Ultra-rare monogenic disorders frequently detected among sex chromosome aneuploidy patients with atypical findings

Kiana Magee; William McGonigle; Rena Pressman; Willa Thorson; Deborah Barbouth; Nicholas A Borja

doi:10.1038/s10038-024-01312-y

Ultra-rare monogenic disorders frequently detected among sex chromosome aneuploidy patients with atypical findings

J Hum Genet. 2024 Dec 19. doi: 10.1038/s10038-024-01312-y. Online ahead of print.

Authors

Kiana Magee¹, William McGonigle¹, Rena Pressman², Willa Thorson², Deborah Barbouth², Nicholas A Borja³

Affiliations

¹ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
² John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
³ John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA. [email protected].

PMID: 39695270
DOI: 10.1038/s10038-024-01312-y

Abstract

Sex chromosome aneuploidies (SCA) such as Turner, Klinefelter, Jacobs, and Trisomy X syndromes are prevalent genetic disorders with well-established phenotypes. Challenges persist, however, in determining the need for further genetic evaluation in cases of affected individuals exhibiting atypical symptoms. The present study retrospectively examined 54 pediatric patients with an SCA diagnosis at a single institution between January 2015 and December 2023. Twelve patients (22.2%) exhibited a discordant phenotype, of which five were confirmed to have a distinct monogenic disorder, a diagnostic rate of 41.7%. The monogenic conditions identified included DNAH5-related primary ciliary dyskinesia, Burn-McKeown syndrome, Tatton-Brown-Rahman syndrome, SETD1B-related neurodevelopmental disorder, and SET-related disorder. The median age at SCA diagnosis was 3.5 months versus 7.0 years for the second genetic condition, indicating significant diagnostic delays. Our findings highlight the importance of comprehensive genetic evaluation in pediatric patients with SCA who exhibit atypical phenotypes.