Multi‐omics analysis reveals multiple mechanisms causing Prader–Willi like syndrome in a family with a X;15 translocation

Eisfeldt, Jesper; Rezayee, Fatemah; Pettersson, Maria; Lagerstedt, Kristina; Malmgren, Helena; Falk, Anna; Grigelioniené, Giedré; Wedell, Anna

doi:10.1002/humu.24440

Cited by 3 publications

(1 citation statement)

References 25 publications

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“…The reasons for this could be due to the specific disease-causing gene is not described or that the underlying cause is not (mono)genetic. However, equally important is a lack of knowledge regarding the human genome composition and structure [3], such as noncoding variants, as well as epigenetic modifications [4,5]. To correctly interpret individual phenotype-genotype interactions we first need to study the normal genome architecture.…”

Section: Introductionmentioning

confidence: 99%

Transposable element insertions in 1000 Swedish individuals

Bilgrav Saether,

Nilsson,

Thonberg

et al. 2023

PLoS ONE

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The majority of rare diseases are genetic, and regardless of advanced high-throughput genomics-based investigations, 60% of patients remain undiagnosed. A major factor limiting our ability to identify disease-causing alterations is a poor understanding of the morbid and normal human genome. A major genomic contributor of which function and distribution remain largely unstudied are the transposable elements (TE), which constitute 50% of our genome. Here we aim to resolve this knowledge gap and increase the diagnostic yield of rare disease patients investigated with clinical genome sequencing. To this end we characterized TE insertions in 1000 Swedish individuals from the SweGen dataset and 2504 individuals from the 1000 Genomes Project (1KGP), creating seven population-specific TE insertion databases. Of note, 66% of TE insertions in SweGen were present at >1% in the 1KGP databases, proving that most insertions are common across populations. Focusing on the rare TE insertions, we show that even though ~0.7% of those insertions affect protein coding genes, they rarely affect known disease casing genes (<0.1%). Finally, we applied a TE insertion identification workflow on two clinical cases where disease causing TE insertions were suspected and could verify the presence of pathogenic TE insertions in both. Altogether we demonstrate the importance of TE insertion detection and highlight possible clinical implications in rare disease diagnostics.

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Section: Introductionmentioning

confidence: 99%

Transposable element insertions in 1000 Swedish individuals

Bilgrav Saether,

Nilsson,

Thonberg

et al. 2023

PLoS ONE

Self Cite

View full text Add to dashboard Cite

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Multi‐omics analysis reveals multiple mechanisms causing Prader–Willi like syndrome in a family with a X;15 translocation

et al. 2022

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Prader-Willi syndrome (PWS; MIM# 176270) is a neurodevelopmental disorder caused by the loss of expression of paternally imprinted genes within the PWS region located on 15q11.2. It is usually caused by either maternal uniparental disomy of chromosome 15 (UPD15) or 15q11.2 recurrent deletion (s). Here, we report a healthy carrier of a balanced X;15 translocation and her two daughters, both with the karyotype 45,X,der(X)t(X;15)(p22;q11.2),−15.Both daughters display symptoms consistent with haploinsufficiency of the SHOX gene and PWS. We explored the architecture of the derivative chromosomes and investigated effects on gene expression in patient-derived neural cells. First, a multiplex ligation-dependent probe amplification methylation assay was used to determine the methylation status of the PWS-region revealing maternal UPD15 in daughter 2, explaining her clinical symptoms.Next, short read whole genome sequencing and 10X genomics linked read sequencing was used to pinpoint the exact breakpoints of the translocation.Finally, we performed transcriptome sequencing on neuroepithelial stem cells from the mother and from daughter 1 and observed biallelic expression of genes in the PWS region (including SNRPN) in daughter 1. In summary, our multi-omics analysis highlights two different PWS mechanisms in one family and provide an example of how structural variation can affect imprinting through long-range interactions.

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Case report: Extending the spectrum of clinical and molecular findings in FOXC1 haploinsufficiency syndrome

et al. 2023

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FOXC1 is a ubiquitously expressed forkhead transcription factor that plays a critical role during early development. Germline pathogenic variants in FOXC1 are associated with anterior segment dysgenesis and Axenfeld-Rieger syndrome (ARS, #602482), an autosomal dominant condition with ophthalmologic anterior segment abnormalities, high risk for glaucoma and extraocular findings including distinctive facial features, as well as dental, skeletal, audiologic, and cardiac anomalies. De Hauwere syndrome is an ultrarare condition previously associated with 6p microdeletions and characterized by anterior segment dysgenesis, joint instability, short stature, hydrocephalus, and skeletal abnormalities. Here, we report clinical findings of two unrelated adult females with FOXC1 haploinsufficiency who have ARS and skeletal abnormalities. Final molecular diagnoses of both patients were achieved using genome sequencing. Patient 1 had a complex rearrangement involving a 4.9 kB deletion including FOXC1 coding region (Hg19; chr6:1,609,721-1,614,709), as well as a 7 MB inversion (Hg19; chr6:1,614,710-8,676,899) and a second deletion of 7.1 kb (Hg19; chr6:8,676,900-8,684,071). Patient 2 had a heterozygous single nucleotide deletion, resulting in a frameshift and a premature stop codon in FOXC1 (NM_001453.3): c.467del, p.(Pro156Argfs*25). Both individuals had moderate short stature, skeletal abnormalities, anterior segment dysgenesis, glaucoma, joint laxity, pes planovalgus, dental anomalies, hydrocephalus, distinctive facial features, and normal intelligence. Skeletal surveys revealed dolichospondyly, epiphyseal hypoplasia of femoral and humeral heads, dolichocephaly with frontal bossin gand gracile long bones. We conclude that haploinsufficiency of FOXC1 causes ARS and a broad spectrum of symptoms with variable expressivity that at its most severe end also includes a phenotype overlapping with De Hauwere syndrome.

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Multi‐omics analysis reveals multiple mechanisms causing Prader–Willi like syndrome in a family with a X;15 translocation

Cited by 3 publications

References 25 publications

Transposable element insertions in 1000 Swedish individuals

Transposable element insertions in 1000 Swedish individuals

Multi‐omics analysis reveals multiple mechanisms causing Prader–Willi like syndrome in a family with a X;15 translocation

Case report: Extending the spectrum of clinical and molecular findings in FOXC1 haploinsufficiency syndrome

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