Contribution of whole genome sequencing in the molecular diagnosis of mosaic partial deletion of the NF1 gene in neurofibromatosis type 1

Pacot, Laurence; Pelletier, Valérie; Chansavang, Albain; Briand-Suleau, Audrey; Coustier, Audrey; Maillard, Théodora; Vaucouleur, Nicolas; Orhant, Lucie; Barbance, Cécile; Lermine, Alban; Hamzaoui, Nadim; Hadjadj, Djihad; Laurendeau, Ingrid; Khattabi, Laïla El; Nectoux, Juliette; Vidaud, Michel; Parfait, Béatrice; Dollfus, Hélène; Pasmant, Éric; Vidaud, Dominique

doi:10.1007/s00439-022-02476-3

Cited by 6 publications

(4 citation statements)

References 42 publications

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“…Pathogenic large deletions of the promoter and noncoding region of the PRKAR1A gene are rare alterations. Similarly to our finding, WGS has been successfully applied in the detection of a partial deletion of the NF1 gene causing neurofibromatosis type 1 even in mosaic form 20 .…”

Section: Discussionsupporting

confidence: 78%

Whole genome sequencing resolves 10 years diagnostic odyssey in familiar myxoma

Pálla,

Tőke,

Bozsik

et al. 2023

Sci Rep

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Carney complex (CNC) is an ultrarare disorder causing cutaneous and cardiac myxomas, primary pigmented nodular adrenocortical disease, hypophyseal adenoma, and gonadal tumours. Genetic alterations are often missed under routine genetic testing. Pathogenic variants in PRKAR1A are identified in most cases, while large exonic or chromosomal deletions have only been reported in a few cases. Our aim was to identify the causal genetic alteration in our kindred with a clinical diagnosis of CNC and prove its pathogenic role by functional investigation. Targeted testing of PRKAR1A gene, whole exome and whole genome sequencing (WGS) were performed in the proband, one clinically affected and one unaffected relative. WGS identified a novel, large, 10,662 bp (10.6 kbp; LRG_514t1:c.-10403_-7 + 265del; hg19, chr17:g.66498293_66508954del) deletion in the promoter of PRKAR1A in heterozygous form in the affected family members. The exact breakpoints and the increased enzyme activity in deletion carriers compared to wild type carrier were proved. Segregation analysis and functional evaluation of PKA activity confirmed the pathogenic role of this alteration. A novel deletion upstream of the PRKAR1A gene was proved to be the cause of CNC. Our study underlines the need for WGS in molecular genetic testing of patients with monogenic disorders where conventional genetic analysis fails.

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Section: Discussionsupporting

confidence: 78%

Whole genome sequencing resolves 10 years diagnostic odyssey in familiar myxoma

Pálla,

Tőke,

Bozsik

et al. 2023

Sci Rep

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“…Variants detected at low allele frequencies can be caused by chimerism, in which cells originating from different zygotes merge during an early embryonic phase, or are due to stem cell transplantation [ 27 ]. Alternatively, such low variant allele frequencies can be caused by somatic de novo mutations, leading to a mosaic distribution of the variant [ 28 , 29 ]. To distinguish between potential mosaicism and chimerism, an analysis of 26 short random repeats was performed.…”

Section: Resultsmentioning

confidence: 99%

First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria

Belosevic,

Minder,

Gueuning

et al. 2023

Life

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Acute porphyrias are a group of monogenetic inborn errors of heme biosynthesis, characterized by acute and potentially life-threatening neurovisceral attacks upon exposure to certain triggering factors. Biochemical analyses can determine the type of acute porphyria, and subsequent genetic analysis allows for the identification of pathogenic variants in the specific gene, which provides information for family counselling. In 2017, a male Swiss patient was diagnosed with an acute porphyria while suffering from an acute attack. The pattern of porphyrin metabolite excretion in urine, faeces, and plasma was typical for an acute intermittent porphyria (AIP), which is caused by inherited autosomal dominant mutations in the gene for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. However, the measurement of HMBS enzymatic activity in the erythrocytes was within the normal range and Sanger sequencing of the HMBS gene failed to detect any pathogenic variants. To explore the molecular basis of the apparent AIP in this patient, we performed third-generation long-read single-molecule sequencing (nanopore sequencing) on a PCR product spanning the entire HMBS gene, including the intronic sequences. We identified a known pathogenic variant, c.77G>A, p.(Arg26His), in exon 3 at an allelic frequency of ~22% in the patient’s blood. The absence of the pathogenic variant in the DNA of the parents and the results of additional confirmatory studies supported the presence of a de novo mosaic mutation. To our knowledge, such a mutation has not been previously described in any acute porphyria. Therefore, de novo mosaic mutations should be considered as potential causes of acute porphyrias when no pathogenic genetic variant can be identified through routine molecular diagnostics.

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“…Molecular diagnosis has important implications in the diagnosis of NF-1, especially in patients who are paucisymptomatic or do not satisfy the clinical diagnostic criteria [ 41 , 46 ]. Precise diagnosis is needed to improve the prognosis and for genetic counseling.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, identification of germline NF1 mutations could be valuable for genotype-phenotype correlation analysis to better guide the management of NF-1. Cost-effective methods and protocols for genetic diagnosis of NF1 are now available, including whole-genome sequencing [ 47 ], NF1 -targeted panel sequencing [ 48 ], cDNA analysis combined with multiplex ligation-dependent probe amplification of genomic DNA [ 49 ], and NF1 transcriptome analysis [ 50 ]. However, because of the complexity and large size of the NF1 gene, sensitive localization of pathogenic variants is challenging and will probably require the combination of multiple detection technologies [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Childhood-Onset Refractory Hypertension Results from Neurofibromatosis Type 1 Caused by a Splicing <i>NF1</i> Mutation

Lu,

Rejiepu,

Zhang

et al. 2023

Kidney Blood Press Res

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Background: Neurofibromatosis type 1 (NF-1) is caused by mutations in the NF1 gene that encodes neurofibromin, a negative regulator of RAS proto-oncogene. Approximately one-third of the reported pathogenic mutations in NF1 are splicing mutations, but most consequences are unclear. The objective of this study was to identify the pathogenicity of splicing mutation in a Chinese family with NF-1 and determine the effects of the pre-mRNA splicing mutation by in vitro functional analysis. Methods: Next-generation sequencing was used to screen candidate mutations. We performed a minigene splicing assay to determine the effect of the splicing mutation on NF1 expression and three-dimensional structure models of neurofibromin were generated using SWISS-MODEL and PROCHECK method, respectively. Results: A pathogenic splicing mutation c.479+1G>C in NF1 was found in the proband characterized by childhood-onset refractory hypertension. In vitro analysis demonstrated that c.479+1G>C mutation caused skipping of exon 4, leading to a Glutamine to Valine substitution at position 97 in neurofibromin and an open reading frame shift terminating at codon 108. Protein modelling showed that several major domains were missing in the truncated neurofibromin protein. Conclusion: The splicing mutation c.479+1G>C identified in a Chinese patient with NF-1 and childhood-onset refractory hypertension caused skipping of exon 4 and a truncated protein. Our findings offered new evidence for the molecular diagnosis of NF-1.

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Contribution of whole genome sequencing in the molecular diagnosis of mosaic partial deletion of the NF1 gene in neurofibromatosis type 1

Cited by 6 publications

References 42 publications

Whole genome sequencing resolves 10 years diagnostic odyssey in familiar myxoma

Whole genome sequencing resolves 10 years diagnostic odyssey in familiar myxoma

First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria

Childhood-Onset Refractory Hypertension Results from Neurofibromatosis Type 1 Caused by a Splicing <i>NF1</i> Mutation

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