Diagnosis; Mutation Confirmation; Predictive; Recurrence

Medium chain acyl CoA dehydrogenase (ACADM, a.k.a. MCAD) deficiency is a recessive trait associated with defective oxidation of fatty acids which may have serious clinical sequelae. In the Ontario population approximately 90%1 of alleles associated with ACADM (MCAD) deficiency have a single A>G mutation at nucleotide #985. Thus approximately 81% … Medium chain acyl CoA dehydrogenase (ACADM, a.k.a. MCAD) deficiency is a recessive trait associated with defective oxidation of fatty acids which may have serious clinical sequelae. In the Ontario population approximately 90%1 of alleles associated with ACADM (MCAD) deficiency have a single A>G mutation at nucleotide #985. Thus approximately 81% of clinically affected members of this population would be expected to be homozygous for the 985A>G mutation, 18% would be compound heterozygotes while 13% of the alleles are expected to carry the 199C>T mutation with the remaining mutations being private mutations distributed throughout the ACADM gene. View more

Establish or confirm diagnosis

Guidance for management

Guidance for selecting a drug therapy and/or dose

Predictive risk information for patient and/or family members

Diagnosis requires the integrated interpretation of multiple analyses, including consideration of the clinical status of the affected individual (i.e., acutely symptomatic vs asymptomatic) at the time of sample collection. The primary source of patients are those identified through newborn screening programs requiring confirmation.

All coding exons and 20 bp of flanking intronic sequence are enriched using an LHSC custom targeted hybridization protocol (Roche Nimblegen), followed by high throughput sequencing (Illumina). Sequence variants and copy number changes are assessed and interpreted using clinically validated algorithms and commercial software (SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; … All coding exons and 20 bp of flanking intronic sequence are enriched using an LHSC custom targeted hybridization protocol (Roche Nimblegen), followed by high throughput sequencing (Illumina). Sequence variants and copy number changes are assessed and interpreted using clinically validated algorithms and commercial software (SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; and Alamut Visual). All exons have >1000x mean read depth coverage, with a minimum 200x coverage at a single nucleotide resolution. This assay meets the sensitivity and specificity of combined Sanger sequencing and MLPA copy number analysis. All variants interpreted as either ACMG category 1, 2, or 3 (pathogenic, likely pathogenic, VUS; PMID: 25741868) are confirmed using Sanger sequencing, MLPA, or other assays. ACMG category 4 and 5 variants (likely benign, benign) are not reported, but are available upon request. View more

Mutations identified are repeated in an independent assay using either Sanger sequence or MLPA

Tests performed
Entire test performed in-house

Testing by this methodology is expected to be >99%

Is proficiency testing performed for this test? Help
Yes

Method used for proficiency testing: Help
Formal PT program

PT Provider: Help
American College of Medical Genetics / College of American Pathologists, ACMG/CAP

Software used to interpret novel variations Help
SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; and Alamut Visual

Laboratory's policy on reporting novel variations Help
All variants interpreted as either ACMG category 1, 2, or 3 (pathogenic, likely pathogenic, VUS; PMID: 25741868) are confirmed using Sanger sequencing, MLPA, or other assays. ACMG category 4 and 5 variants (likely benign, benign) are not reported, but are available upon request.