage, contact the laboratory to discuss.

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.

Machado-Joseph Disease; Olivopontocerebellar Atrophy (OPCA); Cerebelloparenchymal Disease; Menzel type OPCA; Schut-Haymaker type OPCA; Holguin Ataxia; Wadia-Swami Syndrome; Azorean Ataxia; Spinopontine Atrophy; Nigrospinodentatal Degeneration

The spinocerebellar ataxias (SCA) are characterized by slowly progressive gait ataxia, and are often associated with poor coordination of hands, speech, and eye movement.

SCA type 1, 2, 3, 6, and 7 are autosomal dominant conditions caused by expansion of the CAG repeat in ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 respectively. 

SCA alleles are classified based on size, and reported based on classification, as outlined below.  Exact repeat sizes are not reported:

SCA1 (ATXN1):

• Normal: ≤38 repeats or 39-44 interrupted repeats
• Full Penetrance (pathogenic): 39-44 uninterrupted repeats or ≥45 repeats

SCA2 (ATXN2)

• Normal: ≤31 repeats
• Uncertain: 32-34 repeats
• Full Penetrance (pathogenic): ≥35 repeats

SCA3 (ATXN3)

• Normal: ≤44 repeats
• Uncertain: 45-~59 repeats*
• Full Penetrance (pathogenic): ≥~60 repeats*

           *The repeat size of the smallest full penetrance pathogenic allele is not well-defined.

SCA6 (CACNA1A)

• Normal: ≤18 repeats
• Uncertain: 19 repeats
• Full Penetrance (pathogenic): ≥20 repeats

SCA7 (ATXN7)

• Normal: ≤33 repeats
• Uncertain: 34-36 repeats
• Full Penetrance (pathogenic): ≥37 repeats

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of SCA1, 2, 3, 6 or 7.
2. Prenatal testing (prenatal diagnosis requests are not normally accepted from physicians other than Medical Geneticists; technically feasible, but not routinely performed – contact MGL to discuss):
   1. Pregnancies at risk of being affected with one of these ataxias
3. Presymptomatic testing:
   1. Adults at risk to develop one of these ataxias due to a molecularly confirmed family history. Predictive testing will only be performed following genetic counselling by a recognized genetic service.

Sizing of the CAG repeats associated with each gene is carried out on an ABI genetic analyzer following fluorescence-based PCR amplification.  Digestion with SfaN1 is performed on SCA1 alleles between 39 – 44 repeats to differentiate between interrupted (normal) and uninterrupted (pathogenic) repeats.  Alleles ≤44 CAG repeats that are interrupted by CAT repeats are normal, whereas alleles with 39-44 uninterrupted CAG repeats are considered fully penetrant (pathogenic).  As required, triplet-primed (tp) PCR is performed for SCA2 and SCA7.

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., point mutations in the coding region of the gene, large genomic deletions, promoter mutations, regulatory element mutations). For some trinucleotide repeat disorders, repeat expansions have been described that cannot be amplified by PCR. Consideration should be given to this particularly in cases with severe clinical features or early onset; consult the on-service Molecular Geneticist to discuss specific repeat disorders.

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.

In certain scenarios of repeat size mosaicism, false negative results may occur. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

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.

Machado-Joseph Disease; Olivopontocerebellar Atrophy (OPCA); Cerebelloparenchymal Disease; Menzel type OPCA; Schut-Haymaker type OPCA; Holguin Ataxia; Wadia-Swami Syndrome; Azorean Ataxia; Spinopontine Atrophy; Nigrospinodentatal Degeneration

The spinocerebellar ataxias (SCA) are characterized by slowly progressive gait ataxia, and are often associated with poor coordination of hands, speech, and eye movement.

SCA type 1, 2, 3, 6, and 7 are autosomal dominant conditions caused by expansion of the CAG repeat in ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 respectively. 

SCA alleles are classified based on size, and reported based on classification, as outlined below.  Exact repeat sizes are not reported:

SCA1 (ATXN1):

• Normal: ≤38 repeats or 39-44 interrupted repeats
• Full Penetrance (pathogenic): 39-44 uninterrupted repeats or ≥45 repeats

SCA2 (ATXN2)

• Normal: ≤31 repeats
• Uncertain: 32-34 repeats
• Full Penetrance (pathogenic): ≥35 repeats

SCA3 (ATXN3)

• Normal: ≤44 repeats
• Uncertain: 45-~59 repeats*
• Full Penetrance (pathogenic): ≥~60 repeats*

           *The repeat size of the smallest full penetrance pathogenic allele is not well-defined.

SCA6 (CACNA1A)

• Normal: ≤18 repeats
• Uncertain: 19 repeats
• Full Penetrance (pathogenic): ≥20 repeats

SCA7 (ATXN7)

• Normal: ≤33 repeats
• Uncertain: 34-36 repeats
• Full Penetrance (pathogenic): ≥37 repeats

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of SCA1, 2, 3, 6 or 7.
2. Prenatal testing (prenatal diagnosis requests are not normally accepted from physicians other than Medical Geneticists; technically feasible, but not routinely performed – contact MGL to discuss):
   1. Pregnancies at risk of being affected with one of these ataxias
3. Presymptomatic testing:
   1. Adults at risk to develop one of these ataxias due to a molecularly confirmed family history. Predictive testing will only be performed following genetic counselling by a recognized genetic service.

Sizing of the CAG repeats associated with each gene is carried out on an ABI genetic analyzer following fluorescence-based PCR amplification.  Digestion with SfaN1 is performed on SCA1 alleles between 39 – 44 repeats to differentiate between interrupted (normal) and uninterrupted (pathogenic) repeats.  Alleles ≤44 CAG repeats that are interrupted by CAT repeats are normal, whereas alleles with 39-44 uninterrupted CAG repeats are considered fully penetrant (pathogenic).  As required, triplet-primed (tp) PCR is performed for SCA2 and SCA7.

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., point mutations in the coding region of the gene, large genomic deletions, promoter mutations, regulatory element mutations). For some trinucleotide repeat disorders, repeat expansions have been described that cannot be amplified by PCR. Consideration should be given to this particularly in cases with severe clinical features or early onset; consult the on-service Molecular Geneticist to discuss specific repeat disorders.

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.

In certain scenarios of repeat size mosaicism, false negative results may occur. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

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.

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.

Ashkenazi Jewish Carrier Screening

It is the responsibility of the ordering physician to ensure that informed consent has been obtained from the patient/legal guardian before ordering genetic testing. Please review the following Pre-Test Counselling Information with your patient before requesting any of our genetic tests.

Clinical Features

Genetics

Indications for Testing

Contraindications

Description of this Assay

Sensitivity and Limitations

Turnaround Time

Routine

6 weeks

Specimen Requirements

Additional Requirements

Test Price and Billing

Cautions

Thanatophoric Dwarfism; Platyspondylic Skeletal Dysplasia

Thanatophoric dysplasia (TD) is a severe skeletal dysplasia that is usually lethal in the perinatal period. There are 2 types of TD both of which are characterized by micromelia with bowed femurs. In TD type II, moderate to severe cloverleaf skull deformity is virtually always present, while in TD type I, cloverleaf skull deformities of varying severity are observed only occasionally. Other features common to both types of TD include short ribs, narrow thorax, macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. Most infants with TD die of respiratory insufficiency shortly after birth, although rare long-term survivors have been reported.

TD is caused by mutations in the FGFR3 gene. Inheritance is autosomal dominant, although cases are invariably the result of de novo mutations in this lethal condition. Eleven mutations in FGFR3 (p.Arg248Cys; p.Ser249Cys; p.Gly370Cys; p.Ser371Cys; p.Tyr373Cys; p.Lys650Met; p.X807Leu; p. X807Gly; p.X807Arg; p.X807Cys; and p. X807Trp) have been found to account for greater than 99% of cases of TD type I. The missense substitution p.Lys650Glu accounts for all cases of TD type II.

1. Confirmation of diagnosis:
   1. In neonates with clinical features suggestive of TD.
2. Prenatal testing (prenatal diagnosis requests are not normally accepted from physicians other than Medical Geneticists):
   1. When ultrasound findings are suggestive of thanatophoric dysplasia. 
   2. When a couple has had a previous fetus with TD; due to the risk of gonadal mosaicism.

Bidirectional Sanger sequencing of four FGFR3 regions containing the 11 common TD type I mutations and the common TD type II mutation.

NM_000142.4 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)

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.

Transient Neonatal Diabetes Mellitus; Russell-Silver Syndrome; Silver-Russell Syndrome; Prader-Willi Syndrome; Angelman Syndrome

Uniparental disomy 6 (UPD6): Approximately 40% of 6q-linked transient neonatal diabetes mellitus (TNDM) is associated with paternal UPD6.

Uniparental disomy 7 (UPD7): Approximately 7-10% of individuals with Russell-Silver syndrome have maternal UPD7.

Uniparental disomy 14 (UPD14): Uniparental disomy of chromosome 14 is rare although phenotypes have been described for both maternal and paternal UPD14. Maternal UPD14 is associated with premature birth; growth retardation; short stature; developmental delay; and precocious puberty. Paternal UPD14 is associated with polyhydramnios; omphalocoele; characteristic facial features; a small, bell-shaped chest with short ribs; and developmental delay.

Uniparental disomy 15 (UPD15): Maternal and paternal UPD15 result in different phenotypes: maternal UPD15 gives rise to approximately 25-30% of cases of Prader-Willi syndrome while paternal UPD15 is the cause of 3-5% of cases of Angelman syndrome.

UPD typically arises from the rescue of a trisomic or monosomic zygote resulting in a conception with both copies of a chromosome from a single parent, rather than one copy from each parent. Parents of children with UPD usually have normal karyotypes; however, carrying a structurally abnormal chromosome (such as in the case of certain translocations) may increase the risk of UPD in offspring.

Please see Additional Requirements (below), for information about what samples are required to perform this analysis.

1. Confirmation of diagnosis:
   1. UPD6: infants with transient neonatal diabetes mellitus
   2. UPD7: individuals with features consistent with Russell-Silver syndrome
   3. UPD14: individuals with features suggestive of the clinical phenotype of either maternal or paternal UPD14
   4. UPD15: following positive methylation analysis for either Prader-Willi syndrome or Angelman syndrome, and negative deletion analysis (fluorescent in situ hybridization performed in a Cytogenetics laboratory), UPD testing may be requested to determine if this could be the underlying genetic mechanism for the abnormal methylation pattern. See PWS and AS test algorithms for further details.
2. Prenatal testing (prenatal diagnosis requests are not normally accepted from physicians other than Medical Geneticists):
   1. Pregnancies at increased risk of a clinically-signficant UPD, where cytogenetic analysis has confirmed a normal karyotype. Examples include:
      1. Pregnancies where one of the parents carries a Robertsonian translocation involving chromosome(s) 14 or 15.
      2. Pregnancies where confined placental mosaicism for chromosome 7, 14, or 15 has been identified.
      3. Pregnancies where one of the parents carries a balanced reciprocal translocation AND a certified Cytogeneticist has recommended UPD testing for chromosomes 6, 7, 14, or 15.

This assay assesses the inheritance of polymorphic microsatellite markers located across the appropriate chromosome (6, 7, 14 or 15); at least two microsatellite markers must be informative for interpretation. For assessment of UPD7 and 15, this test is performed using the ABI Linkage mapping set ABI HD5 v.2.5.

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

Samples from both biological parents as well as the patient/fetus are required to perform these analyses. If only one parent is available, please consult the on-service Molecular Geneticist.

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.