Challenges to Variant Interpretation for Abcd1 in the Backdrop of Newborn Screening
Speaker: Dr. Nancy Braverman

Defects in ABCD1 cause X linked adrenoleukodystrophy (XALD). Around 30% of males develop the childhood cerebral form, the remainder develop adrenomyeloneuropathy (AMN), whereas a small number have adrenal insufficiency only or remain asymptomatic. The male phenotype is independent of the ABCD1 mutation and depends on genetic and/or environmental modifiers that are not yet identified. Around 20-50% of females develop of AMN. NBS enables treatment of boys at risk for adrenal insufficiency and cerebral disease, which are fatal undetected. The ABCD1 protein is a peroxisome membrane protein needed to transport very long chain fatty acids (VLCFA) into the peroxisome for oxidation. The incidence of XALD is around 1/16,000 male births, but maybe more common. Around 1000 variants were reported, most are familial and 5% de novo. Disease natural history predicts that high VLCFA can diagnose all affected boys and most female carriers. Newborn screening (NBS) using C26:0 lyso PC levels is a more sensitive measure of XALD detection and multiple variants of unknown significance are detected. False positives include inflammatory conditions and other peroxisomal disorders. Unique issues for NBS in XALD include lack of genotype-phenotype correlations, absence of common variants, borderline elevations in C26:0 lyso PC, no family history of disease, and disease in female carriers. In this talk we will discuss the current ClinGen rules for ABCD1 variant curation and their application in real situations.

At the end of the session, participants will be able to:

  • Describe the issues that complicate NBS for XALD

Target Audience: Clinical Geneticists, Laboratory Geneticists, Genetic Counsellors, Trainees, Molecular Pathologists
CanMEDS Roles: Medical Expert (the integrating role), Scholar

Dr. Braverman is a clinician-scientist who studies Peroxisome Biogenesis Disorders (PBD). She participated in identifying defective genes, their mutation spectrums, tested candidate therapies in novel mouse models and runs a natural history study and biobank. She is a Professor in the Depts of Peds and Human Genetics at McGill Univ, attending geneticist at the MUHC, and Senior Scientist at the RI-MUHC. She is co-chair of the ClinGen panel on variant curation in peroxisome disorders and is on the advisory boards for the Global Foundation for Peroxisome Disorders and RhizoKids International. She previously served as Chair of the ACMG Therapeutics Committee, member of the SIMD Board of Directors and the Mid-Atlantic Consortium for Genetic and Newborn Screening Services. She received her MSc in Genetic Counseling at Sarah Lawrence College, her MD from Tulane Univ School of Med, her pediatrics residency at Yale-New Haven Hospital, and genetics fellowship at Johns Hopkins Med Center.

New ACMG classification rules and point system
Speaker: Dr. Les Biesecker

Dr. Biesecker is a Distinguished Investigator, and Director of the Center for Precision Health Research at the National Human Genome Research Institute of the National Institutes of Health, which he joined in 1993. He uses genetic and genomic technologies to study the etiology of genetic disorders and has published over 350 primary research articles, reviews, and chapters and developed the ClinSeq® program, which began clinical genomics research in 2006, before the widespread availability of next generation sequencing. He is double board certified in Pediatrics and Medical Genetics. He was elected to the National Academy of Medicine of the National Academy of Science in 2018 and was the President of the American Society of Human Genetics for 2019.

Clinical Implementation of Ffpe‑based Rna‑seq: Muhc Experience
Speaker: Dr. Andrea Gomez Corredor

This presentation focuses on the validation and ongoing oversight of an FFPE‑based RNA‑seq assay at the McGill University Health Centre, following two years of routine clinical implementation. We summarize the diagnostic yield and assay failure rates, and discuss key challenges associated with delivering FFPE RNA‑seq at a clinical grade, including variable RNA quality from FFPE material, assay robustness, workflow integration, turnaround time constraints, and the need for sustained quality assurance in a high‑throughput diagnostic setting.

At the end of the session, participants will be able to:

  • Identify the key challenges associated with performing RNA‑seq on FFPE samples.
  • To demonstrate that FFPE‑based RNA‑seq can be reliably implemented in routine clinical diagnostics.

Target Audience: Laboratory Geneticists , Trainees, Molecular Pathologists, Medical Lab Technologists
CanMEDS Roles: Professional, Scholar

Andrea Liliam Gomez Corredor, PhD, FACMG, FCCMG is a Clinical Molecular Geneticist and part‑time Assistant Professor in the Departments of Pathology and Genetics at McGill University, and a Clinical Biology Specialist at the McGill University Health Centre. She leads clinical molecular diagnostics at the Core Molecular Diagnostic Laboratory, with expertise in both germline genetic diseases and oncology. She has played a key role in the development, validation, and accreditation of multiple clinical molecular tests, and is actively involved in provincial, national, and international initiatives focused on quality assurance, test harmonization, and guideline development in clinical molecular diagnostics.

Event Timeslots (1)

Afternoon
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Speakers: Dr. Nancy Braverman, Dr. Les Biesecker, and Dr. Andrea Gomez Corredor