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Mol Genet Metab. 2019 Sep - Oct;128(1-2):1-9. doi: 10.1016/j.ymgme.2019.07.011. Epub 2019 Jul 19.

Complex patterns of inheritance, including synergistic heterozygosity, in inborn errors of metabolism: Implications for precision medicine driven diagnosis and treatment.

Author information

1
University of Pittsburgh School of Medicine, Department of Pediatrics, Pittsburgh, PA, United States of America; UPMC Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, United States of America. Electronic address: gerard.vockley@chp.edu.
2
University of Pittsburgh School of Medicine, Department of Pathology, Pittsburgh, PA. UPMC Children's Hospital of Pittsburgh. 4401 Penn Avenue, Pittsburgh, PA 15224, United States of America.
3
University of Pittsburgh School of Medicine, Department of Pediatrics, Pittsburgh, PA, United States of America; UPMC Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, United States of America.
4
Admera Health, South Plainfield, NJ 07080, United States of America.
5
Section of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, PO box 30 001, 9700, RB, Groningen, the Netherlands.
6
Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT 06030, United States of America; GSD Program, Connecticut Children's Medical Center, Hartford, CT 06106, United States of America.

Abstract

Inborn errors of metabolism have traditionally been viewed as the quintessential single gene disorders; defects in one gene leads to loss of activity of one enzyme causing a metabolic imbalance and clinical disease. However, reality has never been quite that simple, and the classic "one gene-one enzyme" paradigm has been upended in many ways. Multiple gene defects can lead to the same biochemical phenotype, often with different clinical symptoms. Additionally, different mutations in the same gene can cause variable phenotypes, often most dramatic when a disease can be identified by pre-symptomatic screening. Moreover, response to therapy is not homogeneous across diseases and specific mutations. Perhaps the biggest deviation from traditional monogenic inheritance is in the setting of synergistic heterozygosity, a multigenic inheritance pattern in which mutations in multiple genes in a metabolic pathway lead to sufficient disruption of flux through the pathway, mimicking a monogenic disorder caused by homozygous defects in one gene in that pathway. In addition, widespread adoption of whole exome and whole genome sequencing in medical genetics has led to the realization that individual patients with apparently hybrid phenotypes can have mutations in more than one gene, leading to a mixed genetic disorder. Each of these situations point to a need for as much precision as possible in diagnosing metabolic disease, and it is likely to become increasingly critical to drive therapy. This article examines examples in traditional monogenic disorders that illustrates these points and define inborn errors of metabolism as complex genetic traits on the leading edge of precision medicine.

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