Multilocus pathogenic variants contribute to intrafamilial clinical heterogeneity: a retrospective study of sibling pairs with neurodevelopmental disorders.

TitleMultilocus pathogenic variants contribute to intrafamilial clinical heterogeneity: a retrospective study of sibling pairs with neurodevelopmental disorders.
Publication TypeJournal Article
Year of Publication2024
AuthorsBozkurt-Yozgatli, T, Pehlivan, D, Gibbs, RA, Sezerman, U, Posey, JE, Lupski, JR, Coban-Akdemir, Z
JournalBMC Med Genomics
Volume17
Issue1
Pagination85
Date Published2024 Apr 16
ISSN1755-8794
KeywordsBiological Variation, Population, Genome, Human, Genotype, Homozygote, Humans, Polymorphism, Single Nucleotide, Retrospective Studies, Siblings
Abstract

BACKGROUND: Multilocus pathogenic variants (MPVs) are genetic changes that affect multiple gene loci or regions of the genome, collectively leading to multiple molecular diagnoses. MPVs may also contribute to intrafamilial phenotypic variability between affected individuals within a nuclear family. In this study, we aim to gain further insights into the influence of MPVs on a disease manifestation in individual research subjects and explore the complexities of the human genome within a familial context.

METHODS: We conducted a systematic reanalysis of exome sequencing data and runs of homozygosity (ROH) regions of 47 sibling pairs previously diagnosed with various neurodevelopmental disorders (NDD).

RESULTS: We found siblings with MPVs driven by long ROH regions in 8.5% of families (4/47). The patients with MPVs exhibited significantly higher F values (p-value = 1.4e-2) and larger total ROH length (p-value = 1.8e-2). Long ROH regions mainly contribute to this pattern; the siblings with MPVs have a larger total size of long ROH regions than their siblings in all families (p-value = 6.9e-3). Whereas the short ROH regions in the siblings with MPVs are lower in total size compared to their sibling pairs with single locus pathogenic variants (p-value = 0.029), and there are no statistically significant differences in medium ROH regions between sibling pairs (p-value = 0.52).

CONCLUSION: This study sheds light on the significance of considering MPVs in families with affected sibling pairs and the role of ROH as an adjuvant tool in explaining clinical variability within families. Identifying individuals carrying MPVs may have implications for disease management, identification of possible disease risks to different family members, genetic counseling and exploring personalized treatment approaches.

DOI10.1186/s12920-024-01852-4
Alternate JournalBMC Med Genomics
PubMed ID38622594
PubMed Central IDPMC11020671
Grant ListR35 NS105078 / NS / NINDS NIH HHS / United States

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