Test Overview
All coding exons (plus 15 bp upstream and downstream of each coding exon) of the targeted gene(s) are captured, sequenced using NGS and aligned to the human reference genome. A minimum NGS coverage of 20X is achieved for all coding exons +/- 5 bp, and a minimum coverage of 10X an additional 10 bp from +/- 6 bp through +/- 15 bp. A minimum coverage of 10X is achieved for all clinically significant promoter regions. Regions which do not meet these coverage metrics are filled with targeted Sanger Sequencing. Variants in the targeted regions that are of potential clinical significance, based on the ACMG guidelines for interpretation of sequence variants (PMID: 25741868), will be reported. All reported variants of potential clinical significance not meeting the sequencing quality criteria will be confirmed by a different technology.
Analysis for the presence of pathogenic variants in ABCD4, ACSF3, ALDH6A1, BTD, CD320, HCFC1, HLCS, LMBRD1, MCEE, MMAA, MMAB, MMACHC, MMADHC, MMUT, PCCA, PCCB, PRDX1, TCN2, and THAP11 genes in patients with elevated C3 (propionylcarnitine) on newborn screening or on plasma acylcarnitine profiles.
Pathogenic variants in the following genes lead to the autosomal recessive disorders with elevated C3: ABCD4 (MIM: 603214) – Methylmalonic aciduria and homocystinuria (MAHC) cobalamin J (cblJ) type (MAHCJ; MIM: 614857; GeneReviews PMID: 20301503); ACSF3 (MIM: 614245) – Combined malonic and methylmalonic aciduria (CMAMMA; MIM: 614265) generally with no elevated C3 on newborn screening; ALDH6A1 (MIM: 603178) – Methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD; MIM: 614105); BTD (MIM: 609019) – Multiple carboxylase deficiency (MCD) due to biotinidase deficiency (MIM: 253260; GeneReviews PMID: 20301497); CD320 (MIM: 606475) – Transient methylmalonic aciduria due to transcobalamin receptor defect (MIM: 613646); HLCS (MIM: 609018) – MCD due to holocarboxylase synthetase deficiency (MIM: 253270; GeneReviews PMID: 20301497); LMBRD1 (MIM: 612625) – MAHC cblF type (MAHCF; MIM: 277380; GeneReviews PMID: 20301503); MCEE (MIM: 608419) – Isolated methylmalonic acidemia (MMA) due to methylmalonyl-CoA epimerase deficiency (MIM: 251120; GeneReviews PMID: 20301409); MMAA (MIM: 607481) – MMA cblA type (MIM: 251100; GeneReviews PMID: 20301409); MMAB (MIM: 607568) – MMA cblB type (MIM: 251110; GeneReviews PMID: 20301409); MMACHC (MIM: 609831) – MAHC cblC type (MAHCC; MIM: 277400; GeneReviews PMID: 20301503); MMADHC (MIM: 611935) – MAHC cblD type (MAHCD; MIM: 277410; GeneReviews PMID: 20301503, 20301409); MMUT (MIM: 609058) – MMA due to methylmalonyl-CoA mutase deficiency (MIM: 251000; GeneReviews PMID: 20301409); PCCA (MIM: 232000) – Propionicacidemia pccA type (MIM: 606054; GeneReviews PMID: 22593918); PCCB (MIM: 232050) – Propionicacidemia pccB and pccC type (MIM: 606054; GeneReviews PMID: 22593918); PRDX1 (MIM: 176763) – MAHC digenic cblC type (MIM: 277400; GeneReviews PMID: 20301503) with specific splicing variants (c.515-1G-T or c.515-2A-T) leading to read-through transcript extended through the adjacent MMACHC; TCN2 (MIM: 613441) – Transcobalamin II deficiency (MIM: 275350); THAP11 (MIM: 609119) – Disorders of intracellular cobalamin metabolism cblX-like type (GeneReviews PMID: 20301503; PMID: 28449119) through its interaction with HCFC1. And pathogenic variants (mostly missense variants in one of the five N-terminal Kelch domains) in HCFC1 (MIM: 300019) lead to X-linked recessive MAHC cblX type (MAHCX ; MIM: 309541; GeneReviews PMID: 20301503) due to down-regulated expression of MMACHC.
Interpretive report provided.
* Reference ranges may change over time. Please refer to the original patient report when evaluating results.
This analysis will not identify variants in the regulatory elements or deep intronic regions not covered in the targeted gene(s) and cannot detect variants in other genes associated with the clinical diagnosis.
Test Details
10 days
Specimen Requirements
Collect specimen in a lavender top tube. Send intact specimen within 24 hours if stored at room temperature or within 5 days if stored refrigerated. Include the patient's family history, pedigree, and ethnicity on the test requisition. Obtaining informed consent from the patient prior to testing is recommended. For a UMHS Request and Consent for Genetic Testing form, contact the MLabs Client Services Center at 800-862-7284 or online at https://mlabs.umich.edu/media/188.