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Updated: Mar 13, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Clinical Testing for Genetic Conditions
Hyung-Goo Kim1, Sumia Brakta2, Afif Ben-Mahmoud3
1Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States.
Abstract:
Clinical genetics in reproductive medicine has moved from cytogenetic assessment to integrated, genome-wide diagnostics that resolve both sequence-level and structural variation. For patients facing infertility, recurrent pregnancy loss, fetal structural anomalies, or early onset pediatric disease, contemporary care follows a reflexive pathway that links karyotyping, chromosomal microarray (CMA), and exome or genome sequencing (GS) with advanced structural platforms including optical genome mapping (OGM) and long-read sequencing. Karyotyping remains indispensable for aneuploidy and balanced rearrangements. CMA outperforms karyotyping for submicroscopic copy number variants and is guideline-endorsed in prenatal diagnosis. Trio exome or GS increases diagnostic yield and clinical utility in fetuses with anomalies and in children with neurodevelopmental disorders or other congenital anomalies. Professional societies now recommend exome or GS as first-tier test in many pediatric scenarios. Long-read sequencing resolves repeats and complex structural variants. OGM provides a single assay, genome wide structural view with strong multisite clinical concordance, including prenatal validations. We present a pragmatic algorithm that orders structure- and sequence-based tests to shorten time, reduce serial testing, and improve counseling and reproductive planning. Together, these modalities support precise diagnoses, tighter recurrence risk estimates, and alignment of care with patient values.
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