Mutational spectrum by phenotype: panel‐based NGS testing of patients with clinical suspicion of RASopathy and children with multiple café‐au‐lait macules

Castellanos, Elisabeth; Rosas, Inma; Negro, Alejandro; Gel, Bernat; Alibés, Andreu; Baena, Neus; Pineda, Merçè; Pi, Graciela; Pintos, Guillem; Salvador, Héctor; Lázaro, Conxi; Blanco, Ignacio; Vilageliu, Lluı̈sa; Brems, Hilde; Grinberg, Daniel; Legius, Eric; Serra, Eduard

doi:10.1111/cge.13649

Cited by 16 publications

(16 citation statements)

References 50 publications

(120 reference statements)

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“…Thus, including the detection of a pathogenic NF1 variant among the revised diagnostic criteria has been very important in facilitating the early diagnosis of NF1 in this subgroup of children (Legius et al 2021 ) (Table 1 ). This conclusion has been confirmed by the results of the studies of Guigliano et al ( 2019 ) and Castellanos et al ( 2020 ) as summarized in Table 3 .…”

Section: Frequent Diagnostic Features In Children With Nf1supporting

confidence: 72%

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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Section: Frequent Diagnostic Features In Children With Nf1supporting

confidence: 72%

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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“…34 Detection rates will vary in oligosymptomatic individuals or individuals with atypical presentation. 14 , 35 Since genetic testing for NF1 PV is heavily biased toward individuals with some aspect of the known NF1 phenotype we might be missing individuals with very atypical presentations. No NF1 inactivating variants have been reported in the alternatively spliced exons of NF1 because these might be associated with no or a different phenotype.…”

Section: Discussionmentioning

confidence: 99%

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Legius¹,

Messiaen²,

Wolkenstein³

et al. 2021

Genetics in Medicine

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362

234

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Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

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“…To minimize the probability of such findings, filters can be applied to restrict the analysis to genes with a known association to the genetic condition(s). Such a collection of relevant genes is typically called a gene panel, and these have been applied for multiple groups of conditions, including CPSs [14,15].…”

Section: Introductionmentioning

confidence: 99%

Selection criteria for assembling a pediatric cancer predisposition syndrome gene panel

et al. 2021

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Increasing use of genomic sequencing enables standardized screening of all childhood cancer predisposition syndromes (CPS) in children with cancer. Gene panels currently used often include adult-onset CPS genes and genes without substantial evidence linking them to cancer predisposition. We have developed criteria to select genes relevant for childhood-onset CPS and assembled a gene panel for use in children with cancer. We applied our criteria to 381 candidate genes, which were selected through two in-house panels (n = 338), a literature search (n = 39), and by assessing two Genomics England’s PanelApp panels (n = 4). We developed evaluation criteria that determined a gene’s eligibility for inclusion on a childhood-onset CPS gene panel. These criteria assessed (1) relevance in childhood cancer by a minimum of five childhood cancer patients reported carrying a pathogenic variant in the gene and (2) evidence supporting a causal relation between variants in this gene and cancer development. 138 genes fulfilled the criteria. In this study we have developed criteria to compile a childhood cancer predisposition gene panel which might ultimately be used in a clinical setting, regardless of the specific type of childhood cancer. This panel will be evaluated in a prospective study. The panel is available on (pediatric-cancer-predisposition-genepanel.nl) and will be regularly updated.

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Mutational spectrum by phenotype: panel‐based NGS testing of patients with clinical suspicion of RASopathy and children with multiple café‐au‐lait macules

Cited by 16 publications

References 50 publications

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

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

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Selection criteria for assembling a pediatric cancer predisposition syndrome gene panel

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