<i>SHANK3</i> Mutation and Mosaic Turner Syndrome in a Female Patient With Intellectual Disability and Psychiatric Features

Accogli, Andrea; Yang, Chunhui; Blain-Juste, M.-E.; Braverman, Nancy; Shah, Jai; Trakadis, Yannis

doi:10.1176/appi.neuropsych.18100228

Cited by 2 publications

(2 citation statements)

References 30 publications

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“…3k ). In addition, a case with a small deletion (3 kb in chr22q.13.33) within a large deletion (20 kb in chr22q.13.33), where one of the breakpoints was the same, in a proband with an NN disorder disrupted SHANK3 associated with a broad spectrum of neurodevelopmental disorders 40 (validated by long-read in Extended Data Fig. 5b ).…”

Section: Resultsmentioning

confidence: 93%

Deciphering the role of germline complex de novo structural variations in rare disorders

Jung,

Yang,

Walker

et al. 2024

Preprint

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De novo structural variants (dnSVs) have emerged as crucial genetic factors in the context of rare disorders. However, these variations often go undiagnosed in routine genetic screening practices. To shed light on their significance in rare disease, we conducted a comprehensive analysis of the largest cohort of parent-offspring whole-genome sequencing data from the UK 100,000 Genomes Project. Our study encompassed a vast cohort of 12,568 families, including 13,702 offspring affected by rare genetic diseases. We identified a total of 1,872 dnSVs, revealing that approximately 12% of the probands harboured at least one dnSV, of which 9% were identified as likely pathogenic in affected probands (151/1696). Advanced parents' age was found to be associated with an increased chance of having dnSVs in probands. We discovered 148 clustered breakpoints resulting from a single event. 60% of these complex dnSVs were classified into 9 major SV types, and could be observed in multiple individuals, while the remaining 40% were private events and had not been previously reported. We found 12% of pathogenic dnSVs are complex SVs, emphasising the critical importance of thoroughly examining and considering complex dnSVs in the context of rare disorders. Furthermore, we discovered an enrichment of maternal dnSVs at subtelometric, early-replicating regions of chromosome 16, suggesting possible sex-specific mechanisms in generation of dnSVs. This study sheds light on the extent of diversity of dnSVs in the germline and their contribution to rare genetic disorders.

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Section: Resultsmentioning

confidence: 93%

Deciphering the role of germline complex de novo structural variations in rare disorders

Jung,

Yang,

Walker

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition, a case with a small deletion (3 kb in chr22q.13.33) within a large deletion (20 kb in chr22q. 13.33), where one of the breakpoints was the same, in a proband with an NN disorder disrupted SHANK3 associated with a broad spectrum of neurodevelopmental disorders 41 (Figure S8B). Collectively, these results highlight the complex nature of dnSVs in rare disorders.…”

Section: The Role Of Complex Svs In Rare Disordersmentioning

confidence: 98%

Complex de novo structural variants are an underestimated cause of rare disorders

Rahbari,

Jung,

Yang

et al. 2024

Preprint

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Complex de novo structural variants (dnSVs) are crucial genetic factors in rare disorders, yet their prevalence and characteristics in rare disorders remain poorly understood. Here, we conducted a comprehensive analysis of whole-genome sequencing data of 12,568 families, including 13,698 offspring with rare diseases, as part of the UK 100,000 Genomes Project. We identified 1,872 dnSVs, constituting the largest dnSV dataset reported to date. Complex dnSVs (n=158; 8.4%) emerged as the third most common type of SV, following simple deletions and duplications. We classified 65% of these complex dnSVs into 11 subtypes, based on the classification established through the analysis of cancer whole genomes. 1.4% of probands with neurodevelopmental disorders harbour at least one complex dnSV, a rate two times higher than previously reported. Intriguingly, 12% of exon-disrupting pathogenic dnSVs and 22% of de novo deletions or duplications previously identified by array-based or exome-seq methods were found to be complex dnSVs. This study highlights the importance of complex dnSVs in rare disorders and demonstrates the necessity of careful genomic analysis to avoid overlooking these variants.

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SHANK3 Mutation and Mosaic Turner Syndrome in a Female Patient With Intellectual Disability and Psychiatric Features

Cited by 2 publications

References 30 publications

Deciphering the role of germline complex de novo structural variations in rare disorders

Deciphering the role of germline complex de novo structural variations in rare disorders

Complex de novo structural variants are an underestimated cause of rare disorders

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