Biochemical Molecular Collaborations Disclaimers 1 I am not
Biochemical & Molecular Collaborations Disclaimers: 1. I am not a biochemical geneticist. 2. I am not a molecular geneticist. 3. I am a clinical cytogeneticist who has seen the benefits of collaborations between cyto and DNA labs. Department of Human Genetics
Cytogenetics-Molecular Transitions & Collaborations n Fragile X testing moved from Cyto->Molec, but still need cyto for neg. results in DD/MR n PWS methylation best r/o test (low index suspicion); n FISH best if PWS dx likely n UPD testing important if FISH negative n karyotype important if all negative n
Cytogenetics-Molecular Transitions & Collaborations n FISH has become important adjunct to banding, but has not replaced banding n a. CGH will become important adjunct or perhaps primary diagnostic platform, but will not completely replace banding or FISH
Biochemical-Molecular Transitions & Collaborations n Not a proposal to replace biochemical testing with molecular testing n Biochemical testing of probands more cost- effective in most cases n high % “rule-out” referrals that will be mutation negative n Carrier detection and prenatal diagnosis often only available or more accurate by molecular methods (specific mutation known)
Biochemical-Molecular Applications Family Proband Carrier Prenatal Dx Biochem +++ +/- ? Molecular +/- ++ ++ Is there adequate emphasis in our counseling on family benefits to molecular testing?
Emory Genetics Laboratories n Long history of biochemical genetics testing, now supplemented by molecular genetics laboratory n Full gene sequencing available for: n n Galactosemia (GALT gene) PKU MSUD MCADD n Developing full gene sequencing for all lysosomal storage diseases n Developing comprehensive biochemical and molecular testing (full gene sequencing) for all disorders on NBS Uniform Panel
Galactosemia – Comprehensive Diagnostic Panel
MCAD Deficiency Acylcarnitine Profile, Plasma Method: LC MS/MS Acylcarnitine umol/ L Normal range Comment Hexanoylcarnitine, C 6 0. 79 0 - 0. 17 H 3 -OH-Isovalerylcarnitine, C 5 -OH 0. 07 0 - 0. 12 Octenoylcarnitine, C 8: 1 0. 40 0 - 0. 61 Octanoylcarnitine, C 8 7. 53 0 - 0. 21 H Decenoylcarnitine, C 10: 1 0. 50 0 - 0. 34 H Decanoylcarnitine, C 10 0. 76 0 - 0. 35 H Age Group: AR 1: Newborn, < 8 Days Abnormal. In this plasma sample, the concentration of C 8 was markedly elevated with elevated C 6, C 10: 1 and C 10, the ratio of C 8/C 10 was also significantly elevated (9. 9, normal <2). This profile is consistent with biochemical diagnosis for Medium Chain Acyl. Co. A Dehydrogenase deficiency. Recommend mutation analysis and immediate follow up with metabolic clinic. MCAD Common Mutation Panel Abnormal. The patient tested positive for one copy of the K 304 E mutation in the Medium Chain Acyl Co. A Dehydrogenase (ACADM) gene. This result does not rule out a diagnosis of MCAD deficiency. Genetic counseling is recommended. DNA ANALYSIS RESULTS Lys 304 Glu (K 304 E) 1 copy Tyr 42 His (Y 42 H) negative INTERPRETATION: This patient tested positive for one copy of the K 304 E MCAD mutation. Sequencing of the ACADM gene is recommended to identify the other mutation for family counseling and management.
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