Molecular characterization of 13 patients with PIK3CA-related overgrowth spectrum using a targeted deep sequencing approach

Leanne de Kock^{1

2}, Alexanne Cuillerier^{1

2}, Meredith Gillespie¹, Madeline Couse³, Taila Hartley¹, Wendy Mears¹, Francois P Bernier^{4

5}, Albert E Chudley^{6

7}, Patrick Frosk^{6

7}, Sarah M Nikkel^{8

9}, A Micheil Innes^{4

5}, Julie Lauzon^{4

5}, Maryann Thomas^{4

5}, Andrea Guerin¹⁰, Christine M Armour¹, Rosanna Weksberg^{11

12}, James N Scott¹³, Debra Watkins¹⁴, Shirley Harvey¹⁵, Cheryl Cytrynbaum¹⁶; Care4Rare Canada Consortium¹; Kristin D Kernohan^{1

2

17}, Kym M Boycott^{1

2

18}

Affiliations

¹ Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
² Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.
³ The Centre for Computational Medicine, the Hospital for Sick Children (SickKids) Research Institute, Toronto, Ontario, Canada.
⁴ Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
⁵ Department of Medical Genetics, Alberta Children's Hospital, Calgary, Alberta, Canada.
⁶ Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
⁷ Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
⁸ Provincial Medical Genetics Program, BC Women's Hospital, Vancouver, British Columbia, Canada.
⁹ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁰ Division of Medical Genetics, Department of Pediatrics, Queen's University, Kingston, Ontario, Canada.
¹¹ Division of Clinical and Metabolic Genetics, Department of Paediatrics and Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
¹² Institute of Medical Sciences and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹³ Departments of Diagnostic Imaging and Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
¹⁴ Northeastern Ontario Medical Genetics Program, Health Sciences North, Greater Sudbury, Ontario, Canada.
¹⁵ Program of Genetics and Metabolism, Health Sciences Centre, Winnipeg, Manitoba, Canada.
¹⁶ Division of Clinical and Metabolic Genetics, Department of Genetic Counselling and Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁷ Newborn Screening Ontario, Ottawa, Ontario, Canada.
¹⁸ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

PMID: 37949664
DOI: 10.1002/ajmg.a.63466

Molecular characterization of 13 patients with PIK3CA-related overgrowth spectrum using a targeted deep sequencing approach

Leanne de Kock et al. Am J Med Genet A. 2024 Mar.

. 2024 Mar;194(3):e63466.

doi: 10.1002/ajmg.a.63466. Epub 2023 Nov 10.

Authors

Affiliations

¹ Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
² Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.
³ The Centre for Computational Medicine, the Hospital for Sick Children (SickKids) Research Institute, Toronto, Ontario, Canada.
⁴ Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
⁵ Department of Medical Genetics, Alberta Children's Hospital, Calgary, Alberta, Canada.
⁶ Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
⁷ Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
⁸ Provincial Medical Genetics Program, BC Women's Hospital, Vancouver, British Columbia, Canada.
⁹ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁰ Division of Medical Genetics, Department of Pediatrics, Queen's University, Kingston, Ontario, Canada.
¹¹ Division of Clinical and Metabolic Genetics, Department of Paediatrics and Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
¹² Institute of Medical Sciences and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹³ Departments of Diagnostic Imaging and Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
¹⁴ Northeastern Ontario Medical Genetics Program, Health Sciences North, Greater Sudbury, Ontario, Canada.
¹⁵ Program of Genetics and Metabolism, Health Sciences Centre, Winnipeg, Manitoba, Canada.
¹⁶ Division of Clinical and Metabolic Genetics, Department of Genetic Counselling and Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁷ Newborn Screening Ontario, Ottawa, Ontario, Canada.
¹⁸ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

PMID: 37949664
DOI: 10.1002/ajmg.a.63466

Abstract

Activating variants in the PIK3CA gene cause a heterogeneous spectrum of disorders that involve congenital or early-onset segmental/focal overgrowth, now referred to as PIK3CA-related overgrowth spectrum (PROS). Historically, the clinical diagnoses of patients with PROS included a range of distinct syndromes, including CLOVES syndrome, dysplastic megalencephaly, hemimegalencephaly, focal cortical dysplasia, Klippel-Trenaunay syndrome, CLAPO syndrome, fibroadipose hyperplasia or overgrowth, hemihyperplasia multiple lipomatosis, and megalencephaly capillary malformation-polymicrogyria (MCAP) syndrome. MCAP is a sporadic overgrowth disorder that exhibits core features of progressive megalencephaly, vascular malformations, distal limb malformations, cortical brain malformations, and connective tissue dysplasia. In 2012, our research group contributed to the identification of predominantly mosaic, gain-of-function variants in PIK3CA as an underlying genetic cause of the syndrome. Mosaic variants are technically more difficult to detect and require implementation of more sensitive sequencing technologies and less stringent variant calling algorithms. In this study, we demonstrated the utility of deep sequencing using the Illumina TruSight Oncology 500 (TSO500) sequencing panel in identifying variants with low allele fractions in a series of patients with PROS and suspected mosaicism: pathogenic, mosaic PIK3CA variants were identified in all 13 individuals, including 6 positive controls. This study highlights the importance of screening for low-level mosaic variants in PROS patients. The use of targeted panels with deep sequencing in clinical genetic testing laboratories would improve diagnostic yield and accuracy within this patient population.

Keywords: PIK3CA; PROS; mosaicism; overgrowth syndrome; rare genetic disease.

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References

REFERENCES

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Molecular characterization of 13 patients with PIK3CA-related overgrowth spectrum using a targeted deep sequencing approach

Affiliations

Molecular characterization of 13 patients with PIK3CA-related overgrowth spectrum using a targeted deep sequencing approach

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous