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Genetics

Angelman Syndrome

Angelman Syndrome (AS) is caused by a lack of maternal contribution of 15q11–q13 caused by deletion (70%), paternal uniparental disomy (UPD) (5%) or mutation (25%). DNA results are based on analysis using a methylation-sensitive multiplex ligation-dependent probe amplication (MLPA) kit to detect both maternal and paternal copies of the 15q11–q13 region. This analysis detects all cases due to deletion, UPD and imprinting mutations. A negative result does not rule out a diagnosis of Angelman Syndrome as up to 25% of cases are due to mutations that do not result in abnormal methylation at the AS locus.

Test available: Routine, Newborn, Prenatal*
Sample requirements: 10 mL blood in EDTA tube
3 mL blood in EDTA tube (infant only - under 1 year of age)
Extracted DNA

Cultured amniocytes                                                                     Note: Extracted DNA will not be accepted

Estimated turn around time: Routine – 4 to 6 weeks
Newborn, Prenatal – 7 working days


*Available if there is a previous family history. Parental peripheral blood samples (5 mL in EDTA tubes) are required when requesting prenatal testing to rule out maternal cell contamination.

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Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Hereditary arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by progressive fibrofatty replacement of myocardium which predisposes individuals to ventricular tachycardia. It is most frequently inherited in an autosomal dominant fashion, although autosomal recessive inheritance has also been described. At least twelve different loci have been linked to ARVC. Most clinically confirmed cases are attributed to mutations in the PKP2, DSG2, or DSP genes (11-43%, 12-40% and 6-16% of cases, respectively). Of relevance to the Canadian population, a single mutation of the TMEM43 gene, c.1073C>T, has been described in unrelated families from Newfoundland. DNA testing for ARVC is performed by sequence analysis of the coding regions and 10 base pairs immediately adjacent to each exon of the DSC2, DSG2, DSP, JUP, PKP2, RYR2 and TMEM43 genes. Large genomic deletions and duplications in PKP2 and select exons of the DSC2, DSG2 and DSP genes are further assessed by muliplex ligation-dependent probe amplification (MLPA). Given the heterogeneity of ARVC, a negative test result does not rule out a diagnosis of arrhythmogenic right ventricular cardiomyopathy.

Test Available:

Routine, Prenatal*
Sample Requirements:10 mL blood in EDTA tube**
3mL blood in EDTA tube (infant only –under 1 year of age)**
Estimated turn around time:

Routine - 10 weeks

 

 * Inquiries about prenatal testing should be directed to the Laboratory.
** Samples are accepted through Cardiology and Genetics Clinics only.

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Arterial Tortuosity syndrome

Arterial Tortuosity syndrome (ATS) is characterized by clinical findings associated with connective tissue disease. Affected individuals have severe and widespread arterial tortuosity of the aorta and mid-sized arteries,with an increased risk of aneurysms and dissections, and focal and widespread stenosis which can involve the aorta and/or pulmonary arteries. Additionally, affected individuals may have characteristic facies with a high palate and dental crowding, and other evidence of a generalized connective tissue disorder including soft/doughy skin, skeletal findings, hernias, hypotonia, and ocular involvement (myopia, keratoconus). ATS is associated with pathogenic variants in the SLC2A10 gene and is inherited in an autosomal recessive manner. DNA results are based on the analysis of the coding sequence and 10 base pairs immediately adjacent to each exon of SLC2A10 (NM_030777.3) This test is performed by oligonucleotide-based target capture (TruSight Cardio Panel, Illumina) followed by next generation sequencing using the MiSeq instrument (Illumina). All rare variants are checked for prior reports in the literature, the ClinVar, ExAC, Exome Variant Server databases and other relevant sources of information. Variant significance is categorized using ACMG Recommendations (Genet Med 2015: 17: 405–423). Variant nomenclature is based on the Human Genome Variation Society recommended guidelines GRCh37 (hg19) human reference genome assembly. Sequence variants of unlikely clinical significance are not reported but are available upon request. Additional Sanger sequencing is performed for regions that have insufficient coverage, and to confirm clinically significant variants and variants of unknown significance when applicable.

Test available:

Routine, Prenatal*

Sample requirements: 

10 mL blood in EDTA tube 
3 mL blood in EDTA tube for infants (under 1 year of age)

Estimated turn around time:

Routine – 8 weeks

*Inquiries about prenatal testing could be directed to the Laboratory
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Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope during exercise or acute emotion, in individuals without structural cardiac abnormalities. Mutations in at least 4 genes have been associated with CPVT and account for 55-65% of cases. DNA testing for CPVT consists of sequence analysis of the coding regions and 10 base pairs immediately adjacent to each exon of 2 genes: RYR2 and CASQ2. Given the heterogeneity of CPVT, a negative test result does not rule out a diagnosis of catecholamineric polymorphic ventricular tachycardia.

Test Available:

Routine, Prenatal*

Sample Requirements:

10 mL blood in EDTA tube**
3 mL blood in EDTA tube (infant only--under 1 year of age)**

Estimated turn around time:

Routine - 10 weeks


* Inquiries about prenatal testing should be directed to the Laboratory.
** Samples are accepted through Cardiology and Genetics Clinics only.
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Cystinosis

Cystinosis is an autosomal recessive disorder. It is caused by mutations in the CTNS gene. DNA results are based on analysis of a subset of mutations (see list below). This analysis detects approximately 86% of CTNS mutations in French Canadians and 67% in other populations. Therefore, in order to calculate residual carrier risk in patients with no CTNS mutation, ethnicity must be provided. Absence of these mutations does not rule out a diagnosis of cystinosis in symptomatic individuals or rule out carrier status in non-symptomatic individuals. Mutation nomenclature is based on the recommendations of the Human Genome Variation Society and nucleotide accession number NM004937.2 or protein accession number NP004928.2.

HGVS Nomenclature Common Nomenclature
c.(?_-593)_848del
p.Trp138X
p.Leu158Pro
p.Asp205Asn
c.198_218del
c.696_697insC
LDM1
W138X
L158P
D205N
537del21
1035insC

 

Test available: Routine, Newborn, Prenatal*
Sample requirements: 10 mL blood in EDTA tube
3 mL blood in EDTA tube (infant only - under 1 year of age)
Extracted DNA
Cultured amniocytes
Cultured CVS
Amniotic fluid
Direct CVS
Estimated turn around time: Routine – 4 to 6 weeks
Newborn, Prenatal – 7 working days


*Available if there is a previous family history. Parental peripheral blood samples (5 mL in EDTA tubes) are required when requesting prenatal testing to rule out maternal cell contamination.

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Dilated Cardiomyopathy

Up to 50% of idiopathic dilated cardiomyopathy is thought to have a genetic basis, and more than 50 genes have been implicated. DNA testing for DCM is based on sequence analysis of the coding regions and 10 base pairs immediately adjacent to each exon of 25 genes: ABCC9, ACTC1, ACTN2, CSRP3, CTF1, DES, EMD, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, NEXN, PLN, RBM20, SGCD, TAZ, TCAP, TNNC1, TNNI3, TNNT2, TPM1, TTN, and VCL. To detect large genomic deletions and duplications, multiplex ligation-dependent probe amplification (MLPA) using the two available kits for analysis of MYH7, MYBPC3 and TNNT2 is also performed. Given the heterogeneity of DCM, a negative test result does not rule out a diagnosis of familial dilated cardiomyopathy.

Test Available:

Routine, Prenatal*

Sample Requirements:

10 mL blood in EDTA tube**
3 mL blood in EDTA tube (infant only--under 1 year of age)**

Estimated turn around time:

Routine - 10 weeks


* Inquiries about prenatal testing should be directed to the Laboratory.
** Samples are accepted through Cardiology and Genetics Clinics only.


Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant disorder. It is associated with a deletion of chromosome 4q35 in 90–95% of cases. DNA results are based on specific restriction enzyme digests followed by Southern blotting. Presence of a chromosome 4q35 specific fragment 35 ≤ kb in size is consistent with a diagnosis of FSHD specifically when on the background of the 4qA haplotype. A deleted fragment on the 4qB haplotype is not associated with FSHD. (Nature Genetics V22:235-236.) As of March 1, 2016, we will no longer be accepting specimens for prenatal testing for FSHD.

Test available: Routine
Sample requirement

20 mL blood in EDTA tube**
3 mL blood in EDTA tube (infant only - less than 1 year of age)

Estimated turn around time:

Routine – 12-14 weeks

**Peripheral blood samples must be received by the Laboratory within 3 days of being drawn to be accepted for this test.

Familial Hypertrophic Cardiomyopathy

Unexplained left ventricular hypertrophy occurs in approximately one in 500 individuals, with approximately 55%-70% attributable to familial hypertrophic cardiomyopathy (HCM). DNA testing is based on sequence analysis of the coding regions and 10 base pairs immediately adjacent to each exon of 19 genes: ACTC1, ACTN2, CAV3, CSRP3, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, MYOZ2, NEXN, PLN, PRKAG2, TNNC1, TNNI3, TNNT2, TPM1, and TTR. This analysis detects >99% of point mutations and small deletions and insertions that may occur in these genes. To detect large genomic deletions and duplications, multiplex ligation-dependent probe amplification (MLPA) using the two available kits for analysis of MYH7, MYBPC3 and TNNT2 is also performed. Given the heterogeneity of HCM, a negative test result does not rule out a diagnosis of familial hypertrophic cardiomyopathy.

Test Available:
 Routine, Prenatal*
Sample Requirements:
10 mL blood in EDTA tube**
3 mL blood in EDTA tube (infant only--under 1 year of age)**

Estimated turn around time:
 Routine - 10 weeks

*   Inquiries about prenatal testing should be directed to the Laboratory.
** Samples are accepted through Cardiology and Genetics Clinics only.

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Familial Thoracic Aneurysms and Aortic Dissections (TAAD)

Familial Thoracic Aneurysms and Aortic Dissections (TAAD) is diagnosed based on the presence of dilatation and/or dissection of the thoracic aorta. Age of onset and presentation of the aortic disease are highly variable even within the same family. Lack of surgical repair can lead to enlargement of the ascending aorta, which may result in an acute aortic dissection. TAAD is inherited in an autosomal dominant manner, with up to 20% of individuals with TAAD having a first-degree relative with thoracic aortic disease. Mutations in the FBN1 and ACTA2 genes account for 23-27% of TAAD cases, whereas pathogenic variants in other genes account for a smaller number. Since only about 20% of familial TAAD is caused by pathogenic variants in known genes, a negative test result does not rule out the diagnosis. DNA results are based on the analysis of the coding sequence and 10 base pairs immediately adjacent to each exon of 11 genes known to be associated with TAAD: ACTA2 (NM_001141945.1), COL3A1 (NM_000090.3), FBN1 (NM_000138.4), MYH11 (NM_001040113.1), MYLK (NM_053025.3), NOTCH1 (NM_017617.3), SLC2A10(NM_030777.3), SMAD3 (NM_005902.3), TGFB2 (NM_001135599.2), TGFBR1 (NM_004612.2) and TGFBR2 (NM_001024847.2). This test is performed by oligonucleotide-based target capture (TruSight Cardio Sequencing kit, Illumina) followed by next generation sequencing using the MiSeq instrument (Illumina). To detect large genomic deletions and duplications, multiplex ligation-dependent probe amplification (MLPA) using the available kits for analysis of FBN1 (P065/P066), COL3A1 (P155), TGFBR1 and TGFBR2 (P148) is performed. This analysis detects >99% of variants within the tested genes. All rare variants are checked for prior reports in the literature, the ClinVar, ExAC, Exome Variant Server databases and other relevant sources of information. Variant significance is categorized using ACMG Recommendations (Genet Med 2015: 17:405–423). Variant nomenclature is based on the Human Genome Variation Society recommended guidelines and GRCh37 (hg19) human reference genome assembly. Sequence variants of unlikely clinical significance are not reported but are available upon request. Additional Sanger sequencing is performed for relevant regions that have insufficient coverage, and to confirm clinically significant variants and variants of unknown significance when applicable.

Test available:

Routine, Prenatal*

Sample requirements:

10 mL blood in EDTA tube 
3 mL blood in EDTA tube for infants (under 1 year of  age

Estimated turn around time:

Routine – 8 weeks

*Inquiries about prenatal testing could be directed to the Laborator

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FMR1-Related Disorders

Fragile X Syndrome

Fragile X syndrome is an X-linked disorder. It is estimated that >99% of Fragile X syndrome cases have an expansion of the CGG repeat in the 5' untranslated region of the FMRI gene. The remaining cases have deletions or point mutations within the FMRI gene. PCR amplification of the CGG repeat and in some cases Southern blot analysis is used to determine the CGG repeat number. Normal individuals have between 5 and 44 repeats. Individuals with premutations have between 56 to 200 repeats. Above 200 repeats is considered a full mutation and is consistent with a diagnosis of Fragile X syndrome in males and in 50% of females. Repeat sizes between 45 and 55 are considered grey zone alleles. These alleles do not appear to expand to full mutations in the next generation but may, if unstable, expand to a premutation size. A normal result does not rule out a diagnosis of Fragile X syndrome.

Test available: Routine, Newborn, Prenatal*
Sample requirements: 20 mL blood in EDTA tube
3 mL blood in EDTA tube (infant only - less than 1 year of age)
Extracted DNA
Cultured amniocytes
Estimated turn around time: Routine – 4 to 6 weeks
Newborn, Prenatal – 10 working days

 

*Available if there is a previous family history. Parental peripheral blood samples (5 mL in EDTA tubes) are required when requesting prenatal testing to rule out maternal cell contamination.

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Fragile X-associated tremor/ataxia syndrome (FXTAS)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by expansion of the CGG repeat in the 5' untranslated region of the FMR1 gene. PCR amplification of the CGG repeat and in some cases Southern blot analysis is used to determine the CGG repeat number. Normal individuals have between 5 and 44 repeats. Individuals with FXTAS have premutation size alleles between 59 to 200 repeats. Penetrance is not complete, therefore not all individuals with FMR1 premutations will develop symptoms of FXTAS.

Test available: Routine
Sample requirements: 20 mL blood in EDTA tube
Extracted DNA
Estimated turn around time: Routine – 4 to 6 weeks


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Hereditary Breast Cancer

Approximately 5–10% of breast cancer is inherited in an autosomal dominant manner and mutations in the BRCA1 and BRCA2 genes have been identified as being the cause of a proportion of these inherited cases. DNA results are based on analysis of all exons of BRCA1 and BRCA2 by direct sequence analysis. For those individuals who have positive DHPLC results, sequencing is performed to confirm the presence of a genomic mutation. In addition, analysis for large genomic rearrangements is performed using the multiplex ligation-dependant probe amplification (MLPA) kit. A negative result does not rule out a mutation in either the BRCA1 or BRCA2 genes or a mutation in another breast cancer susceptibility gene. Mutation nomenclature is based on the Human Genome Variation Society and nucleotide accession #’s NM007294.2 (BRCA1), NM000059.3 (BRCA2) and protein accession #’s NP009225.1 (BRCA1), NP000050.2 (BRCA2). 

Test available: Routine, Expedited
Sample requirements: 20 mL blood in EDTA tube*
Estimated turn around time:

Routine – 12 to 16 weeks
Expedited - 4 to 6 weeks
Family mutation/MLPA only - 4 to 6 weeks

 

*Samples are accepted through Genetics Clinics only.
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Hereditary Hemochromatosis

Hereditary hemochromatosis is an autosomal recessive disorder. Approximately 88% of hemochromatosis cases are caused by two mutations in the HFE gene. Most (~ 82%) are homozygous for the p.Cys282Tyr (C282Y) mutation, while ~ 5% are compound heterozygotes having one copy of p.Cys282Tyr (C282Y) and one copy of p.His63Asp (H63D). Approximately 1% are p.His63Asp (H63D) homozygotes and approximately 5% have only one copy of p.Cys282Tyr (C282Y).  As ~ 7% of patients do not have any of these genotypes, a negative result does not rule out a diagnosis of hemochromatosis. HFE sequences are amplified using the polymerase chain reaction and digested with appropriate restriction enzymes to detect both the p.Cys282Tyr (C282Y) and H63D mutations. Those individuals who have one copy of p.Cys282Tyr (C282Y), are also tested for a rarer HFE mutation p.Ser65Cys (S65C), also by PCR and restriction enzyme digest. Mutation nomenclature is based on the Human Genome Variation Society recommendations and protein accession # NP000401.1.

 Test available:

Routine

 Sample requirements:

5 mL blood in EDTA tube
Extracted DNA

Estimated turn around time:    

Routine- 6 to 8 weeks

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Loeys-Dietz syndrome

Loeys-Dietzy syndrome (LDS) is primarily characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus). LDS can be subdivided into types I and II. LDS type I makes up approximately 75% of affected individuals, and often presents with craniofacial manifestations (widely spaced eyes, bifid uvula/cleft palate, craniosynostosis) in addition to the vascular and skeletal features described above. Individuals with LDS type II have the systemic manifestations of LDSI, but minimal or absent craniofacial features. The diagnosis of LDS is based on identification of the characteristic clinical findings in the proband and family members, and molecular genetic testing of the 6 genes known to harbor mutations in individuals with LDS: TGFBR1, TGFBR2, SMAD3, SMAD4, TGFB2 and TGFB3. It is inherited as an autosomal dominant trait. DNA results are based on the analysis of the coding sequence and 10 base pairs immediately adjacent to each exon of the 6 genes known to be associated with LDS: TGFBR1 (NM_004612.2), TGFBR2 (NM_001024847.2), SMAD3 (NM_005902.3), SMAD4 (NM_005359.5), TGFB2 (NM_001135599.2) and TGFB3 (NM_003239.3). This test is performed by oligonucleotide-based target capture (TruSight Cardio Sequencing kit, Illumina) followed by next generation sequencing using the MiSeq instrument (Illumina). To detect large genomic deletions and duplications, multiplex ligation-dependent probe amplification (MLPA) using the 1 available kit for analysis of TGFBR1 and TGFBR2 (P148) is performed. This analysis detects >99% of variants within the tested genes. All rare variants are checked for prior reports in the literature, the ClinVar, ExAC, Exome Variant Server databases and other relevant sources of information. Variant significance is categorized using ACMG Recommendations (Genet Med 2015: 17: 405–423). Variant nomenclature is based on the Human Genome Variation Society recommended guidelines and GRCh37 (hg19) human reference genome assembly. Sequence variants of unlikely clinical significance are not reported but are available upon request. Additional Sanger sequencing is performed for relevant regions that have insufficient coverage, and to confirm clinically significant variants and variants of unknown significance when applicable.

Test available:

Routine, Prenatal*

Sample requirements:

10 mL blood in EDTA tube 
3 mL blood in EDTA tube for infants (under 1 year of age

 

Estimated turn around time:

Routine – 8 weeks

*Inquiries about prenatal testing could be directed to the Laboratory
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Marfan syndrome

Marfan syndrome is a systemic disorder of connective tissue, typically affecting the ocular, skeletal and cardiovascular systems with a high degree of clinical variability. The hallmark features of Marfan syndrome are ectopia lentis, skeletal overgrowth and joint laxity resulting in extremities that are disproportionately long for the size of the trunk, and dilatation of the aorta. Mutations in FBN1 represent the most common cause (70-90%) of classic Marfan syndrome. Pathogenic variants in this gene are associated with a broad phenotypic continuum, ranging from isolated features of Marfan syndrome to neonatal presentation of severe and rapidly progressive disease in multiple organ systems. It is inherited as an autosomal dominant trait. DNA results are based on the analysis of the coding sequence and 10 base pairs immediately adjacent to each exon of FBN1 (NM_000138.4). This test is performed by oligonucleotide-based target capture (TruSight Cardio Sequencing Kit, Illumina) followed by next generation sequencing using the MiSeq instrument (Illumina). To detect large genomic deletions and duplications, multiplex ligation-dependent probe amplification (MLPA) using two kits for analysis of FBN1 (P065/P066) is performed. This analysis detects >99% of variants within the tested genes. All rare variants are checked for prior reports in the literature, the ClinVar, ExAC, Exome Variant Server databases and other relevant sources of information. Variant significance is categorized using ACMG Recommendations (Genet Med 2015: 17: 405–423). Variant nomenclature is based on the Human Genome Variation Society recommended guidelines and - GRCh37 (hg19) human reference genome assembly. Sequence variants of unlikely clinical significance are not reported but are available upon request. Additional Sanger sequencing is performed for regions that have insufficient coverage, and to confirm clinically significant variants and variants of unknown significance when applicable.

Test available:

Routine, Prenatal*

Sample requirements:

10 mL blood in EDTA tube 
3 mL blood in EDTA tube for infants (under 1 year of age)

 

Estimated turn around time:

Routine – 8 weeks

*Inquiries about prenatal testing could be directed to the Laboratory
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Maternal cell contamination studies

The ABI Identifiler kit is used to analyze 15 polymorphic markers in prenatal and parental DNA samples to assess whether the prenatal DNA sample extracted from amniocytes or chorionic villi is contaminated with DNA of maternal origin.

Test available: Prenatal*
Sample requirements: Cultured amniocytes
Cultured CVS
Amniotic fluid
Direct CVS
Estimated turn around time: Prenatal – 7 working days

 
*Parental peripheral blood samples (5 mL in EDTA tubes) are required when requesting maternal cell contamination studies.

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Myotonic Dystrophy Type 1

Myotonic Dystrophy type 1 is an autosomal dominant disorder. It is caused by an expansion of CTG repeats in the untranslated region of the DMPK gene. The number of DMPK CTG repeats is determined by polymerase chain reaction (PCR) amplification of the repeat region. In some cases, further analysis is done by Southern blot analysis using a probe specific to the repeat region. Less than 36 repeats is considered normal; 36 to 49 repeats are pre-mutations and above 49 repeats is consistent with a diagnosis of myotonic dystrophy type 1. As a small proportion of individuals with symptoms of myotonic dystrophy do not have a CTG expansion in the DMPK gene, a negative result does not rule out this diagnosis. In those cases, a diagnosis of myotonic dystrophy type 2 should be considered.

Test available: Routine, Newborn, Prenatal*
Sample requirements: 20 mL blood in EDTA tube
3 mL blood in EDTA tube (infant only - less than 1 year of age)
Extracted DNA
Cultured amniocytes
Cultured CVS
Estimated turn around time: Routine – 6 to 8 weeks
Newborn, Prenatal – 10 working days

 
*Available if there is a previous family history. Parental peripheral blood samples (5 mL in EDTA tubes) are required when requesting prenatal testing to rule out maternal cell contamination.

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Myotonic Dystrophy Type 2

Myotonic Dystrophy type 2 is an autosomal dominant disorder. It is associated with an expansion of a CCTG repeat in intron 1 of the Zinc Finger Protein 9 (ZNF9) gene. The CCTG is part of a repeat tract consisting of (TG)n (TCTG)n (CCTG)n. Allele sizes are based on the size of the whole repeat tract in base pairs (bp). To date, normal individuals are reported to have repeat tract sizes between 104 and 176 bp. Affected individuals are reported to have CCTG repeat sizes 300 to 44,000 bp larger than normal sized alleles. The size of the alleles is determined by polymerase chain reaction (PCR) amplification using primers flanking the repeat. In some cases, further analysis is done by southern blotting using a probe specific to the repeat region in intron 1 of ZNF9. A negative result does not rule out a diagnosis of myotonic dystrophy.

Test available: Routine
Sample requirements: 20 mL blood in EDTA tube*
Estimated turn around time: Routine – 8 to 12 weeks

 

*Peripheral blood samples must be received by the Laboratory within 3 days of being drawn to be accepted for this test.
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Oculopharyngeal Muscular Dystrophy

Oculopharyngeal muscular dystrophy has been shown to be associated with a short expansion of a GCG repeat in the PABPN1 gene in greater than 99% of individuals. Normal individuals have 10 or less repeats. Affected individuals have either two alleles of 11 repeats (recessive OPMD) or at least one allele with 12 or more repeats (dominant OPMD). The polymerase chain reaction (PCR) amplification is used to determine the number of PABPN1 GCG repeats.

Test available: Routine
Sample requirements: 10 mL blood in EDTA tube
Extracted DNA
Estimated turn around time: Routine – 4 to 6 weeks

Return to Testing Services

Pan-Cardiomyopathy Genetic Testing Panel

Inherited cardiomyopathies are a group of clinically and genetically heterogeneous cardiac diseases affecting the heart muscle. They are usually attributed to a genetic component and have a relatively high population frequency. The main types are hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy and left ventricular non-compaction (LVNC). In patients with features overlapping or atypical of conventional disease cagetories, the pan-cardiomyopathy panel may be more appropriate to order than a disease-specific panel. DNA results for the Pan cardiomyopathy panel coding regions and 10 base pairs immediately adjacent to each exon of 45 genes: ABCC9, ACTC1, ACTN2, ANKRD1, CASQ2, CAV3, CRYAB, CSRP3, CTF1, DES, DSC2, DSG2, DSP, EMD, FHL2, GLA, JUP, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, PKP2, PLN, PRKAG2, RBM20, RYR2, SGCD, TAZ, TCAP, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, and VCL.  To detect large genomic deletions and duplications, multiplex ligation-dependent probe amplification (MLPA) using the available kits for analysis of DSC2, DSG2, DSP, MYH7, MYBPC3, PKP2 and TNNT2 is also performed. Given the heterogeneity of these conditions, a negative test result does not rule out a diagnosis of an inherited cardiomyopathy.

Test Available:

Routine, Prenatal*

Sample requirements:

10 mL blood in EDTA tube**
3 mL blood in EDTA tube (infant only--under 1 year of age)**

Estimated turn around time:

Routine - 10 weeks

 * Inquiries about prenatal testing should be directed to the Laboratory.
** Samples are accepted through Cardiology and Genetics Clinics only.

Pompe Disease

Glycogen storage disease, type II (GSDII: Pompe disease) is an autosomal recessive disorder caused by mutations of the acid alpha-glucosidase (GAA) gene. DNA results are based on sequencing of the complete coding region, 3’UTR, and flanking intronic sequences from exons 2 through 20 of the GAA gene. This analysis will not detect mutations within the GAA regulatory region, exon 1 or most of the intronic sequence, nor will it detect large gene rearrangements. Therefore, a negative result does not rule out a diagnosis of GSDII. Mutation nomenclature is based on the recommended guidelines from the Human Genome Variation Society and nucleotide accession # NM000152.3 and protein accession # NP000143.2.

Test available: Routine, Newborn, Prenatal*
Sample requirements: 10 mL blood in EDTA tube
3 mL blood in EDTA tube (infant only - less than 1 year of age)

Extracted DNA
Cultured amniocytes
Cultured CVS
Estimated turn around time: Routine – 12 to 16 weeks
Newborn – 10 working days
Prenatal – 7 working days

 

*Available if there is a previous family history. Parental peripheral blood samples (5 mL in EDTA tubes) are required when requesting prenatal testing to rule out maternal cell contamination.

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Prader Willi Syndrome

Prader Willi Syndrome (PWS) is caused by a lack of paternal contribution of 15q11-q13 caused by deletion (70%), maternal uniparental disomy (UPD) (28%) or mutation (2%). DNA results are based on analysis using a methylation-sensitive multiplex ligation-dependent probe amplification (MLPA) kit to detect both maternal and paternal copies of the 15q11-q13 region. This analysis detects all cases of PWS due to deletion, UPD and imprinting mutations.

Test available: Routine, Newborn, Prenatal*
Sample requirements: 10 mL blood in EDTA tube
3 mL blood in EDTA tube (infant only - less than 1 year of age)
Cultured amniocytes
Note: Extracted DNA will not be accepted.
Estimated turn around time: Routine – 10 to 12 weeks
Newborn, Prenatal – 7 working days

 

*Available if there is a previous family history. Parental peripheral blood samples (5 mL in EDTA tubes) are required when requesting prenatal testing to rule out maternal cell contamination.

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Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is inherited in an autosomal recessive manner. Approximately 95% of individuals with spinal muscular atrophy (SMA) are homozygous for a deletion of the telomeric survival motor neuron gene SMN1. Analysis for deletions and duplications of exons in SMN1 and SMN2 is performed using the multiplex ligation-dependent probe amplification (MLPA) kit. In cases where a homozygous deletion is not detected, copy number of the SMN1 gene is determined by dosage analysis. Dosage analysis is also performed to determine carrier status for SMA. A negative result does not rule out SMA in affected individuals or carrier status in unaffected individuals.

Test available: Routine, Newborn, Prenatal*
Sample requirements: 10 mL blood in EDTA tube
3 mL blood in EDTA tube (infant only - less than 1 year of age)
Cultured amniocytes
Cultured CVS
Direct CVS

Amniotic fluid 

Note: Extracted DNA will not be accepted.

Estimated turn around time: Routine – 4 to 6 weeks
Newborn, Prenatal – 7 working days

 

*Available if there is a previous family history. Parental peripheral blood samples (5 mL in EDTA tubes) are required when requesting prenatal testing to rule out maternal cell contamination.

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Thrombophilia (Factor V Leiden, Prothrombin)

Two mutations and one variant have been described as risk factors in the development of thrombosis. The F5 p.Arg534Gln (Factor V Leiden) mutation is associated with inherited APC resistance and increased risk of venous thrombosis. The F2 c.*97G>A (prothrombin 20210G>A) mutation is associated with an increased risk for venous thrombosis. Analysis of both nucleotide changes is performed using PCR amplification followed by restriction enzyme digest. Additional inherited and environmental causes of thrombosis are known to exist, therefore, negative results do not eliminate the possibility of thrombophilia in the patient. Mutation nomenclature is based on the Human Genome Variation Society recommendations and protein accession #’s NP00012.2 (F5), and nucleotide accession number NC000011.8 (F2).

Factor V Leiden Information Sheet
Prothrombin Information Sheet

Test available: Routine, Newborn
Sample requirements: 10 mL blood in EDTA tube
3 mL blood in EDTA tube (infant only - less than 1 year of age)
Extracted DNA
Estimated turn around time: Routine, Newborn – 8 to 10 weeks
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