Constitutional mismatch repair deficiency is the diagnosis in 0.41% of pathogenic NF1/SPRED1 variant negative children suspected of sporadic neurofibromatosis type 1

Pérez-Valencia, Juan Alberto; Gallon, Richard; Chen, Yunjia; Koch, Jakob; Keller, Markus A.; Oberhuber, Klaus; Gomes, Alicia; Zschocke, Johannes; Burn, John; Jackson, Michael S.; Santibanez‐Koref, Mauro; Messiaen, Ludwine; Wimmer, Katharina

doi:10.1038/s41436-020-0925-z

Cited by 17 publications

(23 citation statements)

References 38 publications

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“…Finally, an NF1 (like) clinical phenotype, might also be explained by molecular defects in other genes, causing syndromes with overlapping phenotypes. These are, for example, Noonan syndrome (MIM PS163950; multiple genes/loci), Constitutional mismatch repair deficiency (MIM 276300; mismatch repair genes) and Proteus syndrome (MIM 176920; AKT1) 1,2,5 .…”

Section: Discussionmentioning

confidence: 99%

“…Most patients are clinically diagnosed in childhood, according to NIH consensus criteria 4 . However, genetic testing to confirm a clinical diagnosis is still warranted, because of the clinical overlap with Legius syndrome (MIM 611431; SPRED1) 1,2,5 . In addition, an accurate genetic diagnosis facilitates appropriate screening and follow-up, reproductive options (prenatal testing and pre-implantation genetic diagnosis) and access to clinical studies and potential future trials and treatments.…”

Section: Introductionmentioning

confidence: 99%

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Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

et al. 2021

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Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. For this method RNA was extracted from lymphocytes, followed by targeted RNAseq. Next, an in-house developed tool (QURNAs) was used to calculate the enrichment score (ERS) for each splicing event. This method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants in NF1. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%). These results suggest that targeted RNAseq can be successfully used to detect pathogenic RNA splicing variants in NF1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

et al. 2021

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“…These are for example Noonan syndrome (MIM PS163950; multiple genes/loci), Constitutional mismatch repair deficiency (MIM 276300; mismatch repair genes) and Proteus syndrome (MIM 176920; AKT1 ). 1,2,5…”

Section: Discussionmentioning

confidence: 99%

“…4 However, genetic testing to confirm a clinical diagnosis is still warranted, because of the clinical overlap with Legius syndrome (MIM 611431; SPRED1) . 1,2,5 In addition, an accurate genetic diagnosis facilitates appropriate screening and follow-up, reproductive options (prenatal testing and pre-implantation genetic diagnosis) and access to clinical studies and potential future trials and treatments.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

Koster

Brandão

Tserpelis

et al. 2021

Preprint

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PurposeNeurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. A targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants.MethodsRNA was extracted from lymphocytes, followed by targeted NF1 RNAseq. An in-house developed tool (QURNAS) was used to calculate the enrichment score (ERS) for each splicing event.ResultsThis method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%).ConclusionTargeted NF1 RNAseq can be successfully used to detect pathogenic RNA splicing variants, complementary to DNA based diagnostics.

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“…Differential diagnosis is particularly difficult in children with multiple isolated CALM without a family member with multiple CALM, NF1 or Legius syndrome. These children may not be affected by NF1 but instead by Legius syndrome or less frequently by another RASopathy such as Noonan syndrome with multiple lentigines (formerly known as LEOP-ARD syndrome, MIM#151100) or Constitutive mismatch repair deficiency (CMMRD) (Brems et al 2007;Shah et al 2010;Santoro et al 2014;Santos et al 2016;Wimmer et al 2017;Suerink et al 2019;Anderson 2020;Jha et al 2020;Perez-Valencia et al 2020).…”

Section: Differential Diagnosis Of Nf1 Versus Legius Syndrome and Cmmrdmentioning

confidence: 99%

Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants

Kehrer‐Sawatzki

Cooper

2021

Hum Genet

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Neurofibromatosis type 1 (NF1) is the most frequent disorder associated with multiple café-au-lait macules (CALM) which may either be present at birth or appear during the first year of life. Other NF1-associated features such as skin-fold freckling and Lisch nodules occur later during childhood whereas dermal neurofibromas are rare in young children and usually only arise during early adulthood. The NIH clinical diagnostic criteria for NF1, established in 1988, include the most common NF1-associated features. Since many of these features are age-dependent, arriving at a definitive diagnosis of NF1 by employing these criteria may not be possible in infancy if CALM are the only clinical feature evident. Indeed, approximately 46% of patients who are diagnosed with NF1 later in life do not meet the NIH diagnostic criteria by the age of 1 year. Further, the 1988 diagnostic criteria for NF1 are not specific enough to distinguish NF1 from other related disorders such as Legius syndrome. In this review, we outline the challenges faced in diagnosing NF1 in young children, and evaluate the utility of the recently revised (2021) diagnostic criteria for NF1, which include the presence of pathogenic variants in the NF1 gene and choroidal anomalies, for achieving an early and accurate diagnosis.

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Constitutional mismatch repair deficiency is the diagnosis in 0.41% of pathogenic NF1/SPRED1 variant negative children suspected of sporadic neurofibromatosis type 1

Cited by 17 publications

References 38 publications

Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

Pathogenic Neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants

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