Uniparental disomy in a population of 32,067 clinical exome trios

Scuffins, Julie; Keller‐Ramey, Jennifer; Dyer, Lindsay; Douglas, Ganka; Torene, Rebecca; Gainullin, Vladimir G.; Juusola, Jane; Meck, Jeanne; Retterer, Kyle

doi:10.1038/s41436-020-01092-8

Cited by 42 publications

(53 citation statements)

References 29 publications

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“…In this cohort, whole-chromosome UPD was observed in 0.31% of cases, resulting in a diagnostic finding in 0.14%. Isodisomy, as found in our patient, was more commonly observed in large chromosomes along with a higher rate of homozygous pathogenic variants [8].…”

Section: Discussionsupporting

confidence: 81%

“…UPD with homozygosity of recessive alleles is being increasingly recognized as the molecular basis for several autosomal recessive disorders, however, data on the clinical prevalence and spectrum of UPD remain limited. Scuffins et al have recently analyzed 32,067 trio exomes referred for diagnostic testing to create a profile of UPD events and their disease associations [8]. In this cohort, whole-chromosome UPD was observed in 0.31% of cases, resulting in a diagnostic finding in 0.14%.…”

Section: Discussionmentioning

confidence: 99%

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Maternal Isodisomy of Chromosome 3 Combined with a De Novo Mutation in the ABHD5 Gene Causes Autosomal Recessive Chanarin-Dorfman Syndrome

Köpp

Has

Hotz

et al. 2021

Genes

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Autosomal recessive Chanarin-Dorfman syndrome (CDS, MIM #275630) is defined as a neutral lipid storage disease with ichthyosis (NLSDI) due to an accumulation of lipid droplets in a variety of different tissues including liver and muscle cells, leucocytes, fibroblasts and nerve cells It is caused by biallelic mutations in the abhydrolase domain containing 5 gene (ABHD5, MIM *604780) which is localized on the short arm of chromosome 3. Here we report an 18 month-old girl in whom we have identified the homozygous ABHD5 mutation c.700C > T, p.(Arg234*). Since none of the parents carried this point mutation, parentage was confirmed by microsatellite marker analysis. Suspected uniparental disomy (UPD) was confirmed by microsatellite genotyping over the entire chromosome 3 and indicated a maternal origin. UPD is an extremely rare event that is not necessarily pathogenic, but may cause disease if the affected chromosome contains genes that are imprinted. Here we report the first case of Chanarin-Dorfman syndrome due to a de novo ABHD5 mutation in the maternal germ cell, combined with a maternal uniparental isodisomy of chromosome 3. This case demonstrates that genetic analysis of the patient and both parents is crucial to provide correct genetic counseling.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Maternal Isodisomy of Chromosome 3 Combined with a De Novo Mutation in the ABHD5 Gene Causes Autosomal Recessive Chanarin-Dorfman Syndrome

Köpp

Has

Hotz

et al. 2021

Genes

View full text Add to dashboard Cite

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“…In addition to exome‐based CNVs analysis, the detection of uniparental disomy (UPD) based on trio‐exome sequencing also increased the diagnostic yield by 0.14%–0.2% (Scuffins et al, 2021; Yauy et al, 2020). Even though the UPD events were not detected in our cohort, it still demonstrated the value of additional analysis using trio‐WES data in clinical diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Incorporation of exome‐based CNV analysis makes trio‐WES a more powerful tool for clinical diagnosis in neurodevelopmental disorders: A retrospective study

et al. 2021

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Neurodevelopmental disorders (NDDs) are a genetically heterogeneous group of diseases, affecting 1%-3% of children. Whole-exome sequencing (WES) has been widely used as a first-tier tool for identifying genetic causes of rare diseases. Trio-WES was performed in a cohort of 74 pedigrees with NDDs. Exome-based copy number variant (CNV) calling was incorporated into the traditional single-nucleotide variant (SNV) and small insertion/deletion (Indel) analysis pipeline for WES data. An overall positive diagnostic yield of 54.05% (40/74) was obtained in the pipeline of combinational SNV/Indel and CNV analysis, including 35.13% (26/74) from SNV/ Indel analysis and 18.92% (14/74) from exome-based CNV analysis, respectively. In total, SNV/Indel analysis identified 38 variants in 28 different genes, of which 24 variants were novel; exome-based CNV analysis identified 14 CNVs, including 2 duplications and 12 deletions, which ranged from 440 bp (single exon) to 16.86 Mb (large fragment) in size. In particular, a hemizygous deletion of exon 1 in the SLC16A2 gene was detected. Based on the diagnostic results, two families underwent prenatal diagnosis and had unaffected babies. The incorporation of exomebased CNV detection into conventional SNV/Indel analysis for a single trio-WES test significantly improved the diagnostic rate, making WES a more powerful, practical, and cost-effective tool in the clinical diagnosis of NDDs.

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“…Risk of AR conditions, such as CHS, are easily estimated with siblings having a 25% risk of developing the disease. However, the prevalence of germline UPD is harder to quantify with frequencies from 0.03 -0.3% (37)(38)(39)(40), being partial-UPiD s i g n ifi c a n t ly l ow er ( 4 0 ) . D e s p i te th e l o w r i s k o f recurrence, having detected the heterozygosis c.8380dupT variant in the mother of this child and defined the inheritance mechanism, will allow a more accurate genetic counseling for future pregnancies and other family members at risk.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Partial Uniparental Disomy Unmasks a Novel Recessive Mutation in the LYST Gene in a Patient With a Severe Phenotype of Chédiak-Higashi Syndrome

et al. 2021

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Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive (AR) immune disorder that has usually been associated to missense, nonsense or indels mutations in the LYST gene. In this study, we describe for the first time the case of a CHS patient carrying a homozygous mutation in the LYST gene inherited as a result of a partial uniparental isodisomy (UPiD) of maternal origin. Sanger sequencing of the LYST cDNA and single nucleotide polymorphism (SNP)-arrays were performed to identify the causative mutation and to explain the molecular mechanism of inheritance, respectively. Partial-UPiD leads to a copy neutral loss of heterozygosity (CN-LOH) of the telomeric region of chromosome 1 (1q41q44), unmasking the potential effect of the mutation detected. The mutation (c.8380dupT) is an insertion located in exon 32 of the LYST gene resulting in a premature stop codon and leading to the loss of all the conserved domains at the C-terminal of the LYST protein. This would account for the severe phenotype observed. We also reviewed the only two previously reported cases of CHS as a result of a uniparental disomy. In this study, we show that the combination of different strategies, including the use of SNP-arrays, is pivotal to fine-tune the diagnosis of rare AR disorders, such as CHS. Moreover, this case highlights the relevance of uniparental disomy as a potential mechanism of CHS expression in non-consanguineous families.

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Uniparental disomy in a population of 32,067 clinical exome trios

Cited by 42 publications

References 29 publications

Maternal Isodisomy of Chromosome 3 Combined with a De Novo Mutation in the ABHD5 Gene Causes Autosomal Recessive Chanarin-Dorfman Syndrome

Maternal Isodisomy of Chromosome 3 Combined with a De Novo Mutation in the ABHD5 Gene Causes Autosomal Recessive Chanarin-Dorfman Syndrome

Incorporation of exome‐based CNV analysis makes trio‐WES a more powerful tool for clinical diagnosis in neurodevelopmental disorders: A retrospective study

Case Report: Partial Uniparental Disomy Unmasks a Novel Recessive Mutation in the LYST Gene in a Patient With a Severe Phenotype of Chédiak-Higashi Syndrome

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