Long-read sequencing enables trio-assisted phasing of <i>de novo</i> variants in the imprinted gene <i>MAGEL2</i>

, p.(Gln638Ter) variant identified in two unrelated probands referred for congenital hyperinsulinism genetic testing. Long reads spanning both the variant and informative parental heterozygous variants confirmed that the variant was on the paternal allele and was therefore pathogenic and causative of Schaaf-Yang syndrome and associated with hyperinsulinism in both individuals. Our findings demonstrate the clinical utility of long-read sequencing for enabling trio-assisted variant phasing in imprinting disorders, particularly when phenotypes are incomplete or overlapping. Our findings further highlight congenital hyperinsulinism as a rare but important feature associated with Schaaf-Yang syndrome.

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Publication Details

Journal
Journal of Medical Genetics
Published
2026-03-31
DOI
https://doi.org/10.1136/jmg-2025-111282
Primary Topic
Genetic Syndromes and Imprinting
Type
article
Field-Weighted Citation Impact
0.00

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article

Long-read sequencing enables trio-assisted phasing of de novo variants in the imprinted gene MAGEL2

Sarah Elizabeth Flanagan, Yağmur Ünsal, Lucy Mallin, Thomas W. Laver et al.
Journal of Medical Genetics
Genetic Syndromes and Imprinting
article

Long-read sequencing enables trio-assisted phasing of de novo variants in the imprinted gene MAGEL2

Sarah Elizabeth Flanagan, Yağmur Ünsal, Lucy Mallin, Thomas W. Laver, Jonna M. E. Männistö, Hüseyin Demirbilek, Emma Louise Dempster, Jasmin J Bennett, Jayne A L Houghton, Michal Cohen, Preeah Sangha, Matthew N Wakeling
article en

Abstract

, p.(Gln638Ter) variant identified in two unrelated probands referred for congenital hyperinsulinism genetic testing. Long reads spanning both the variant and informative parental heterozygous variants confirmed that the variant was on the paternal allele and was therefore pathogenic and causative of Schaaf-Yang syndrome and associated with hyperinsulinism in both individuals. Our findings demonstrate the clinical utility of long-read sequencing for enabling trio-assisted variant phasing in imprinting disorders, particularly when phenotypes are incomplete or overlapping. Our findings further highlight congenital hyperinsulinism as a rare but important feature associated with Schaaf-Yang syndrome.

Journal of Medical Genetics
University of Eastern Finland (FI), University of Exeter (GB), Royal Devon & Exeter NHS Foundation Trust (GB), Rappaport Family Institute for Research in the Medical Sciences (IL), Hacettepe University (TR)
Wellcome Trust, European Society for Paediatric Endocrinology, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, Diabetes UK, Academy of Medical Sciences, NIHR Exeter Clinical Research Facility
Decent work and economic growth
Openalex Percentile: Top 28%
Genetic Syndromes and Imprinting
DOIOpen Access PDFOpenAlex
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